CH 1993 -K-No. 937
HC 1999 No. 02916
HC 1999 No. 02917
HC 1999 No. 03241
(instructed by Messrs. Taylor Joynson Garrett) appeared on
behalf of the Amgen parties.
(instructed by Messrs. Herbert Smith) appeared on behalf of
the Roche Parties.
(instructed by Messrs. Bird & Bird) appeared on behalf
of the TKT parties.
This is an approved judgment of the Court and I direct that
no further note or transcript be made.
The Honourable Mr. Justice Neuberger
MR. JUSTICE NEUBERGER:
- This case comprises a number of conjoined patent actions relating to the
protein erythropoietin ("EPO"). Two patents are involved. They are
European Patent (UK) No: 0148605B2 ("the 605 patent" or "605")
and European Patent (UK) No: 0411678B ("the 678 patent" or "678").
- Over ten different parties are concerned in the actions, but they can be
effectively divided into three groups. First, there are Kirin-Amgen Inc.,
Ortho-McNeil Pharmaceutical Inc., Ortho Biotech Inc., Ortho Biotech Products
LP and Janssen-Cilag Ltd ("Amgen"). Secondly, Roche Diagnostics
GmbH, Roche Diagnostics Ltd and Genetics Institute Inc. ("Roche").
Thirdly, there are Hoechst Marion Roussel Inc., Hoechst Marion Roussel Ltd
and Transkaryotic Therapies Inc. ("TKT"). For the purpose of these
proceedings the precise nature of the interest or involvement of each member
of each group does not matter.
- The registered proprietor of the 605 patent is Amgen, and the registered
proprietor of the 678 patent is Roche.
- So far as 605 is concerned, Roche and TKT each contend that it should be
revoked; their respective arguments for so saying are, in the main, somewhat
different, but they are not mutually inconsistent. Amgen argues that Roche
and TKT infringe 605. The nature of Roche’s processes is rather different
from those of TKT.
- As to 678, Amgen argues that it should be revoked, and Roche contends that
Amgen infringes. TKT is not involved in the arguments on 678, save, of course,
to the extent that they may impinge on the arguments relating to 605.
- The 605 Patent has been considered by the Technical Board of Appeal of the
European Patent Office on two occasions (T412/93, on 21st November 1994 and
T636/97 on 26th March 1998). The 678 Patent was also considered by the Technical
Board of Appeal on 16th April 1999, T277/95.
- The 605 Patent has also been the subject of proceedings in two other Member
States of the European Patent Convention ("EPC") and elsewhere.
Thus it has been considered by the District Court of the Hague on 13th March
1993, upheld by the Netherlands Appeal Court on 27th January 2000 (Kirin-Amgen
Inc. -v- Boehringer Mannheim GmbH). It has also been the subject of a decision
of the German Patent Court on 14th December 2000, (Hoffman La Roche A.G. -v-
Kirin-Amgen Inc.). There have also been decisions of the Federal Court and
Court of Appeal in Canada (15th February 1999 and 20th December 2000, Kirin-Amgen
Inc. -v- Hoffman La Roche Ltd) and of the Federal Court of Australia (25th
June 1998, Genetics Institute Inc. -v- Kirin-Amgen Inc.) in relation to similar
patents in their jurisdiction. There have also been proceedings on the equivalent
US Patent in the District Court of Massachusetts and Court of Appeal, Federal
Circuit (11th December 1989 and 5th March 1991, Amgen Inc. -v- Chugai Pharmaceutical
Co. Ltd).
Erythropoietin
- Natural human EPO is a hormone which circulates in the bloodstream of healthy
people. It stimulates the production of red blood cells. Those cells are,
of course, an essential component of blood. They contain haemoglobin, the
agent which carries oxygen from the lungs to those parts of the body which
require oxygen. Anaemia is a condition which involves the lack of sufficient
red blood cells; it leads to loss of the oxygen-carrying capability of blood,
which results in a serious, often indeed debilitating, loss in the quality
of life.
- In healthy humans, EPO is produced, albeit in very small, indeed minuscule,
quantities in the kidneys. Only very little EPO is needed, at least partly,
because red blood cells have a relatively long life - about four months. However,
when the level of oxygen in the blood drops, the kidneys respond by manufacturing
more EPO. In 1983, it was known that EPO production was stimulated by hypoxia
(reduced oxygen transported by blood cells).
- People suffering from kidney failure are normally treated by a blood purification
process. It was discovered that they nonetheless become anaemic in the absence
of additional treatment, so they required regular blood transfusions. By 1967,
it was realised that EPO deficiency was the key factor explaining this anaemia,
and it was hoped that administration of EPO to such patients might deal with
the problem, if and when EPO became available in sufficient quantities. Because
EPO was naturally produced in such very small amounts, it proved difficult
to isolate it in any significant quantity. Nor was it easy to determine the
structure of EPO, or the gene responsible for its production, although, at
least according to Amgen’s case, considerable effort was put into this exercise.
By 1977 very small amounts of EPO had been reported as isolated from the urine
of patients suffering from aplastic anaemia.
- On Amgen’s case, Dr Fu-Kuen Lin, a scientist then employed by Amgen, made
a breakthrough; he cloned the DNA responsible for the manufacture of EPO -
i.e. EPO DNA. Amgen contend that his invention not only provided the DNA sequence
that codes for EPO, but also new glycoprotein products, which are therapeutically
useful pharmaceutical compositions, cells and processes to make EPO available
in sufficient quantity and quality to treat the hundreds of thousands of patients
world-wide suffering from various types of anaemia.
- Indeed, accurately, so far as I can see, Amgen also argue that EPO manufactured
substantially in accordance with the teaching of Dr Lin in 605, "recombinant
EPO", reverses the most debilitating effect of renal failure not solved
by dialysis. They also say that patients to whom recombinant EPO is administered
have received an enormous benefit and that the availability of recombinant
EPO has been the most important advance in the treatment of end stage renal
failure in the past 20 years.
Outline of issues
- The hearing of these proceedings lasted over 25 full days, during which
I heard evidence from a number of very eminent scientists relating to a number
of different issues of fact and expert opinion. I also entertained argument
relating to a fair number of different points, some of which may be of some
general significance, in the field of patent law, and especially in the field
of genetic engineering patents.
- I propose, in Part B, to set out the technical background, without which
anybody ignorant of the science of, and techniques involved in, genetic engineering
(such as myself until very recently) could not understand the issues and arguments.
I shall then turn, in Part C, to the state of the common general knowledge
as at the relevant time for the purpose of 605 - i.e. around 1984. When dealing
with the common general knowledge, I will trespass into developments which
have occurred since the relevant time, hopefully making it clear when I am
doing so. While, by definition, developments after 1984 could not have been
known as at the relevant date, those developments are relevant when considering
issues of infringement, as well, at least arguably, of construction, insufficiency
and even novelty.
- I will then, in Part D, seek to summarise, and quote the centrally relevant
parts of, the 605 patent itself. It is, perhaps inevitably, a long document,
involving a net 24 pages (each running to some 60 lines) of description, including
12 Examples (some of which are two-pronged), a total of 31 claims, 21 tables
of sequences (one of which runs to five pages) and 4 figures.
- I shall then deal, in Part E, with various issues of construction which
have been raised in relation to 605. I think it is then appropriate to deal
with an issue which in a sense is one of construction, albeit that it could
also be said to be a question of policy, and could, indeed, be dealt with
in relation to the argument that the patent, or certain claims in the patent,
are invalid for want of novelty. However, because it is arguably an issue
of construction, and also because it is a point of principle, I propose to
deal with the construction and effect of product by process claims immediately
after I have discussed the other issues of construction, in Part F.
- So far as 605 is concerned, that then leaves issues of infringement and
validity. Reported cases suggest that it is more normal to deal with infringement
before validity, but I propose to deal with the validity issues first. This
is primarily because there is one important and difficult issue relating to
insufficiency and breadth of claim, which appears to me to have a significant
bearing on, or at least interrelationship with, the issue of whether TKT infringes
605. I believe that it is therefore more convenient to consider that insufficiency
and breadth of claim question before turning to infringement.
- There are a number of issues relating to the validity of the 605 patent.
First, there are a number of insufficiency allegations in relation to 605
and its claims. Some of these allegations are of a detailed and technical
nature; others raise points of principle. Because the insufficiency issues
need fully detailed discussion, I have divided up the issues. In Part G, I
set out the law on this topic and summarise the issues. In Part H, I deal
with the one specific insufficiency allegation which requires fairly extensive
consideration. In Part I, I turn to various other insufficiency issues relating
to Claim 1 of 605. Part J is concerned with the insufficiency arguments on
Claims 19 and 20. In Part K, I deal with the permissible breadth of the Claims
in light of the approach of the House of Lords in Biogen Inc -v- Medeva plc
[1997] RPC1.
- Having dealt with insufficiency, I will deal in Part L with the argument
that 605 is invalid because it constitutes a discovery rather than an invention.
In Part M, I will then turn to the attack on 605 based on the contention that
it suffers from lack of novelty. The final attack on 605 which I must discuss
is that it is invalid on the ground that it contains added matter: that is
in Part N.
- Having considered the issues relating to the alleged invalidity of 605,
I will then turn to the question whether Roche infringe 605 (Part O), and
then to the question whether TKT infringe 605 (Part P). I will then turn,
in Part Q, to deal with 678, Roche’s patent. In summary, the issue (albeit
that it raises a number of sub-issues) is whether, as Amgen contends, 678
was anticipated by 605, and is therefore invalid. I will then summarise my
conclusions, in Part R.
The witnesses
- The expert evidence in this case was extensive in terms of quantity (and
indeed volume of paper) and impressive in terms of quality. The witnesses
were experts in one of two main fields (albeit that there was, inevitably,
a degree of overlap in the expertise of at least some of the witnesses). Those
fields were molecular biology and glycoprotein chemistry and biochemistry.
When preparing for trial, and indeed in opening, the three parties tried to
ensure that there was no significant overlap between the evidence given by
one expert and the evidence given by another expert for the same party. To
the extent that there was any such overlap, it was agreed that any cross examination
on the issue need only be directed to one of the experts (to be selected by
the party calling the witnesses).
- Amgen called three expert witnesses in relation to the molecular biology
issues. Professor Randolph Wall is a Professor in the Department of Microbiology
and Immunology at the UCLA School of Medicine and a member of the UCLA Molecular
Biology Institute. He received his PhD in microbiology in 1970, and for the
last 28 years his interest has focused mostly on molecular genetics and immunology
using recombinant DNA technology, and in particular cloning. His evidence
was directed primarily to the state of recombinant DNA and cloning technology
as at the end of 1983, the attacks on the validity of 605 on the grounds of
lack of novelty and insufficiency, and the alleged infringement of 605 by
Roche.
- Dr Sydney Brenner obtained a D.Phil. at Oxford, and worked in the Medical
Research Council - "the MRC" - Laboratory of Molecular Biology from
1956 to 1987 (as the Director for the last 9 years). He then became a director
of the MRC Unit of Molecular Genetics in Cambridge until 1992. He has retired
from that post, and he is now a director of the Molecular Sciences Institute
in Berkeley, California. It was as a result of research which he carried out
with Dr Francis Crick that the genetic code was shown to be the triplet code,
or codon, a concept I will try and explain in a little more detail below.
His evidence involved explaining in a little detail the technology involved
in, and disclosed by, 605, and the technology involved in TKT’s work (so-called
"gene activation technology") leading to TKT’s allegedly infringing
product, and the connection, at least as he saw it, between the disclosure
of 605 and TKT’s work.
- Dr Michael Gait is a senior group leader in the MRC Laboratory of Molecular
Biology at the MRC Unit in Cambridge. Throughout his career since 1973, he
has researched and practised innovative methods of synthesising oligonucleotides
and synthetic genes, and has carried out related work. His evidence was directed
towards the state of the art in synthesis of genes in 1984, and the feasibility
of carrying out some of the work taught by the 605 patent, or suggested in
the evidence or argument.
- Roche also called three expert witnesses on the molecular biology issues.
Professor William Brammar has been Professor of Biochemistry at Leicester
since 1977, having acquired his PhD in microbial physiology at University
College London during the 1960s. His evidence was directed towards most of
the issues which Professor Wall dealt with on behalf of Amgen, save that he
was not concerned with the issue of whether Roche infringed 605, although
he did consider whether human cDNA was claimed or enabled by 605, an issue
which is of relevance to the question of Roche’s infringement.
- Professor Hans Gassen is the Director of the Institute of Biochemistry at
Darmstadt University of Technology in Germany, having obtained his doctorate
in 1966. Much of his research has been in the area of synthesis, analysis
and biological functions of DNA and RNA. In terms of his evidence, he was
effectively the opposite number of Dr Gait.
- Dr Edward Fritsch worked for Genetics Institute Inc. ("GI", one
of the Roche parties) from 1982 until 2000, having been a Vice-President from
1986. He was called in part as a witness of fact, because he was part of the
GI team seeking to sequence and obtain EPO and the EPO gene and to find a
way of expressing EPO in commercial quantities, at the same time as Dr Lin
was carrying out his research. However, he also gave expert evidence, particularly
in relation to human tissue as a possible source of EPO in 1984, and also
as to certain cell lines.
- TKT called one expert witness on the molecular biology issues. He was Professor
Nicholas Proudfoot, the Professor of Experimental Pathology at Oxford University.
He has worked at Oxford since 1984, having obtained his PhD at Cambridge in
1975. His evidence was directed to the state of the art in 1984, how the various
claims of 605 would strike the notional skilled reader at the time, and a
comparison of TKT’s technology with the state of the art in 1984 and the teaching
of 605.
- On the glycoprotein issues, Amgen called two expert witnesses. The first
was Professor Richard Cummings, Professor of Biochemistry and Molecular Biology
in the University of Oklahoma Health Sciences Centre. Since 1980, he has worked
in molecular biology. His research has concentrated on glycoproteins, and
in particular the carbohydrate portions, including biosynthesis, structure
and their biological effects. He gave evidence relating to the construction,
sufficiency and novelty of 605, and also relating to the added matter issue.
His evidence also extended to the issues relating to 678.
- Sir John Walker worked at the MRC Laboratory of Molecular Biology between
1974 and 1998, and is now Director of the MRC’s Dunn Human Nutrition Unit,
both in Cambridge. He is a Fellow of the Royal Society and a Nobel Laureate
in Chemistry. His evidence related to the isolation and purification of EPO,
and the carrying out of SDS-PAGE and blotting experiments (whose function
is to identify the approximate molecular weight of polypeptides).
- Roche called one expert on the glycoprotein issues. He was Professor Henrik
Clausen, the Senior Associate Professor (Docent) in the Department of Oral
Diagnostics in the School of Dentistry at Copenhagen University; he is also
a Visiting Professor of Harvard Medical School. Throughout his career, he
has concentrated on research in protein and carbohydrate chemistry and immunology,
and over the past 10 years his research has focused on the biology of carbohydrates
and biosynthesis and genetic regulation of glycosylation of proteins. His
evidence related to the purity and isolation of glycoproteins, a comparison
of urinary EPO and recombinant EPO by reference to published papers, and experiments
carried out for the purpose of these proceedings. His evidence was also directed
to the insufficiency issues relating to 605 (so far as they were glycoprotein,
as opposed to molecular biology, issues) and the validity of 678.
- TKT called two expert witnesses on the glycoprotein issues. Professor Phillips
Robbins is Professor Emeritus in the Department of Biology at MIT and Professor
in the Department of Molecular and Cell Biology in Boston University of Dental
Medicine. He obtained a PhD in Biochemistry in 1955, and much of his research
has been into topics connected with the glycosylation of proteins. His evidence,
which was of a fairly general nature (which does not in any way cast doubt
upon its expertise or relevance) concerned the state of knowledge as to the
glycosylation of proteins in general, and of EPO in particular, both as at
the relevant date for 605 and thereafter.
- Professor Paul Matsudaira is a member of the Whitehead Institute for Biomedical
Research, and Professor of Biology in Bioengineering at MIT, and obtained
his PhD in biology in 1981. Much of his research has involved electrophoresis
and electrophoretic methods, which includes SDS-PAGE and blotting. His evidence
was largely concerned with analysing, and expressing views about, relevant
experiments which were reported in learned journals or had been carried out
for the purpose of these proceedings.
- There were also some witnesses of fact, apart from Dr Fritsch. Amgen put
in written evidence from Dr Christopher Winearls, a consultant nephrologist
at the Renal Unit at the Oxford Radcliffe Hospital. He was the lead clinician
in the research team which first described the successful use of Amgen’s recombinant
EPO to treat renal anaemia. He was also involved in trials of such EPO in
transfusion-dependent patients. His evidence explained the substantial benefits
of having recombinant EPO available to treat patients with chronic renal failure
or anaemia. There was also written evidence from Professor Stuart Orkin, Professor
of Paediatrics at Harvard Medical School, who worked on a number of different
genetic technology projects. One of those projects related to EPO, and started
in 1981 and lasted for about 3 years. Like Dr Fritsch, therefore, he was in
a group which was effectively working in competition with Dr Lin with a view
to obtaining and sequencing the EPO gene and EPO itself, and thereafter seeking
to express EPO in cells. Amgen also put in a witness statement from Dr Lin,
the inventor of 605.
- Evidence of fact was also given by Dr Thomas Strickland. He obtained his
PhD in biochemistry in 1981, was a consultant for Amgen between 1995 and 1999,
and then became employed by Amgen, for whom he now works as Quality Technical
Evaluator. He carried out experiments for the purpose of these proceedings,
including purification procedures with a view to isolating EPO from human
urine, and then running the product on SDS-PAGE against certain recombinant
EPOs. There was also evidence from Dr Jeffrey Browne, who received a PhD in
molecular biology in 1982, and worked for Amgen between 1981 and 1998. Although
not directly responsible for much of the work carried on in Amgen’s laboratory
in 1984 and 1985, investigating the performance of various urinary EPOs and
various recombinant EPOs on SDS-PAGE, he was indirectly involved in some of
the work, and was named in one or two papers published in that connection
in learned journals. Dr Strickland’s name also appeared on at least one of
those papers.
- Amgen also put in a proof from Professor Julian Davies, Professor of Microbiology
and Immunology at the University of British Columbia, who worked for Biogen,
another well-known major commercial company carrying on research in the biotechnology
field, between 1981 and 1985. He explained how, between 1980 and 1983, a team
of scientists at Biogen, of which he was one, tried to clone the EPO gene.
Amgen also put in one or two other witness statements which I do not think
necessary specifically to describe, at any rate at this stage.
- TKT had a witness of fact. He was Dr Michael Heartlein, Vice President,
Molecular Biology, at TKT, having obtained his doctorate in genetics in 1984.
His evidence concerned the experiments carried out by TKT in connection with
its technology, and in particular the experiments carried out in relation
to seeking to identify the optimum location for the artificial promoter relative
to the encoding part of the EPO gene.
- Apart from the experiments carried out in Amgen’s laboratories in 1984 and
1985, to which I have already briefly referred, and the work carried out by
Dr Strickland on behalf of Amgen for the purpose of these proceedings, some
experiments were also put in on behalf of Roche and on behalf of TKT. I will
deal with the nature of, evidence and arguments about, and the effect of,
those experiments in due course in this judgment.
- The expert witnesses from whom I heard were all very distinguished. I have
very briefly summarised their respective careers, and have not gone into their
many distinguished posts, the very substantial number of publications in prestigious
journals they have published, the books they have written, edited or contributed
to, the courses they have run, or the honours which they have been awarded.
Inevitably, some of the experts would be regarded, at any rate by some people,
as even more distinguished than others. There is no suggestion that any of
these witnesses was anything other than a highly respected expert in the field
in which he professed to practice, and more than competent to give evidence
on the topic or topics on which he spoke.
- Equally, there is no attack on the honesty of any of the experts, quite
rightly in my view. However, it is alleged against some of the expert witnesses
that they were not as impartial as they are required to be by the Civil Procedure
Rules ("the CPR"). I have to say that, in respect of one expert,
namely Professor Cummings, I consider that allegation to be well-founded;
the reasons for this will appear later. However, it is only fair to Professor
Cummings to make it clear that this in no way impugns his expertise or honesty.
He certainly did not strike me as so partisan as to lead me to conclude that
his evidence should be rejected whenever it conflicted with evidence the other
way. On the contrary, on some of the issues on which he was in conflict with
other experts, I found his evidence more convincing than theirs.
B. TECHNICAL BACKGROUND
Proteins
- EPO is a protein. Proteins are molecules which carry out many vital biochemical
functions. They consist of one or more chains of polypeptides. (EPO only has
one polypeptide chain, so I shall ignore proteins with more than one chain).
A polypeptide is a chain of amino acids. There are twenty different amino
acids, and some of them are more common than others. Each amino acid has a
carboxyl group (-COOH) at one end and an amino group (-NH2) at
the other end. Each amino acid can be written:
H
|
NH2—C—COOH, where R is its specific constituent, which varies
from one
|
R
amino acid to another. This specific constituent is known as the side chain
of the amino acid, because, when the amino acid is in a polypeptide, this
constituent is, in effect, a branch off the polypeptide chain.
- In a polypeptide, amino acids are linked by a peptide bond, which is formed
with the loss of an -OH from the carboxyl group of one amino acid and an -H
from the amino group of the other acid, i.e. with the effective loss of a
water molecule. Thus, the simplest polypeptide (i.e. one with two amino acids)
has one peptide bond and may be written:
H O H
| || |
NH2—C—C—N—C—COOH. Strictly each amino acid component in a
| | |
R1 H R2
polypeptide or protein is referred to as an amino acid residue, but a residue
is sometimes called simply an amino acid.
- Many side chains are subjected to modification during the process of their
formation. An important and relevant example of such modification is the addition
of saccharides (or sugar residues), a process known as glycosylation.
- While glycosylation does not normally occur in bacteria, it does occur in
higher organisms. Glycosylation can involve addition of a single sugar residue,
or a substantial number of sugar residues. Such residues can substantially
vary in size, structure, and composition one from the other. There are two
common types of glycosylation, N-glycosylation and O-glycosylation. The reference
to N and O is a reference to the atom (nitrogen and oxygen respectively) to
which the carbohydrate residue (known as the "glycan") attaches.
A glycosylated protein is known as a glycoprotein. EPO is in a glycoprotein.
- In a polypeptide, the amino acid chain is treated as starting at the amino
end of the first amino acid, known as the N-terminus or NH2-terminus,
and ending with a carboxyl group of the last amino acid, known as the C-terminus
or COOH-terminus. A polypeptide only becomes a protein once it is folded into
the correct shape, often with cross linking between cysteine amino acids known
as disulphide bridges. If a protein loses its correct shape, it ceases to
be effective as a protein: it is denatured. A protein also has some internal
sequences - known as active sites - which are more important for its biological
functions than other such sequences.
- Although a given protein has a specific sequence of amino acids in its polypeptide
chain, a change, or indeed a number of changes, in the identity of the amino
acids in a protein may not destroy its effectiveness. A single change might
reduce or even destroy a protein’s effectiveness; another change or other
changes might have no effect on, or actually improve, its effectiveness; sometimes
a change can result in side effects. Variants of protein where amino acid
residues have been changed (or even removed) without the effectiveness of
the protein being lost are known as analogues of the protein.
- In general the greater the number of changes in the amino acids in a given
protein the more likely it would be that its effectiveness will be diminished
or will cease. Further, as I have mentioned, some of the amino acid sequences
in a protein were of greater importance than others. Accordingly, changes,
even a number of changes, in the amino acids in less significant locations
might have little, if any effect; whereas a single change in a more sensitive
area, in particular the protein’s active site or (if more than one) its active
sites, could destroy the effectiveness of the protein. The characteristics
of amino acids vary, so a change from one amino acid to another with similar
characteristics might be expected to be less significant than a change to
an amino acid with different characteristics.
The genetic code
- In order to make (or "express") a protein, the amino acids have
to be assembled in the correct sequence. The sequence for a particular protein
is specified by a gene which is present in the genetic material of a cell
- i.e. within the DNA in the cell. The "genetic code" is the relationship
between a sequence of genetic material and the amino acid sequence of the
corresponding protein.
- All living organisms are composed of cells. Eukaryotic cells have a nucleus
containing the cell’s genetic material; the nucleus is surrounded by a cytoplasm
which is in turn bordered by the cell membrane. Prokaryotic cells have a single
cellular compartment bounded by a cell membrane and a cell wall. Mammals (including
humans) plants and fungi are made up of eukaryotic cells; bacteria are made
up of prokaryotic cells.
- The genetic material in a cell is made from deoxyribonucleic acid, DNA,
which consists of two strands of complexes called nucleotides. Each nucleotide
includes a nitrogenous base, a phosphate and a sugar. DNA contains four different
types of nucleotide, each of which is characterised by a different nitrogenous
base, namely Adenine, Guanine, Cytosine and Thymine, abbreviated respectively
to A, G, C and T. The nucleotide bases in DNA are linked by bonds between
a carbon atom of one nucleotide, known as a 3’-carbon, and another carbon
atom, known as the 5’-carbon, of the neighbouring nucleotide. By convention
a strand of DNA begins with the 5’end and finishes with the 3’end. The 5’end
is "upstream" (to the left of the DNA sequence as written out) and
the 3’end is "downstream" (to the right).
- In its normal state, DNA consists of two strands of nucleotides in the well-known
"double helix" configuration. Each of the two strands of DNA is
complementary - i.e. linked to the other strand - by the invariable rule that
A pairs with T, and G pairs with C. In eukaryotic cells, the double helix
DNA is divided into a number of different chromosomes, which are compact structures,
in which the DNA is complexed with many proteins.
- Cells divide and duplicate their genetic material. Accordingly, on division
of a cell, each DNA molecule becomes two identical molecules each carrying
the same information as was in the original. This process, known as replication,
involves the two strands of DNA separating so that each strand acts as a template,
with new nucleotides being added one by one on the basis already mentioned,
namely A pairing with T, and G with C.
- The order of the nucleotides in a particular segment of DNA - called a gene
- provides the blueprint for the "expression" of a particular protein.
In effect, the DNA blueprint is a succession of code words, each consisting
of a set of three nucleotides, known as codons, in the gene. Each codon (i.e.
each set of three nucleotides) specifies a particular amino acid. With three
exceptions, a particular codon instructs the cellular machinery to add a particular
amino acid to a growing polypeptide chain. The three exceptions are "stop
codons" which instruct that machinery where to stop the manufacture of
the protein.
- As there are twenty different amino acids and four different nucleotide
bases, once one excludes the three stop codons, there are 61 possible permutations
of bases to encode 20 amino acids. Two amino acids are encoded by only one
group of three bases, i.e. by only one codon. Some amino acids are encoded
by as many as six different codons. The majority of amino acids are encoded
by two or four codons.
- This feature of the genetic code, namely that (with two exceptions) each
amino acid can be encoded by more than one codon, is known as degeneracy.
As a result of degeneracy, once a protein’s amino acid sequence is known,
many (normally many millions or billions) of different possible gene sequences
could theoretically encode that protein. However, only very few may in fact
do so.
Expression of proteins
- The cells of a given organism almost all contain the same DNA, namely the
same genetic material which, according to the evidence, can encode for tens
of thousands of different proteins ("the genome"). However, each
particular type of cell produces only a few of the proteins encoded by the
DNA. Thus virtually all human cells contain DNA encoding for insulin, but
only pancreatic cells actually produce that protein. In eukaryotic cells,
as I have mentioned, DNA is divided into a number of different chromosomes,
in which the DNA is combined with certain proteins. DNA sequences in a particular
cell may, depending on their chromosomal regions, be "open" or "closed".
If "open" (like the insulin gene in pancreatic cells), the sequence
is capable of expression; if "closed", it is not. The EPO gene is
included in the DNA in Chromosome 7.
- When a cell responsible for the production of a particular protein detects
the need for that protein, the relevant segment of DNA that codes for that
protein (i.e. the relevant gene) produces a substance related to DNA, called
ribonucleic acid, RNA. This is made from a slightly different nucleic acid
from DNA, and consists of a single strand rather than a double strand. Further,
in place of one of DNA’s bases, Thymine, it has a different base, Uracil:
it contains U instead of T. The RNA manufactured in the cell is known as mRNA
- i.e. Messenger RNA. mRNA is made by a process called transcription. Transcription
involves an enzyme called RNA polymerase travelling along the relevant gene
making the single stranded RNA with bases complementary to the bases on the
DNA. Thus, A is reproduced as U (there being no T in RNA), G is reproduced
as C, T is reproduced as A, and C is reproduced as G.
- In higher organisms (i.e. those with eukaryotic cells), structural genes
have non-coding sequences of bases, called "introns", between the
portions, called "exons", which correspond to the portions of the
mRNA which encode the protein. The introns are effectively edited out before
translation of the mRNA, leaving only those regions of codons in the mRNA
which are protein encoding, i.e. the exons. This process, which involves the
removal of the segments which do not encode for the protein (most notably
the introns) and joining the encoding exons together, is known as splicing.
The splicing process is determined by sequences near the exon-intron junctions
and the intron-exon junctions in the RNA; these sequences are known respectively
as splice donor sites and splice acceptor sites.
- Once the transcription of the mRNA is complete, its code must be "translated"
to the amino acid sequence. For this purpose, the RNA is released from the
cell cytoplasm (in the case of a eukaryotic cell). Translation takes place
in a complex known as the ribosome, a microscopic structure in the cell. The
ribosome effectively reads off the base sequence of the whole of the mRNA
(starting at the 5’end with a start codon) and translates it into polypeptide
by use of another type of RNA called transfer RNA, tRNA. This translation
ends when a stop codon is reached. The tRNA contains the appropriate codons
for the amino acids of the particular protein, and is joined by specific enzymes
to the amino acid which corresponds to the particular codon. These amino acids
are expressed and then joined by peptide bonds, with the assistance of an
enzyme called peptidyl transferase.
- Genes from higher organisms also have a non-coding regulatory region before
the encoding regions (i.e. upstream of the first encoding region) and another
non-encoding region downstream of the last exon. The start of the gene, i.e.
where the RNA polymerase starts transcribing, is known as the cap site. The
regulatory region controls the transcriptional activity of the gene. The promoter
is that portion of the regulatory region which initiates the transcription
and is upstream of the cap site. The promoter is thus upstream of the encoding
region of the gene, and it provides a binding site for RNA polymerase, the
enzyme which transcribes the gene into mRNA. In fact, there are sometimes
two promoter sites in a particular gene. Immediately before the start of the
protein encoding region is a series of nucleotides known as the Kozak sequence,
which, in effect, helps the ribosome to recognise when translation should
start. Dr Kozak found that certain sequences worked better than others for
this purpose.
- The encoding region of the gene which actually transcribes is also called
the structural gene or the reading frame. Failure to translate the mRNA precisely
from the correct reading frame (i.e. the correct triplet of nucleotides) results
in failure to produce the desired protein. The first codon, known as the initiation
codon, of the first encoding exon in a gene is almost always ATG (or AUG in
the corresponding RNA). Immediately after the last encoding exon of the gene
is the terminator sequence which instructs the RNA polymerase to stop copying
the DNA. There then follows the downstream non-coding region, which almost
always ends with a number of consecutive adenines - the so called "poly
A tail".
- Chemical modifications may occur to proteins
immediately after, or even during, their expression. Thus, after expression,
mammalian proteins are normally glycosylated - i.e. sugar or saccharide sub-units
are chemically attached to some side chains of the protein. Glycosylation
can enable a protein to persist longer in the bloodstream. Further, after
(or during) translation, certain amino acids may be cleaved from the protein.
In many cases, the first several amino acids at the N-terminus of the protein
serve as a chemical signal directing the protein into the first of a series
of membrane-enclosed compartments within the cell. These initial amino acids
are often referred to as a leader peptide. The
leader peptide, which marks the protein for secretion from the cell, causes
the protein to enter the secretory pathway, which is a series of membrane-enclosed
compartments within the cytoplasm of the cell.
- The first of the compartments within the secretory
pathway is called the rough endoplasmic reticulum ("RER"). As a
protein produced with a leader peptide emerges from the ribosome, it directs
the ribosome to bind to the RER so that the growing protein is inserted through
the membrane of the RER into its internal space. The leader peptide sequence
may then be cleaved from the protein (which therefore becomes "mature"),
and the protein remains in the central cavity of the RER. It is also within
the RER that initial glycosylation occurs. Then, the protein moves to another
array of membrane-enclosed compartments, called the Golgi apparatus ("the
Golgi"), where certain modifications to the
sugar chains take place. Finally, the protein is secreted by the cell and
travels through the body to act on other cells.
C. COMMON GENERAL KNOWLEDGE IN 1984 AND RECENT SUBSEQUENT DEVELOPMENTS
Common general knowledge: the law
- A patent must be construed as at the relevant date through the eyes of a
person (or, as in the present case, a team of persons) suitably skilled, albeit
not inventive, in the relevant art or arts. Such an addressee is "likely
to have a practical interest in the subject matter of the invention (i.e.
"skilled in the art")" and is deemed to have "practical
knowledge and experience of the kind of work in which the invention was intended
to be used" - see per Lord Diplock in Catnic Components Limited -v- Hill
& Smith Limited [1982] RPC 183 at 242 to 243.
- The skilled addressee is treated as informed with "common general knowledge",
and the extent of this common general knowledge has been discussed in a number
of cases. In particular, I would refer to Beloit Technologies Inc. -v- Valmet
Paper Machinery Inc. (No. 2) [1997] RPC 489 at 494 line 21 to 495 line 28
and Raychem Corporation’s Patents [1999] RPC 497 at 503 line 39 to 504 line
19. In the latter case, Laddie J said:
"The common general knowledge... is not limited to material [the notional
addressee] has memorised and has at the front of his mind. It includes all
that material in the field he is working in which he knows exists, which he
would refer to as a matter of course if he cannot remember it and which he
understands is generally regarded as sufficiently reliable to use as a foundation
for further work or to help understand the pleaded prior art. This does not
mean that everything on the shelf which is capable of being referred to without
difficulty is common general knowledge nor does it mean that every word in
a common text book is either. In the case of standard text books it is likely
that all or most of the main text will be common general knowledge."
- In the former case, Aldous LJ said:
"It has never been easy to differentiate between common general knowledge
and that which is known by some. It has become particularly difficult with
the modern ability to circulate and retrieve information. ...The notional
skilled addressee is the ordinary man who may not have the advantages that
some employees of large companies may have. The information in a patent specification
is addressed to such a man and must contain sufficient details for him to
understand and apply the invention.
...It follows that evidence that a fact is known or even well-known to a
witness does not establish that that fact forms part of the common general
knowledge. Neither does it follow that it will form part of the common general
knowledge if it is recorded in a document."
While this emphasises that the notional skilled man is not the highest common
denominator in the field, it seems to me equally clear that he is not the
lowest either.
- Aldous LJ went on to quote with approval what Luxmoore J said in British
Acoustic Films 53 RPC 221 at 250:
"[I]t is not sufficient to prove common general knowledge that a particular
disclosure is made... in a scientific journal, no matter how wide the circulation
of that journal may be, in the absence of any evidence that the disclosure
is accepted generally by those who are engaged in the art to which the disclosure
relates. The piece of particular knowledge as disclosed in the scientific
paper does not become common general knowledge merely because it is widely
read, and still less because it is widely circulated. Such a piece of knowledge
only becomes general knowledge when it is generally known and accepted without
question by the bulk of those who are engaged in the particular art; in other
words, when it becomes part of their common stock of knowledge relating to
the art."
- Accordingly, particularly in a field where the technology is unfamiliar,
save perhaps in the most general terms, even to members of the public who
may consider themselves to be generally well educated, the court will rely
very much on expert evidence before it in deciding whether a particular fact
was or was not within the stock of common general knowledge of the skilled
addressee at the relevant date. As with expert evidence on questions of construction,
the court will normally have to bear in mind that the experts from whom it
is hearing will normally suffer from two problems. The first is that they
are giving evidence about the state of knowledge as at a date significantly
earlier than that on which they are considering the matter; particularly in
an area where the science and technology are advancing very fast, as in the
present case, that is a particular difficulty. Secondly, the court will normally
be hearing from experts who are considerably more skilled, considerably more
informed, and indeed inventive, than the notional addressee.
- However, this should not cause the court to take too restrictive a view
of what constitutes common general knowledge, not least because to some extent
these two points cut both ways. In a fast growing area, the amount of available
information in the form of publications and other communications, is likely
to be substantially greater at the hearing date than at the publication date,
particularly where the gap, as here, is more than 15 years. To that extent,
it would be easier for a particular fact to have been common general knowledge
at an earlier date, as that fact would have had, as it were, less competition.
Secondly, there is no intrinsic reason why a person who was inventive or particularly
skilled in the field should have more knowledge than an uninventive person
of average skill; indeed, it is not unknown for the averagely skilled and
uninventive in any field to be rather better informed than their more inventive
and skilful colleagues. On the other hand, where, as here, the expert witnesses
are people of outstanding experience, as well as outstanding skill and inventiveness,
one would expect them to have more knowledge than the notional addressee,
albeit that one must remember that one is removing, as it were, more than
15 years experience from each of the witnesses when judging common general
knowledge as at 1984.
- In the following sections of this part of the judgment, I propose to deal,
in the main, with the common general knowledge of the notional addressee as
at the priority date, to the extent that it was either undisputed or, in my
view, indisputable. However, because I think it helpful when considering issues
of construction and sufficiency, I also propose to explain some of the developments
which occurred in the field after 1984, while trying to make it clear when
I am dealing with that aspect.
Recombinant production of proteins
II. RECOMBINANT PRODUCTION OF PROTEINS
- From the 1920s, some proteins were obtained by purifying them from human
or animal tissues or from bodily fluids. During the 1970s, recombinant DNA
technology was developed. This is a technique which involves isolating or
synthesising the gene which codes for the desired protein, combining the gene
with other ("vector") DNA, inserting this "recombinant"
DNA into a "host cell", which then expresses the protein.
- One reason for preparing recombinant DNA is to produce - or to "express"
- large quantities of the protein encoded by a particular gene. In order to
express a particular protein using recombinant DNA, one needs enough information
regarding the gene encoding the protein, so that additional vector DNA segments
can be recombined with the gene to effect protein expression. This requires
the relevant gene to be isolated, identified and characterised. The difficulty
of this exercise will be appreciated from the fact that the amount of DNA
present in each cell of a human (and most higher animals) amounts to around
6,000,000,000 nucleotides in two complementary strands of DNA (i.e. 3,000,000,000
"base pairs"). This is known as the genome, and the evidence in
this case suggested that it comprises over 50,000 genes (although very recently
reported research appears to suggest that this may be somewhat on the high
side).
- A frequent starting point is the selection of a suitable library of genetic
information and a set of "probes" with which to screen a "library"
consisting of strands of DNA. There are two normal types of libraries that
can be used for these purposes: genomic DNA libraries and complementary DNA
("cDNA") libraries. A library consists of fragments of DNA resulting from
cleaving the DNA at certain points. The identity of the fragments of DNA will
depend of course on the source of the DNA.
- Ideally, a genomic library should contain a complete set of all the DNA
sequences present in the genome, i.e. it will contain all the genetic information
present in the cells from which the library was made. However, there is no
guarantee that every part of the genome will find its way into the library.
A genomic library is stored as pieces of the DNA in a suitable set of carriers.
Complementary DNA is so called because it is the complement of the mRNA. Unlike
genomic DNA, cDNA does not contain introns or promoters and rarely contains
repetitive sequences. Further, only a sub-set of the genomic sequences is
expressed in any one cell-type or tissue, and a cDNA library can only contain
DNA sequences derived from reverse transcription of mRNA of these expressed
sequences.
- As at the priority date, a genomic DNA library of repute was the Lawn library
disclosed in 1978 by Lawn et al in Cell 15:1174. Its use was described in
the standard work in the field, the so-called Maniatis Manual (Molecular Cloning,
A Laboratory Manual, by Maniatis, Fritsch and Sambrook 1982, especially in
Chapter 7). While it was not clear that the Lawn library contained all the
genes, there was a high probability that the gene one was searching for would
be present. By 1983 the technique of Okayama and Berg (Mol.Cell Biol 2(2):161)
was also widely known and accepted as a method for constructing cDNA libraries.
- Researchers construct probes in order to screen libraries based on information
concerning the actual or putative amino acid sequence of the protein of interest.
Probes are typically fairly short sequences of DNA nucleotides, called oligonucleotides,
made synthetically. They are constructed with bases which are complementary
to the bases of the targeted gene according to the base pairing rules (A with
T, C with G) so that the probes will bind - or hybridise - to the gene in
the same way that the two complementary strands of the DNA molecule bind to
each other in the cell. "Screening" is the process of finding a
desired clone from within a population in a library. Such a screening exercise
is likely to be futile if the probes are based on unreliable amino acid sequencing
of the relevant part of the protein of interest.
- A significant problem with genomic libraries in 1983 was that there was
no index or map leading researchers to a desired clone or gene: as explained
above, each gene comprises a tiny fraction of the overall DNA, or genome.
Another problem that compounded the difficulty of using such libraries is
that the DNA was fragmented in a random manner. Thus, while part of the sequence
of a gene of interest may be contained in a single fragment of DNA, the complete
sequence may very well be split between two or even more fragments, and those
fragments might well contain sequences which were not part of the gene concerned.
- If the targeted gene (or a significant part of it) has previously been isolated,
identified and sequenced, the probing exercise is normally relatively easy.
One designs a probe which is an exact complement to that gene (or the part).
Otherwise knowledge of the amino acid sequence of at least a fragment of the
targeted protein is essential for determining the constitution of the probe.
Armed with that knowledge, probes may be designed and used to screen the library
in an attempt to find the gene which codes for that sequence. Probes are designed
by determining which codons code for the amino acid sequence which is being
targeted. However, this process is greatly complicated by the existence of
degeneracy.
- The targeted sequence will inevitably include amino acids which are coded
for by more than one codon so, in order to be sure of having a sequence which
is an exact match to the gene of interest, one has to screen the library with
a set of probes containing multiple nucleotide sequences each of which will
be different. A "fully degenerate" set of probes covers all possible sequences
coding for the targeted amino acid sequence. As a matter of logic, the longer
the amino acid sequence selected for targeting, the greater the number of
probes required. The probes are normally "labelled" with a radioactive atom
so they can be traced.
- The library, which is to be screened, is first "plated out" so that one
can distinguish individual clones among the potentially millions of clones
in the library. The DNA in the individual clones is denatured, i.e., the double-stranded
helix structure is disrupted, making it single-stranded. The probes are then
reacted with the denatured colonies or plaques in the two types of libraries.
The plates are washed to remove the surplus probe material. They are then
inspected to see whether any of the probes have stuck ("hybridised") to any
parts of the library - i.e. whether there are any "positives". Positives may
be missed if the background "noise" is too high. If a probe hybridises to
one of the clones in the library, then the clone is sequenced to determine
whether it contains part or all of the gene of interest. The ability to confirm
the sequence is limited by the information known concerning the gene and/or
the corresponding protein.
- Screening a genomic DNA library is complicated by the fact that the probe
for the selected amino acid sequence may target parts of the exon portions
of the gene that are interrupted by an intron. Such a probe, described as
"spanning an intron", might not hybridise to the clones in the library; thus
it would not enable identification of the desired gene. Until the gene has
been cloned (i.e. isolated, identified and sequenced), the existence, number
and location of any introns are usually unknown. Screening a cDNA library
also has problems. For the library to be useful, the cell or tissue from which
it has been obtained needs to have been expressing a sufficient amount of
the mRNA of interest at the time when the cell or tissue was harvested. If
the cell or tissue was not expressing sufficient amounts of the mRNA of interest,
or was expressing no such mRNA, there will not have been enough or any "message",
hence there will be insufficient or nothing appropriate from which the complementary
DNA can be derived.
- "False positives" can result where a probe matches or hybridises to
a sequence outside of the region of interest. Given the size of the DNA libraries
(especially genomic DNA libraries) and the fact that there are only four bases
in DNA, it is possible that a selected sequence may be repeated several times
in the genome. The longer the probe the less likely that will be. However,
longer probes may show certain sequences which would also lead to false positives.
- The conditions in which the probing takes place can vary. The more stringent
the conditions the more difficult it is for the probes to hybridise with the
DNA strands. Accordingly, high stringency conditions have the advantage of
reducing the potential for false positives: however, they have the disadvantage
of increasing the risk of there being no positives. The stringency of the
hybridisation conditions is normally related to the temperature and the salt
concentration of the solution in which the hybridisation exercise is being
carried out. A technique often used is to increase the stringency gradually
in a particular experiment, so that a number of probes hybridise initially,
and thereafter, as the stringency increases, the number of hybridising probes
decreases, ending ideally with only one probe hybridising, namely the gene
one is looking for.
- After hybridising, the resultant material is often subjected to "washing"
which involves subjecting it to somewhat higher stringency conditions in a
solution. This is with a view to washing off all or some false positives which
still remain. Once a particular gene has been isolated, identified and characterised,
there are various ways in which that information can be utilised to form recombinant
DNA, that will enable a cell that contains the gene to produce greater quantities
of the desired protein.
- While the basic processes of transcription and translation are common to
all cells, not all types of cell are appropriate as host cells. Bacteria cells
cannot deal with introns and therefore cannot deal with genomic DNA (as opposed
to cDNA). Further, bacteria do not glycosylate proteins; accordingly, proteins,
such as EPO, which require glycosylation in order to be fully effective, need
to be produced in eukaryotic cells. Even in different eukaryotic cells, the
same protein may be glycosylated differently.
- In 1984 the types of mammalian cells which were thought to be suitable host
cells was limited. Those in conventional use included the Chinese Hamster
Ovary ("CHO") cell, the baby hamster kidney ("BHK") cell,
and the COS monkey ("COS") cell, as well as certain types of human
cells.
Recombinant DNA techniques
- There are a number of techniques for introducing DNA into a cell (which,
in 1983, would normally have been a bacterium or a yeast), with a view to
expressing a gene which it would not ordinarily express. The process of introducing
DNA into a cell is called transformation or transfection. If a transformed
cell is to express quantities of a desired gene, the relevant DNA which has
been introduced must replicate as the cell replicates. Isolated fragments
of DNA do not, in general, replicate in a bacterium; this is why one inserts
the relevant DNA into another piece of DNA (the vector) which replicates in
the cell. Suitable vectors are the DNAs of bacterial viruses or bacteriophages
("phages") which naturally infect bacteria and replicate within
them. Alternatively, bacterial plasmids (circular pieces of DNA capable of
self-replication) can be used.
- In order to manufacture this recombinant DNA, the vector DNA and the DNA
of interest are first both cleaved. The two sets of fragments are then incubated
to join the fragments to form recombinant DNA. These recombinant DNA techniques
were and are often carried out, in E.coli cells. A single transformed phage
cell gives rise to a plaque. Within a particular plaque each phage particle
is genetically identical. Such a group of genetically identical organisms
is called a clone, and the process of creating a colony of cells which all
contain the same inserted DNA is called gene cloning.
- Two principle techniques in gene cloning are (a) cutting (cleavage) and
joining (ligation) of nucleic acids, and (b) synthesising oligo- and polynucleotides.
- The discovery of restriction enzymes rendered possible the cleavage of a
double-stranded DNA molecule into discrete gene fragments, thereby enabling
gene manipulation. Restriction enzymes catalyse the breaking of a specific
type of bond between adjacent nucleotides at particular sites ("restriction
sites") within a DNA molecule. They are sometimes called restriction
endonucleases, distinguishing them from exonucleases, which catalyse the breaking
of the bond between the last nucleotide in a nucleic acid chain and the remainder
of the nucleic acid.
- Restriction endonucleases are highly specific. Most of them are of so called
Type II; they cleave DNA molecules only in regions where particular sequences
(usually of from 4 to 6 nucleotides) are present. The resultant DNA fragments
can associate by hydrogen bonding with other DNA fragments. If produced by
some enzymes, they can have overlapping 5' and/or 3’ends; for this reason
the fragments are said to have "sticky ends". DNA fragments from
diverse sources can be joined by means of such cohesive ends. Other enzymes
make even cuts giving rise to so-called "blunt-ended" fragments
with no cohesive ends at all. Some enzymes recognise tetranucleotide sequences,
while others recognise longer sequences, and this has an effect on the average
fragment length produced. HindII, apparently the first Type II restriction
endonuclease to be discovered, is an example of an enzyme which recognises
more than one sequence.
- If a restriction endonuclease is used to produce fragments with sticky ends,
these fragments will be capable of associating with fragments produced by
the action of the same restriction endonuclease on a different DNA molecule.
They will then be able to ligate. When the sticky ends associate, the join
has "nicks" in the backbone of the DNA chains a few base pairs apart
in opposite strands. The E.coli bacterium has an enzyme, DNA ligase, which
can be used to repair these nicks in the sugar-phosphate backbone of DNA chains
to form an intact double-strand.
- A problem in the development of cloning techniques was the dependence on
the availability of restriction endonuclease cleavage sites in suitable positions.
Although vector molecules were developed with restriction sites at specific
and useful locations, the position of sites in the DNA to be cloned was effectively
random. In 1976, a method was developed to enable any double stranded DNA
molecule generated by a particular restriction enzyme to be inserted into
a cloning vector at a non-matching restriction endonuclease site. This involved
the chemical synthesis of a short oligonucleotide containing the desired specific
restriction endonuclease recognition site, known as a linker. Such linkers
could be joined by DNA ligase onto the DNA to be inserted and the resulting
molecule cut with a restriction enzyme to generate sticky ends. The molecule
could then be inserted into the matching restriction site in the cloning vector.
- As I have mentioned, in the regulatory region upstream of the coding sequence
of a gene there is a promoter. In gene cloning, an artificial promoter may
be inserted into the regulatory region (or even upstream of that region).
In 1983, specific viral promoters which were generally effective for production
of recombinant DNA in E.coli were well known; indeed, they were commercially
available. It was generally considered that insertion of the new promoter
should occur as near the initiation codon (ATG) as possible, and that it should
be accompanied by removal of the natural promoter.
- The resultant "recombinant" DNA is inserted - or "transfected"
- into the host cell where it integrates with the native DNA essentially at
random. In a eukaryotic cell, the chromosomal structure around the recombinant
gene will influence whether it expresses, and, if so to what extent, just
as with a naturally occurring gene. By 1983, it was known that the level of
protein expression depended on the number of copies of the relevant gene present
in the cell and the expression level of those genes. There were also techniques
available to select cells which contained multiple - or "amplified"
- copies of a particular gene.
- Indeed, DNA amplification can occur spontaneously in many lines of mammalian
cells. When it occurs as a desirable event, those cells that contain amplified
copies of DNA can be selected by various means from those that do not. One
means of selection of cells that have amplified DNA involves the use of the
gene that directs the synthesis of dihydrofolate reductase ("DHFR"),
a protein normally produced in cells because it is required by the cell to
synthesise the nucleotides for DNA. DHFR can be blocked by a cancer drug called
methotrexate ("MTX"); this inhibition will kill the cell unless
the cell can avoid the inhibition. One way the cell can avoid the inhibition
by MTX is to produce more DHFR, so that it escapes the MTX inhibition.
- Amplification normally confers no advantage to the cell, and it is not stable.
However, in the presence of MTX, amplification of the DHFR gene means that
the amplified cells can produce more DHFR, and so are better able to survive.
The cells in which no DHFR gene amplification occurs ("DHFR-cells")
die. Therefore, in the presence of MTX, the cells that have spontaneously
amplified the DHFR gene ("DHFR+ cells") are selected for survival.
The more DHFR made by the cell, the higher the concentration of MTX in which
the cells can grow.
- During amplification, the amplified DNA segment usually includes more than
the DHFR gene. If another gene is within the amplified region of DNA, it will
therefore be amplified with the DHFR gene. Such gene segments that are amplified
along with a selectable gene, such as DHFR, are called passenger genes. To
take advantage of the ability of cells to amplify passenger genes, a DHFR
gene is linked recombinantly to the gene which is to be amplified. Cells containing
this recombinant DNA are then treated with MTX, resulting in some cells surviving
due to the presence of amplified DHFR genes. In addition to increased numbers
of the DHFR gene, these cells also contain proportionately increased numbers
of the passenger gene. As a result, these amplified cells will make increased
amounts of the protein encoded by the passenger gene.
- Synthesising DNA developed during the late 1970's, when several independent
laboratories pioneered oligonucleotide synthesis. Various scientists reported
the synthesis of specific genes in learned journals. At that time, chemical
synthesis of oligonucleotides was carried out by solution-phase chemistry
using a phosphodiester or phosphotriester method The solid-phase method then
took over using phosphotriester or phosphoramidite chemistries, which although
still a manual process, was a labour-reduced process. On the basis of the
evidence, synthesis of a polynucleotide with up to 400 or 500 bases was possible
in 1984, but only a limited number of groups of scientists could reliably
achieve it.
Homologous recombination
- As I have mentioned, when a DNA construct manufactured outside the host
cell ("exogenous DNA") is transfected into a eukaryotic host cell,
it integrates randomly with the chromosomes. However, by 1984, it was known,
in relation to yeast and bacteria, that if the exogenous DNA had significant
regions which were substantially identical, or "homologous", to
sequences of the DNA in the nucleus of the host cell ("the chromosomal
DNA") then the chromosomal DNA might integrate with the homologous exogenous
DNA, effectively replacing the chromosomal DNA. This process is known as homologous
recombination.
- In 1984, the skilled worker in the field could target native genes in the
host cell ("endogenous" genes) by homologous recombination in lower
organisms such as bacteria and yeast. This targeting was effected by, in effect,
"knocking out" a specific gene in order to determine its function.
There were no reports of gene targeting by homologous recombination in mammalian
cells prior to 1985. It was, however, appreciated that targeting endogenous
mammalian cells was highly desirable, not least because it would enable gene
function of mammalian cells to be studied, leading to the correction of defects
in genes which were disease-associated.
- In 1984, it was perceived that there were barriers to the development of
gene targeting by homologous recombination in mammalian cells. The size of
the mammalian genome is considerably larger than that of bacteria or yeast:
given that the integration of exogenous DNA with chromosomal DNA was effectively
random, this was seen to lead to obvious problems. Further, even if the exogenous
DNA could be targeted at specific sites, it was not clear how one was to select
the desired integration event from the vast number of other, random, insertions.
Even after the first report of targeting an endogenous mammalian gene by homologous
recombination (Smithies et al. 1985 Nature 317:230) in 1985, there were difficulties.
The reported method required one to analyse thousands of cells to find one
in which gene targeting had occurred. It is clear to my mind from the evidence
that the technique of gene targeting by homologous recombination was impractical
until the late 1980s (see for instance Nature 336:348 in 1998). Indeed, even
now, gene targeting by homologous recombination has not been achieved in many
eukaryotic organisms which have been well studied. For example, it was only
successfully achieved in the past couple of years in cells of the fruit fly,
which had been widely studied in the laboratory (see for instance Rong et
al. 2000 Science 288:2013).
- As well as gene targeting, another use for homologous recombination is activation
of endogenous genes. As already explained, the great majority of the cells
of an organism contain the whole of the genome in respect of that organism.
Thus, as I have explained, the great majority of cells of the human body contain
DNA which will encode for all the proteins expressed by DNA in the human body,
but, save in cells of a particular type, the sequence which encodes for a
particular protein is "switched off". This switching off is effected
by a negative regulatory element, or "NRE". Gene activation involves
introducing into the genome of a human cell where the relevant gene is "switched
off" by an NRE, a sequence just upstream of the gene concerned which
overrides the NRE and effectively "switches on" the gene.
- Gene activation involves targeting a promoter upstream of an endogenous
gene, with a view to the promoter operating with the endogenous regulatory
elements to express the gene. Gene activation involves several steps. First,
a targeting construct is produced: this is a polynucleotide containing a promoter
(normally a viral promoter) flanked by sequences which allow the promoter
to be targeted by homologous recombination to a specific location upstream
of the desired endogenous gene. Secondly, the targeting construct is transfected
into cells containing the desired gene. Thirdly, the flanking ("or targeting")
sequences then undergo homologous recombination, as a result of which the
promoter is positioned upstream of the endogenous encoding sequences. Fourthly,
the "switched on" gene then expresses the desired protein. The art
in this field includes the choice of flanking sequences, which determine the
position of the targeted promoter with respect to the endogenous gene.
- Gene activation in mammalian cells was reported for the first time around
1991, and was obviously not being carried out, even by particularly skilled
workers in this field in 1984.
Glycosylation of proteins
- As I have mentioned, many proteins, including EPO, are glycosylated - i.e.
they have sugar - or saccharide - units attached to them. Glycosylation can
determine the conformation of a protein, and this in turn may affect its functionality;
it can also prolong the life of a protein.
- The glycosylation of any protein is and was known in 1984 to be heterogeneous.
In other words, the glycans were known to consist of a combination or combinations
of monosaccharides, attached to the polypeptide chain of the protein ("the
back bone"), which vary from molecule to molecule. A number of different
monosaccharide units are found in glycoproteins. The most common are the hexoses
galactose ("Gal") and mannose ("Man"), the hexosamines
N-acetylglucosamine ("GlcNAc") and N-acetygalactosamine ("GalNAc"),
fucose ("Fuc") and sialic acids (most commonly N-acetylneuraminic
acid, abbreviated to "NeuNAc"). The saccharide units are linked
together to form oligosaccharides, by enzyme-catalysed reactions between hydroxy
(OH) groups of each monosaccharide. There are many hydroxy groups on monosaccharides,
and so the units can be linked together in a number of different ways. Because
each monosaccharide can link to more than one other monosaccharide, oligosaccharides
can be branched.
- The formation of oligosaccharides on a protein is controlled by enzymes,
collectively known as glycosyltranferases. Formation of a specific linkage
between two sugars is catalysed by a specific enzyme. Thus, there is at least
one enzyme for each known combination of any two saccharides in any linkage
in a given configuration. The final glycosylation of a protein therefore depends
upon the presence or absence of particular glycosyltransferases in a cell
and the extent to which they succeed, under particular conditions, in carrying
out their functions. A glycosylation unit, or "glycan", can, as
I have mentioned, either be N-linked or O-linked.
- In mammalian cells, it was known in 1984 that N-glycosylation starts by
the attachment of a precursor oligosaccharide unit to the nitrogen atom in
the side chain of the amino acid asparagine. This takes place in the RER of
the cell. The precursor unit consists of two GlcNAc residues, nine mannoses
and three glucoses. This precursor is then trimmed by enzymes to remove the
three glucose residues and up to four of the mannose residues. If four mannoses
are removed, a GlcNAc is added to one branch of the oligosaccharide. GlcNAc
and fucose units can then be further added to the oligosaccharide unit.
- Further modification can occur with addition of different saccharides in
different linkages (NeuNAc, Fuc, Gal, GalNAc, GlcNAc). Many of these modifications
will "cap" the oligosaccharide and terminate further elongation/branching.
These capping structures (and therefore the overall structures of the glycans),
in general, differ among species and among individuals within the species.
The blood group system is based on differences in capping structures, which
is why immunogenicity to carbohydrates is one of the major barriers in blood
transfusion and organ transplantation between individuals as well as between
species.
- The attachment of oligosaccharides to a protein is not like the translation
of mRNA into protein by ribosomes and tRNAs: there is no unique result (i.e.
no particular glycan) prescribed by a given template. The process is carried
out by a large number of glycosyltransferase enzymes; there are many processing
stages, and most of them are governed by specific pathways or rules. Accordingly,
there can be a very large number of different outcomes. In the case of complex
N-linked glycoforms the branching can lead to the glycan being bi-, tri- or
tetra-antennary. Each branch or antenna may include repeating structures.
In an antennary structure, some antennae may be capped by sialic acid whereas
others may be uncapped. Some N-linked structures may be fucosylated (i.e.
have a fucose unit linked) at the innermost GlcNAc and others not. The result
is that a glycoprotein produced even by one specific cell type will consist
of a heterogeneous mixture of different species, termed glycoforms.
- The particular glycosyltransferase enzymes produced by a cell will depend
on the genome. A mutation in the genome may knock out the gene for a particular
glycosyltransferase or reduce, or indeed increase, its activity. However,
there is and was in 1984, no reason to think that the introduction of a mutation
in CHO cells to produce cells which are DHFR - would suffer any other mutation.
- By 1983 the general biosynthetic pathway for N-glycosylation in mammalian
cells was well understood. That for O-glycosylation was less well understood.
However, a number of things were known about O-glycosylation. The glycan was
known to be always attached to the oxygen atom in the side chain of a serine
or threonine amino acid. It was also known that there was no precursor unit
attached as a starting point. O-glycosylation was understood to be initiated
by attachment of a GalNAc residue in the RER and/or Golgi, and the oligosaccharide
structure was built up residue by residue by individual enzymes in the Golgi.
It was also known that GalNAc is not found in N-linked oligosaccharides (except
in certain specific cases which are not relevant to this case). Accordingly,
the presence or absence of GalNAc was regarded as diagnostic of O-linked glycosylation.
What was not known in 1983/85, but is known now, is that O-glycosylation is
a differentiated process that varies with cell type.
- Bacteria (including E.coli) do not glycosylate proteins. In the case of
proteins such as EPO, where glycosylation is vital for in vivo activity, this
means that bacteria will produce inactive material. Yeast cells (such as those
of S. cerevisiae) are able to produce and attach a certain precursor and process
it to remove glucose and one mannose. However, in the Golgi of yeast, only
mannose is added, so yeast produce only highly mannosylated structures. Plant
and insect cells also produce structures which are different from those produced
by mammalian cells.
- As I have mentioned, the actual glycoproteins produced by mammalian cells
are mixtures of (normally a very large number of) different glycoforms, and
the glycoforms produced depend upon the glycosyltransferases which are active
in the cell. Glycosylation is a highly sensitive parameter of cell biological
processes. Different cell types have different glycosylation properties. Cells
from the same species and of the same type can glycosylate differently.
- It is now known (but was not known in 1984) that CHO cells almost exclusively
engage in a form of capping found in human cells and therefore, recombinant
glycoproteins expressed in CHO cells will be appropriate for use in human
therapy. In 1984, there was limited knowledge about the way in which non-human
mammalian cells would glycosylate proteins produced by the expression of recombinant
DNA.
- The glycosylation capacity of a cell line is dictated by the properties
and functions of the glycosyltransferases expressed in the cell. However,
cells normally only express a subset of the glycosyltransferases for which
their genome encodes. As I have mentioned, cells from one organism normally
contain the same DNA regardless of their tissue origin. Thus, a normal cell’s
potential for glycosylation is generally much larger than that which is dictated
by the expressed enzymes.
- It was becoming clear by 1984 that the identification of a suitable cell
line was important not only from the perspective of ensuring appropriate glycosylation
to enable the glycoprotein to function, but also to ensure that the recombinant
glycoprotein did not generate an immunogenic response. Little was known that
would guide the researcher towards the best cell line for any given glycoprotein.
Purification and deglycosylation of proteins
- Any protein of interest (whether naturally occurring or recombinant) has
to be separated - or "isolated" - from other material. At the present
time (and in 1984) there are a number of well known techniques. Some depend
on the physico-chemical differences between the protein and other material
(including other proteins). These include factors such as the size, charge,
hydrophobicity or solubility of the molecules. Filtration depends on the relative
size of the molecules. There are various forms of chromatography which depend
on differences in charge between the protein molecules and the molecules of
other material from which the protein is to be isolated. Other techniques
depend on the electric charge of the molecules; an example is isoelectricfocusing.
- As there will normally be a large number of different contaminatory materials,
and as the proteins of interest may be present in low concentration, most
purification schemes will involve a combination of steps using different properties
of the protein of interest. However, as each step inevitably results in the
loss of a proportion of the protein, part of the art of the protein chemist
is to seek a scheme which involves the minimum number of purification steps.
Glycoproteins present a particular problem because they have so many glycoforms.
Their heterogeneity extends to differences in shape, size and charge (this
last largely depending on the number of sialic acids).
- It was known in 1984 that various substances could remove some or all of
the glycans from a glycoprotein. Treatment with neuraminidase would remove
all the sialic acid residues. It was also known that endoglycosidase removed
N-glycans. It was also known in 1984 that there were various ways of analysing
the glycans in a glycoprotein. Normally a combination of chemical and chromatographic
methods were used.
SDS-PAGE and Blotting
- SDS-PAGE is (and was in 1984) a well-established form of an experimental
technique called electrophoresis; it enables the apparent molecular weights
of proteins or glycoproteins to be assessed. It is inexpensive and relatively
easy; its results are not precise but approximate.
- Building on the basic principle that charged proteins will move in an electrical
field, the SDS-PAGE method of electrophoresis was developed to allow the mass
(molecular weight) of the protein to play the most direct role on the rate
of migration of the protein in the electrical field. In SDS-PAGE, an electrical
field is applied across a gel, which is cast from a particular type of plastic,
polyacrylamide. The gel acts like a sieve, allowing smaller proteins to pass
through it faster than larger proteins.
- Most proteins are, as I have said, in a three-dimensional, "folded"
structure. Although, in general, smaller molecules will move more quickly
through a polyacrylamide gel than larger molecules, two molecules of the same
size might appear to be of different sizes on gel electrophoresis if one is
folded tightly into a compact shape and the other is not. In SDS-PAGE, the
effect of the shape of the protein on its movement through the gel is minimised
by disrupting the three-dimensional structure of the proteins to be tested,
i.e., by unfolding or "denaturing" the protein molecules. In this manner,
all the proteins have, at least roughly, the same "linear" shape.
- SDS is a detergent that carries a negative electrical charge. In SDS-PAGE,
protein samples that are to be run on the gel are pre-treated with SDS. SDS
has two relevant effects on proteins. First, when mixed with proteins, SDS
causes the proteins to denature. Sometimes a reducing reagent, such as mercaptoethanol,
is also mixed with the proteins, to disrupt certain bonds between amino acids.
The result is that all the proteins being tested have nearly the same extended
linear shape. Secondly, when SDS is mixed in sufficient quantities with protein
molecules, it effectively "coats" the protein giving each the same
charge per amino acid residue. However, SDS typically will not bind to carbohydrates.
Accordingly, the shape and charge contributed by the carbohydrate side chains
of a glycoprotein can affect the protein’s mobility on a gel.
- SDS-PAGE does not provide the "absolute" molecular weight of the
protein, but its "apparent" molecular weight. The "absolute"
molecular weight of a molecule is calculated by adding together the weights
of the atoms that form the molecule, and it is measured in Daltons or Kilo
Daltons - KDa. The SDS-PAGE technique measures the relative mobility of molecules
on a gel. A scientist may then deduce the relative apparent molecular weight
of the molecules by comparing the mobility of that molecule with the mobility
of other molecules and/or standard molecules having known molecular weights.
As discussed above, there can be residual effects on the mobility of a molecule
on a gel, particularly in the case of glycoproteins, that are not directly
the result of molecular weight (e.g., charge and shape). Thus it is generally
understood that SDS-PAGE provides a "relative" and "apparent"
molecular weight, not an absolute molecular weight.
- A number of different lanes may be run on a given SDS-PAGE experiment. Thus,
if comparing two different proteins, one may have three lanes of each of the
two proteins, so that the reliability of the gel and of the samples, as well
as the comparison between the two proteins can be taken into account. There
may also be one or two bands of "marker", a mixture of substances
of known molecular weight, to act as a guide to the apparent molecular weight
of material in the other bands. Unglycosylated proteins will produce fairly
narrow and sharp bands. Because their glycosylation is heterogeneous, as I
have explained, most glycoproteins will have wider and more "fuzzy"
bands as differences in glycosylation will normally result in different apparent
molecular weights.
- The comparison of the apparent molecular weight of two materials is more
reliable if they are run on adjoining lanes in the same gel. This became possible
in about the mid-1970s when so-called "slab" gels became available
- i.e. single gels in which separate lanes for different materials (including
markers) became available. Even then, there was the possibility of distortions
in the gel - e.g. due to the presence of a little air. Distortions would be
less likely in relation to columns near the centre of the slab gel, as opposed
to the edges.
- The result of an SDS-PAGE experiment is the separation of proteins on a
gel. After the separation, it is necessary to be able to see the separated
proteins. One sensitive technique for doing this is referred to as Western
blotting or immunoblotting. There are three basic steps involved in a Western
blot.
- First, after electrophoresis of the proteins through a polyacrylamide gel,
they are transferred by blotting to a porous membrane sheet. Secondly, this
membrane sheet is treated with a solution containing an antibody to the protein
of interest. An antibody is a type of protein that is capable of specifically
recognising and binding to part of a molecule (referred to as its epitope).
After this step, the antibody will have (hopefully) bound to the separated
protein of interest. Thirdly, the presence of the antibody, and thus the presence
of the protein of interest, is detected. One way to detect the presence of
the antibody which bound to the protein is by adding a second antibody solution
to the membrane sheet, termed a two-antibody method. This second antibody
solution contains the detectable antibody, which specifically binds to the
first antibody. The second antibody is detected, such as by treatment with
another solution that creates a visually coloured band corresponding to the
location in the gel of the antibodies, and thus the protein of interest. Alternatively,
the presence of the protein of interest on the gel can be detected by using
a detectable label – e.g. a radioactive ion or compound to the protein. Exposure
of the gel to radiographic film will produce a band identifying the presence
of the labelled protein. This is called autoradiography. A method for detecting
the amount of protein in a sample is radio-immunoassay ("RAI").
- A very similar exercise for DNA fragments is known as Southern blotting.
A Southern blot involves separating the DNA fragments in the genomic library
on an agarose gel according to size, absorbing the separated fragments from
the gel onto a membrane and probing the resultant separated fragments with
a DNA probe (with radioactive phosphorous).
D. THE 605 PATENT
Introduction
- The 605 patent claims a priority date of 13th December 1983 and it is entitled
"Production of Erythropoietin". The application was filed on 12th
December 1984, and it was published on 17th July 1985. 605 disclosed for the
first time the DNA sequence for the human EPO gene, and the corresponding
amino acid sequence, for human EPO. 605 disclosed novel DNA sequences, glycoprotein
products, pharmaceutical compositions, and processes and cells producing EPO.
The Examples in 605 teach ways to obtain these claimed inventions.
- Before the disclosure afforded by 605, the state of the art with regard
to EPO was as follows. It was known to be a glycoprotein with a molecular
weight of about 34,000 Daltons, or 34 Kilo Daltons or KDa. Naturally occurring
human EPO had only been isolated from one source, namely urine, and then only
in very limited quantities. It had therefore not been possible to obtain sufficient
EPO for the purpose of determining its amino acid sequence, let alone to treat
patients. A proposed sequence for the first twenty-six amino acids (from the
N-terminal) had been published in 1983 (by Sue and another in PNAS USA 80:3651).
However, it was incomplete and had only been put forward as "putative",
and it was not believed to be reliable. Indeed, the disclosure of 605 demonstrated
that two of the amino acids had been wrongly identified. Further, this reported
sequence was highly degenerate which rendered its use in connection with the
detection of the EPO gene extremely difficult. Nothing was known about the
sequence, length, size, or location within the genome, of the EPO gene, let
alone about the arrangement of exons and introns within it. Further, there
was no satisfactory source for obtaining EPO DNA, because it was impossible
to identify an EPO-expressing cell which could be used as an appropriately
enriched source of mRNA to obtain EPO cDNA clones on the basis of the data
then available. Further, probing a small genomic DNA library would not have
been considered a viable option.
- In 1962, Kuratowska et al (Erythropoiesis (1962) p. 58) had reported partial
production of EPO from human blood plasma and in 1973 Essers et al (Klinische
Wochenschrift 51:1005) reported satisfactory treatment of anaemic patients
with EPO-rich plasma. In 1977 Miyake and Goldwasser in a paper ("Miyake")
in J.Biol.Chem 252: No.15 p5558, reported how they had purified "milligram
quantities" of EPO "with a potency of 20,400 at 21% yield"
from the urine of anaemic patients. In 1983, Ascensao et al (Blood 62(5):1132)
described an EPO-producing human testicular germ cell that had been sustained
in culture for two years; it had a biological activity of 100-600 milliunits/ml
of cell culture. A similar level of production was reported by Sherwood et
al, in Clinical Research 31(2): 323A, in 1983 for an EPO-producing human renal
carcinoma cell line which was cultured for over 3 years.
- In summary, the 605 patent reveals that what Dr Lin did was as follows:
a. he located the human EPO gene within a genomic library comprising
literally millions of fragments of human chromosomes, although the library
contained no effective index, and, indeed, although it was not in fact known
that the EPO gene was in the library;
b. he identified and extracted the EPO gene from the library;
c. he disclosed the amino acid sequence of human EPO;
d. he determined the structure of the EPO gene and disclosed its sequence,
the extent and location of the introns and exons, and the up stream and down
stream sequences; and
e. he used this information to effect relatively large-scale production
of glycoproteins having the biological activity of naturally occurring human
EPO.
- In terms of originality, what he did was "to use mixed [oligonucleotide]
probes to probe a genomic [DNA] library" according to Professor Brammar,
whereas prior to Dr Lin’s work "genomic [DNA] libraries [had] previously
been screened successfully only with cDNA probes". That evidence is consistent
with that of Professor Wall who said that, in 1984, probing a genomic DNA
library to seek out the EPO gene by Dr Lin’s method would not have been expected
to succeed.
- The 605 patent disclosed for the first time the complete nucleotide sequence
and organisation of the structural region of the human EPO gene. In particular,
Table VI of 605 includes the amino acid sequence of EPO, the identity and
location of the nucleotide sequences of the exons, i.e. those that code for
human EPO, where the initial EPO is processed to remove the leader peptide
(consisting of 27 amino acids) and the sequences of the introns which precede,
follow and separate the protein-coding exon sequences, including the splice
sites at the intron-exon junctions.
- In brief terms, using recombinant DNA techniques then available, Dr Lin
inserted a fragment of DNA containing these human EPO sequences into a plasmid,
and, before transfecting this recombinant plasmid into vertebrate cells, he
inserted a strong viral promoter, a DNA fragment from the simian virus known
as "SV40", upstream from the EPO gene structural region of the fragment
in the plasmid. This resulted in a recombinant gene in which the SV40 viral
promoter was able to control the expression of human EPO from the human EPO
gene.
- In order to increase the amount of RNA transcribed from this recombinant
construct, and thus to increase the amount of recombinant human EPO produced
by a cell transfected with the construct, he also inserted a DHFR gene at
a location upstream from the viral promoter. By inserting this DHFR gene,
and treating cells transfected with the construct with MTX, he was able to
select cells containing amplified copies of the recombinant human EPO gene,
as I have explained.
- Using recombinant techniques then available, Dr Lin inserted the genetic
construct created as described above in the chromosomal DNA of a host cell
line (in Example 10, a CHO cell line) by transfecting the cell with the DNA
of the construct. When this genetic construct was inserted into the CHO cells,
the viral promoter sequences, lying upstream from the structural region of
the human EPO gene, directed the RNA polymerase to transcribe an RNA copy
of the DNA sequences downstream from the promoter site, including the exons
and introns that make up the structural region of the human EPO gene. The
resultant primary RNA transcript was processed by other cellular enzymes to
remove the intron sequences and splice the exon sequences back together to
form an mRNA. The cell then used the mRNA as a template to translate the amino
acid backbone of human EPO from individual amino acids.
- As described in 605, the "immature" human EPO polypeptide as it
is first synthesised in the cell contains 193 amino acids, beginning with
a 27-amino-acid leader peptide. As the EPO polypeptide is being synthesised
in the cell, this leader peptide directs it into the RER. Once the EPO polypeptide
begins to enter the RER, the leader peptide is removed. The human EPO polypeptide,
now substantially "mature" and 166 amino acids in length, continues
through the RER into the Golgi, where the polypeptide undergoes glycosylation
before being secreted from the cell.
- After the filing of the application for 605, it was discovered that the
final amino acid residue in the human EPO polypeptide (the arginine residue
at position 166), is removed during or following the secretion of the polypeptide
from the cell to generate the fully mature human EPO polypeptide having the
165-amino acid sequence set out in Table VI of 605.
The notional addressee
- There is a limited dispute as to the identity of the notional addressee
of the Patent. It is agreed that it would consist of a team of people. The
team would include three PhD’s with several years experience in gene technology,
molecular biology and cell biology, respectively. At least one of these three
would have had experience of proteins in general and glycoproteins in particular.
The team would also include two laboratory technicians well acquainted with
gene technology and biochemical techniques.
- At least one member of this notional team would have skill and experience
in purification and preparation of proteins and, in particular, of assessing
apparent molecular weights by SDS-PAGE. There is an issue as to the extent
that the team would include a member who had skill and experience in assessing
the carbohydrate content of a glycoprotein which had been isolated, but that
is best dealt with under the issue of Added Matter.
The disclosure and specification
- Under the heading "Background", 605 opens with these words:
"The present invention relates generally to the manipulation of genetic
materials and, more particularly, to recombinant procedures making possible
the production of polypeptides possessing part or all of the primary structural
conformation [of EPO]" (page 2 lines 5ff).
- There then follows a summary of techniques for the manipulation of genetic
materials. 605 then turns to explain why EPO is of interest, what was known
about it, and the attempts to isolate it from blood and urine. At page 2 lines
41ff, there is the description of:
"The attempt [in the last decade] to manufacture industrially and pharmaceutically
significant substances using organisms which either do not initially have
genetically coded information concerning the desired product included in their
DNA or (in the case of mammalian cells in culture) do not ordinarily express
a chromosomal gene at appreciable levels. Simply put, a gene that specifies
the structure of a desired polypeptide product is either isolated from a "donor"
organism or chemically synthesised and then stably introduced into another
organism.... Once this is done, the existing machinery for gene expression
in the "transformed" or "transfected" microbial host cells
operates to construct the desired product, using the exogenous DNA as a template
for transcription of mRNA..."
- The patent then goes on to describe the existence of publications on such
"further "recombinant DNA" methodologies for the isolation
synthesis purification and amplification of genetic materials for use in the
transformation of selected host organisms" (page 2 lines 50-51). At page
2 lines 55ff:
"Selected foreign ("exogenous" or "heterologous")
DNA strands usually including sequences coding for desired product are prepared....
The linear viral or plasmid DNA is incubated with the foreign DNA in the presence
of ligating enzymes capable of effecting a restoration process and "hybrid"
vectors are formed which include the selected exogenous DNA segments "spliced"
into the viral or circular DNA plasmid."
- At page 3 lines 11ff, there is this:
"At the risk of over simplification, it can be stated that three alternative
principal methods can be employed: (1) the "isolation" of double-stranded
DNA sequence from the genomic DNA of the donor; (2) the chemical manufacture
of a DNA sequence providing a code for a polypeptide of interest; and (3)
the in vitro synthesis of a double-stranded DNA sequence by enzymatic "reverse
transcription" of mRNA isolated from donor cells. The last-mentioned
methods which involve formation of a DNA "complement" of mRNA are
generally referred to as "cDNA" methods."
- On the same page at lines 29ff, the patent continues:
"When the entire sequence of amino acid residues of the desired polypeptide
is not known, direct manufacture of DNA sequences is not possible and isolation
of DNA sequences coding for the polypeptide by a cDNA method becomes the method
of choice despite the potential drawbacks. ...Among the standard procedures
for isolating cDNA sequences of interest is the preparation of plasmid-borne
cDNA "libraries" derived from reverse transcription of mRNA abundant
in donor cells selected as responsible for high level expression of genes."
- On page 4 lines 6-7, there is this:
"The use of genomic DNA isolates is the least common of the three above-noted
methods for developing specific DNA sequences for use in recombinant procedures."
- The patent then goes on to the Lawn library. On the same page at lines 20ff,
there is a reference to a paper published in 1983 by Anderson and Kingston
in PNAS (USA) 80,6838, which reports on "probing a genomic library using
a mixture of labelled probes". The patent then quotes a passage from
the paper which explains that "such a method [is] impractical for the
isolation of mammalian protein genes when the corresponding mRNAs are unavailable".
- On the same page, at lines 34ff, the patent continues:
"There... continues to exist a need in the art for improved methods
for effecting the rapid and efficient isolation of cDNA clones in instances
where little is known of the amino acid sequence of the polypeptide coded
for and where "enriched" tissue sources of mRNA are not readily
available for use in constructing cDNA libraries."
- At page 5, lines 30ff of the 605 patent, there is this:
"Prior attempts to obtain erythropoietin in good yield from plasma
or urine have proven relatively unsuccessful. Complicated and sophisticated
laboratory techniques are necessary and generally result in the collection
of very small amounts of impure and unstable extracts containing erythropoietin.
...
Initial attempts to isolate erythropoietin from urine yielded unstable,
biologically inactive preparations of the hormone. US Letters Patent No. 3,865,801
describes a method of stabilising the biological activity of a crude substance
containing erythropoietin recovered from urine. The resulting crude preparation
containing erythropoietin purportedly retains 90% of erythropoietin activity,
and is stable.
Another method of purifying human erythropoietin from urine of patients
with aplastic anaemia is described in Miyake, et al., J. Biol. Chem., Vol.
252, No. 15 (August 10, 1977), pp. 5558-5564. This seven-step procedure includes
ion exchange chromatography, ethanol precipitation, gel filtration, and adsorption
chromatography, and yields a pure erythropoietin preparation with a potency
of 70,400 units/mg of protein in 21% yield.
US Letters Patent No 4,397,840 to Takezawa et al describes methods of preparing
"an erythropoietin product" from healthy human urine...
UK Patent Application No 2,085,887 by Sugimoto et al ... describes a process
for the production of hybrid human lymphoblastoid cells, reporting production
of ... erythropoietin..."
- After discussing the use of antibodies for the purpose of isolating EPO,
the patent goes on to explain at page 6 lines 57ff:
"While substantial efforts appear to have been made in attempted isolation
of DNA sequences coding for human and other mammalian species erythropoietin,
none appear to have been successful. This is due principally to the scarcity
of tissue sources, especially human tissue sources, enriched in mRNA such
as would allow for construction of a cDNA library from which a DNA sequence
coding for erythropoietin might be isolated by conventional techniques. Further,
so little is known of the continuous sequence of amino acid residues of erythropoietin
that it is not possible to construct, e.g., long polynucleotide probes readily
capable of reliable use in DNA/DNA hybridisation screening of cDNA and especially
genomic DNA libraries. ...It is estimated that the human gene for erythropoietin
may appear as a "single copy gene" within the human genome and, in any event,
the genetic material coding for human erythropoietin is likely to constitute
less than 0.00005% of total human genomic DNA which would be present in a
genomic library.
To date, the most successful of known reported attempts at recombinant-related
methods to provide DNA sequences suitable for use in microbial expression
of isolatable quantities of mammalian erythropoietin have fallen far short
of the goal."
- There are then set out what are often known as "consistory clauses"
which (save that the word "point" is used in place of the word "claim")
follow, almost word for word, the 31 claims.
- At page 9, lines 31ff of 605, there is this:
"Vertebrate (e.g., COS-1 and CHO) cells provided by the present invention
comprise the first cells ever available which can be propagated in vitro continuously
and which upon growth in culture are capable of producing in the medium of
their growth in excess of 100U (preferably in excess of 500U and most preferably
in excess of 1,000 to 5,000U) of erythropoietin per 106 cells in
48 hours as determined by radioimmunoassay."
- The ensuing paragraphs of the patent illustrate the scope of the invention
with reference to "cloned DNA sequences of monkey and human species origins
and polypeptide sequences suitably deduced therefrom" (page 9, lines
42-43).
- At page 10, lines 7ff there is this:
"Novel DNA sequences of the invention include all sequences useful
in securing expression in prokaryotic or eukaryotic host cells of polypeptide
products having at least a part of the primary structural conformation and
one or more of the biological properties of [EPO] which are comprehended by:
(a) the DNA sequences set out in Tables V and VI herein or their complementary
strands; (b) DNA sequences defined in (a) or fragments thereof; and (c) DNA
sequences which hybridise (under hybridisation conditions such as illustrated
herein or more stringent conditions) to DNA sequences."
- Thereafter, under the heading "Detailed Description", the Patent
explains how DNA sequences encoding all or part of the polypeptide sequences
of human and monkey species EPO have been isolated and characterised, and
how each species of EPO have been expressed eukaryotically and prokaryotically,
thereby producing isolatable quantities of polypeptides which display the
biological properties of naturally occurring EPO. How this was achieved is
then set out in rather more detail with reference to twelve Examples which
take up pages 12-45 inclusive of the Patent.
- Example 1 relates to amino acid sequencing of human urinary EPO fragments
and construction of mixtures of radio labelled probes based on the results
of this sequencing. The Example includes Table I which sets out the sequence
of 17 different polypeptide fragments, the last two of which (containing seven
and twenty one amino acid residues respectfully) are said to provide a useful
basis for oligonucleotide probes, in view of their comparatively low degeneracy.
- Example 2 relates to identification of monkey EPO cDNA clones and thus provides
information concerning animal treatment and preliminary RIA analysis of animal
sera.
- Example 3 relates to preparation of a monkey cDNA library, hybridisation
procedures for screening that library a protocol for verification of positive
clones, DNA sequencing of a positive cDNA clone and the generation of the
monkey EPO polypeptide’s amino acid sequence. Table V at pages17-18 provides
the amino acid sequence for monkey EPO (including identification of the leader
peptide) and the nucleotide sequence of a monkey EPO cDNA. As Table V sets
out cDNA, it excludes the intervening introns, but it includes part of the
non-coding sequences both upstream and downstream of the encoding regions.
- Example 4 relates to identification of positive human genomic clones and
thus provides information concerning the source of the genomic library, plaque
hybridisation procedures and verification of positive clones. Part A describes
the use of the human foetal liver genomic library prepared in accordance with
the procedures of Lawn et al Cell 18, pp: 533-543 (1979). Part B describes
how the library was screened and that (at page19, lines 14ff):
"Autoradiography of the filters revealed three positive clones (reactive
with both probe mixtures) among the 1,500,000 phage plaques screened. Verification
of the positive clones as being EPO-encoding was obtained through DNA sequencing
and electron micrographic visualization of heteroduplex formation with the
monkey cDNA of Example 3. This procedure also gave evidence of multiple introns
in the genomic DNA sequence."
- Example 5 relates to nucleotide analysis of one genomic clone (l hE1)
and the generation of human EPO polypeptide amino acid sequence information.
These are set out in Table VI on pages 20-24. This table sets out, over five
pages, the sequence (consisting of the letters A, T, C and G) for the human
EPO gene. It includes much of the upstream sequence (i.e. the regulatory region
5’ of the first exon) - namely the 620 bases before the first exon. It includes
the two endogenous transcription start sites. It then continues with the five
encoding exons and the four intervening introns. It also contains the downstream
(i.e. 3’ of the last exon) non-coding region. Two of the 620 bases in the
regulatory region are not identified, as is indicated by "XX"; some
of the bases in the first intron are not identified as indicated by "[I.S.]".
Under the exons it identifies the amino acids for which the codons encode:
thus it gives the full amino acid sequence for human EPO.
- After describing the arrangement of introns and exons (all of which are
shown in Table VI) in the sequence Example 5 continues at page 25, lines 3ff:
"Table V1 thus serves to identify the primary structural conformation
(amino acid sequence) of mature human EPO as including 166 specified amino
acid residues (estimated M.W. = 18,399). Also revealed in the Table is the
DNA sequence coding for a 27 residue leader sequence along with 5' and 3'
DNA sequences which may be significant to promoter/operator functions of the
human gene operon. Sites for potential glycosylation of the mature human EPO
polypeptide are designated in the Table by asterisks."
- The example then explains how the sequence of human and monkey polypeptides
are compared in Table VII, in which the degree of homology is shown by reference
to asterisks where the amino acids are the same. The patent observes at page
25, lines 16ff that:
"It should be noted that the deduced human and monkey EPO sequences
reveal an "additional" lysine (K) residue at (human) position 116. Cross-reference
to Table VI indicates that this residue is at the margin of a putative mRNA
splice junction in the genomic sequence. Presence of the lysine residue in
the human polypeptide sequence was further verified by sequencing of a cDNA
human sequence clone prepared from mRNA isolated from COSP-1 cells transformed
with the human genomic DNA in Example 7, infra."
- Example 6 describes the construction of a vector incorporating EPO-encoding
DNA derived from a monkey cDNA clone, the use of the vector for transfection
of COS-1 cells and the cultured growth of the transfected cells.
- Example 7 sets out construction of two vectors incorporating EPO-encoding
DNA derived from a positive "human genomic DNA EPO clone", the use
of the vector for transfection of COS-1 cells and the cultured growth of the
transfected cells. Example 7A involves an endogenous promoter, whereas Example
7B involves the SV40 viral promoter. Example 7A refers to "initial attempts
at microbial synthesis of isolatable quantities of human EPO polypeptide material
coded for by the human genomic DNA EPO clone [which] also involved expression
in mammalian host cells" (page 27 lines 46-47). Later, it goes on to
describe how human EPO which had been introduced into a specific plasmid "was
used to express human EPO polypeptide material in COS-1 cells" (page
28 line 18). A similar expression was used in relation to Example 7B as recorded
on the same page at lines 41-42.
- Example 8 relates to RAI procedures performed on media supernatants obtained
from the cultured growth of transfected cells according to Example 6 and 7.
- Example 9 refers to assays for the biological activity of microbially expressed
EPO of Examples 6 and 7. The in vitro assay referred to is that described
in Goldwasser, et al., Endocrinology 97 (2), pp: 315-323 (1975) and the in
vivo activity was determined according to the general procedures of Cotes
et al., Nature 191 pp: 1065-1067 (1961) and Hammond, et al., Ann. N.Y. Acad.
Sci., 149 pp: 516-527 (1968).
- Example 10 exemplifies mammalian host cell expression systems for monkey
EPO cDNA and human EPO genomic DNA involving CHO cells. It describes the immunological
and biological activities of products of these expression systems as well
as characterisation of such products. In particular, the cells described are
a particular type of CHO DHFR-cell namely the DuX-B11 CHO KI cell line as
described in 1980 by Urlaub et al, PNAS 77:4461. The use of MTX amplification
to enhance EPO production is described at page30, lines 1ff, and the in vitro
and in vivo activities are given at page30, lines 44ff. At page 31 lines 10ff
the patent describes:
"A preliminary attempt was made to characterize recombinant glycoprotein
products from conditioned medium of COS-1 and CHO cell expression of the human
EPO gene in comparison to human urinary EPO isolates using both Western blot
analysis and SDS-PAGE. These studies indicated that the CHO-produced EPO material
had a somewhat higher molecular weight than the COS-1 expression product which,
in turn, was slightly larger than the pooled source human urinary extract.
All products were somewhat heterogeneous. Neuraminidase enzyme treatment to
remove sialic acid resulted in COS-1 and CHO recombinant products of approximately
equal molecular weight which were both nonetheless larger than the resulting
asialo human urinary extract. Endoglycosidase F enzyme (EC 3.2.1) treatment
of the recombinant CHO product and the urinary extract product to totally
remove carbohydrate from both) resulted in substantially homogeneous products
having essentially identical molecular weight characteristics.
Glycoprotein products provided by the present invention are thus comprehensive
of products having a primary structural conformation sufficiently duplicative
of that of a naturally-occurring erythropoietin to allow possession of one
or more of the biological properties thereof and having an average carbohydrate
composition which differs from that of naturally-occurring erythropoietin."
- Example 11 exemplifies synthetic genes encoding human EPO and EPO analogues.
It begins by explaining that it "relates to the total manufacture by
assembly of nucleotide bases of two structural genes encoding the human species
EPO sequence of Table VI" (page 31, lines 26-27). These genes include
a number of preferred codons for expression in E.coli and yeast host cells,
and expression systems based on them. These genes were made without introns
for expression in such cells. The gene for expression in E.coli is referred
to as ECEPO (for E.coli EPO) and the gene for expression in yeast referred
as SCEPO (for S.cerevisiae EPO). The structure of these constructs is given
in Tables VIII to XXI. It is explained at page 38, lines 20ff that "the
manufactured ECEPO gene... may be variously modified to encode erythropoietin
analogues", which it then specifies.
- Example 12 relates to the immunological and biological activity profiles
of "recombinant products of the manufactured ECEPO and SCEPO genes within
the expression systems of Example 11". The in vitro and in vivo assay
values are given at page 45 lines 29ff. Including reference to the "expression
product" in line 38, which is followed in line 39ff:
"In the expression system designed for use of S. cerevisiae host cells;
[the relevant] plasmid was transformed into two different strains...."
- At the conclusion of the Examples, the patent goes on to explain at page
45, lines 54ff:
"It should be readily apparent from consideration of the above illustrative
examples that numerous exceptionally valuable products and processes are provided
by the present invention in its many aspects.
Polypeptides provided by the invention are conspicuously useful materials,
whether they are microbially expressed products or synthetic products, the
primary, secondary or tertiary structural conformation of which was first
made known by the present invention."
- The pharmaceutical and diagnostic values of the invention are then explained,
as are the possibilities of allelic variations of EPO based on the sequences
disclosed in the patent. At page 47, lines 27-28, there is this:
"In addition to naturally-occurring allelic forms of mature EPO, the
present invention also embraces other "EPO products" such as polypeptide
analogues of EPO and fragments of "mature" EPO."
605 goes on at lines 34ff to explain, by way of example, that such analogues
can include deletions of certain amino acid residues or even part of the sequence,
including "having the residues coded for by an entire exon deleted"
(lines36-37) or the deletion of "one or more potential sites for glycosylation"
(lines 38-39). This passage also contains reference to two or three specific
amino acid sequences in EPO (as shown in Table VI) which can be removed without
loss of efficacy and two or three specific substitutions which can similarly
be made.
- At page 47, lines 53ff, the patent points out that:
".the cloned DNA sequences described herein which encode human and
monkey EPO polypeptides are conspicuously valuable for the information which
they provide concerning the amino acid sequence of mammalian erythropoietin
which has heretofore been unavailable despite decades of analytical processing
of isolates of naturally-occurring products."
- At page 48, lines 3ff the patent continues:
"DNA sequences of the invention are also conspicuously suitable materials
for use as labelled probes in isolating EPO and related protein encoding cDNA
and genomic DNA sequences of mammalian species other than human and monkey
species herein specifically illustrated. The extent to which DNA sequences
of the invention will have use in various alternative methods of protein synthesis
(e.g., in insect cells) or in genetic therapy in humans and other mammals
cannot yet be calculated. DNA sequences of the invention are expected to be
useful in developing transgenic mammalian species which may serve as eukaryotic
"hosts" for production of erythropoietin and erythropoietin products in quantity.
See, generally, Palmiter et al., Science, 222 (4625), 809-814 (1983).
Viewed in this light, therefore, the specific disclosures of the illustrative
examples are clearly not intended to be limiting upon the scope of the present
invention and numerous modifications and variations are expected to occur
to those skilled in the art. As one example, while DNA sequences provided
by the illustrative examples include monkey cDNA and genomic DNA sequences,
because this application provides amino acid sequence information essential
to manufacture of DNA sequence, the invention also comprehends such manufactured
DNA sequences as may be constructed based on knowledge of EPO amino acid sequences.
These may code for EPO (as in Example 12) as well as for EPO fragments and
EPO polypeptide analogs (i.e., "EPO Products") which may share one or more
biological properties of naturally-occurring EPO but not share others (or
possess others to different degrees).
In a like manner, while the above examples illustrate the invention of microbial
expression of EPO products in the context of mammalian cell expression of
DNA inserted in a hybrid vector of bacterial plasmid and viral genomic origins,
a wide variety of expression systems are within the contemplation of the invention.
Conspicuously comprehended are expression systems involving vectors of homogeneous
origins applied to a variety of bacterial, yeast and mammalian cells in culture
as well as to expression systems not involving vectors (such as calcium phosphate
transfection of cells). In this regard, it will be understood that expression
of, e.g., monkey origin DNA in monkey host cells in culture and human host
cells in culture, actually constitute instances of "exogenous" DNA expression
inasmuch as the EPO DNA whose high level expression is sought would not have
its origins in the genome of the host. Expression systems of the invention
further contemplate these practices resulting in cytoplasmic formation of
EPO products and accumulation of glycosylated and non-glycosylated EPO products
in host cell cytoplasm or membranes (e.g. accumulation in bacterial periplasmic
spaces) or in culture medium supernatants as above illustrated, or in rather
uncommon systems such as P.aeruginosa expression systems (described in Gray,
et al.. Biotechnology, 2, pp. 161-165 (1984)."
The claims
- As already mentioned, there are 31 claims. For the purpose of these proceedings,
it is necessary to set out over half of them. Claim 1 is in the following
terms:
"1. A DNA sequence for use in securing expression in a prokaryotic
or eukaryotic host cell of a polypeptide product having at least part of the
primary structural confirmation [sic] of that of erythropoietin to allow possession
of the biological property of causing bone marrow cells to increase production
of reticulocytes and red blood cells and to increase hemoglobin [sic] synthesis
or iron uptake, said DNA sequence selected from the group consisting of:
(a) the DNA sequences set out in Tables V and VI or their complementary
strands;
(b) DNA sequences which hybridise under stringent conditions to the protein
coding regions of the DNA sequences defined in (a) or fragments thereof; and
(c) DNA sequences which, but for the degeneracy of the genetic code,
would hybridise to the DNA sequences defined in (a) and (b).
- Claims 2, 3 and 5 to 7 are in these terms:
2. A DNA sequence according to Claim 1 encoding human erythropoietin.
3. A cDNA sequence according to Claim 1 being a monkey species erythropoietin
coding DNA sequence.
5. A genomic DNA sequence according to Claim 1 or 2.
6. A human species erythropoeitin coding DNA sequence according to Claim
5.
7. A DNA sequence according to Claim 6 and including the protein encoding
region set forth in Table VI.
- Claim 19 is in these terms:
19. A recombinant polypeptide having part or all of the primary structural
conformation of human or monkey erythropoietin as set forth in Table VI or
Table V or any allelic variant or derivative thereof possessing the biological
property of causing bone marrow cells to increase production of reticulocytes
and red blood cells to increase hemoglobin synthesis or iron uptake and characterized
by being the product of eukaryotic expression of an exogenous DNA sequence
and which has higher molecular weight by SDS-PAGE from erythropoietin isolated
from urinary sources.
- I turn now to Claims 20 to 23:
20. A glycoprotein polypeptide according to Claim 19 having an average
carbohydrate composition which differs from that of human erythropoietin isolated
from urinary sources.
21. A polypeptide according to Claim 19 or 20 wherein the exogenous sequence
is a cDNA sequence.
22. A polypeptide according to Claim 19 or 20 wherein the exogenous DNA
sequence is a genomic DNA sequence.
23. A polypeptide according to Claim 19 or 20 wherein the exogenous DNA
sequence is carried on an autonomously replicating circular DNA plasmid or
viral vector.
- Claims 26 and 27 are in these terms:
26. A polypeptide product of the expression in a eukaryotic host cell
of a DNA sequence according to any of Claims 1, 2, 3, 5, 6 and 7.
27. A process for production of a polypeptide having at least part of
the primary structural conformation of erythropoietin to allow possession
of the biological property of causing bone marrow cells to increase production
of reticulocytes and red blood cells and to increase hemoglobin synthesis
or iron uptake, which process is characterized by culturing under suitable
nutrient conditions a prokaryotic or eukaryotic host cell transformed or transfected
with a DNA sequence according to any of Claims 1, 2, 3, 5, 6 and 7 in a manner
allowing the host cell to express said polypeptide; and optionally isolating
the desired polypeptide product of the expression of the DNA sequence.
- Finally, I must set out Claims 28 to 31:
28. A process according to Claim 27, characterised by culturing a host
cell of any one of Claims 12 to 16 [which refer back to Claim 1].
29. A process according to Claim 27 or 28 for production of a polypeptide
of any one of Claims 19 to 23 and 26.
30. A pharmaceutical composition comprising a polypeptide produced in accordance
with the process of Claim 27, 28 or 29 and a pharmaceutically acceptable diluent,
adjuvant or carrier.
31. A pharmaceutical composition according to Claim 30, comprising a
polypeptide of any one of Claims 19 to 23 and 26.
The procedural history
- As I have mentioned, the application for the grant of 605, which I shall
call 605A, was filed on 12th December 1984 at the European Patent Office.
In its original form, which I shall call 605B, the patent was granted on 25th
July 1990. It was then subject to opposition proceedings which came before
the Technical Board of Appeal ("the Board") who gave a decision
on, as I have mentioned, 21st November 1994. As is not unusual, some changes
were made between filing and initial grant, and other changes were made as
a result of the arguments before, and the decision of, the Board.
- There are three significant differences between (i) the application for
the grant of 605, namely 605A and/or the patent granted in its original form,
605B, before the hearing before the Board, and (ii) 605 in its present form.
First, there is a paragraph contained in Example 10, which was subsequently
deleted. Then there are two relevant amendments to the Claims.
- The paragraph which was included in Example 10 in 605A and 605B, but was
not followed through into the patent in its present form, namely 605, is to
be found immediately after the first paragraph, and immediately before the
second paragraph, of Example 10 in the passage I have quoted from earlier
in this Judgment. The paragraph in question which was deleted (and which I
shall refer to as "the deleted matter") was on page 65 of 605A (and
on page 29 of 605B). It was in these terms:
"Purified human urinary EPO and a recombinant, CHO cell-purified, EPO
according to the invention were subjected to carbohydrate analysis according
to the procedure of Ledeen, et al. Methods in Enzymology, 83 (Part D), 139-191
(1982) as modified through use of the hydrolysis procedures of Nesser, et
al., Anal.Biochem., 142, 58-67 (1984). Experimentally determined carbohydrate
constitution values (expressed as molar ratios of carbohydrate in the product)
for the urinary isolate were as follows: Hexoses, 1.73; N-acetylglucosamine,
1; N-acetylneuraminic acid, 0.93; Fucose, O; and N-acetylgalactosamine, O.
Corresponding values for the recombinant product (derived from CHO pDSVL-gHuEPO
3-day culture media at 100 nM MTX) were as follows: Hexoses, 15.09; N-acetylglucosamine,
1; N-acetylneuraminic acid, 0.998; Fucose, O; and N-acetylgalactosamine, O.
These findings are consistent with the Western blot and SDS-PAGE analysis
described above."
- The second significant difference is to be found in Claim 3. In 605A, Claim
3 is in these terms:
"A polypeptide according to Claim 1 [which was in fairly similar terms
to Claim 1 of 605] wherein the exogenous DNA sequence is a cDNA sequence."
In 605B Claim 3 was to:
"A cDNA sequence according to Claims 1 [which was in fairly similar
terms to Claim 1 of 605] or 2 [which was a claim to a DNA sequence within
Claim 1 encoding for human EPO]."
- The third significant difference is between 605B and 605. In 605B Claim
20 on page 37 was the equivalent of Claim 19 in 605. While it differed from
Claim 19 in a number of respects, the only relevant feature was that, unlike
Claim 19, it omitted any comparison between recombinant EPO and urinary EPO:
it ended with the reference, also found in Claim 19, to "an exogenous
DNA sequence".
E. CONSTRUCTION ISSUES
General
- There are a number of issues as to the proper interpretation of the Claims
of the 605 patent. In order to deal with them, I need only to focus on Claim
1 and 2 and Claim 19, as the issues all relate to expressions in those three
Claims, albeit that the issues also impinge on many of the other Claims, which
refer directly or indirectly to Claim 1, 2 or Claim 19.
- The scope of any claim of the Patent is to be determined in accordance with
Section 125 of the Patents Act 1977 ("the 1977 Act"). The effect
of Section 125(1) is that an invention is taken to be that specified in the
claim as interpreted by the description and any drawings contained in the
specification. Section 125(3) specifically incorporates the Protocol on the
Interpretation of Article 69 of the European Patent Convention ("the
Protocol"). The effect of the Protocol is that claims in Patents should
be construed neither too strictly nor too loosely. When interpreting a claim,
the court should adopt a middle course between these two extremes, "which
combines a fair protection for the patentee with a reasonable degree of certainty
for third parties".
- While the patent is to be construed through the eyes of a person (or team
of persons) appropriately skilled in the relevant art (or arts), construction
is ultimately a matter for the court - see per Aldous LJ in Lubrizol Corporation
-v- Esso Petroleum Co Ltd [1997] RPC 727 at 738. Expert evidence will often
be of assistance, especially in a case such as the present, where the technology
is relatively new and sophisticated. However, it is important to remember
that, particularly in a fast developing field, such as that in the present
case, the evidence must be judged bearing in mind the passage of time since
the relevant date - in this case over 15 years ago. Where the technology has
developed significantly since the priority date, the meaning of an expression
may have expanded to incorporate a new development, contracted to be limited
to the previous art, or even changed in a significant way. Further, as is
undoubtedly the case here, the knowledge, experience and skill of the expert
witnesses may be considerably greater than that of the notional addressee
. In particular, the notional addressee is deemed to be non-inventive; the
experts in this case were far from satisfying that criterion, albeit in their
skill as opposed to their evidence.
- In Glaverbel SA -v- British Coal Corporation [1995] RPC 255 at 268 to 271,
Staughton LJ set out seven propositions of law which had been agreed between
the parties in that case, and which he considered to be "well founded".
Those propositions were as follows:
1. "The interpretation of a patent... is a question of law",
and therefore the question of construction itself is not a matter for evidence;
2. The court should have regard to the surrounding circumstances at the
date of publication "(or perhaps the priority date)" but only in
so far as those facts would be available to "every skilled addressee";
3. Expert evidence is admissible as to technical terms in the patent,
and "it may be that expert evidence can go somewhat further";
4. Any claim must be construed in the context of the patent as a whole,
but a claim "expressed in clear language... cannot be extended or cut
down by reference to the rest of the specification";
5. The Court adopts "a purposive construction rather than a purely
literal one derived from applying... meticulous verbal analysis" - per
Lord Diplock in Catnic [1982] RPC 183 at 243;
6. Subsequent conduct cannot be relied on;
7. A claim should not be construed by reference to prior material, at
least in order to avoid its effect. In Beloit -v- Valmet [1995] RPC 705 at
720, Jacob J, consistent with this observation, stated his view that Article
69 of the EPC "does not legitimately allow courts to construe claims
using the prior art either to widen them or narrow them".
- As Jacob J said in Minnesota Mining & Manufacturing Co. -v- Plastus
Kreativ A.B. [1997] RPC 737 at 743 (affirmed by the Court of Appeal at [1997]
RPC 747):
"The words are to be construed having regard to the inventor’s purpose
as set out in the rest of his patent. That is why the words "purposive
construction" are apt."
- The Court of Appeal has also given guidance on the correct approach to construction
in Wheatley -v- Drillsafe Ltd [2000] IP&T 1067 at paragraphs 18 to 26,
as applied in American Home Products Corp. -v- Novartis Pharmaceuticals UK
Ltd [2000] IP&T 1308. In Wheatley, Aldous LJ (in what was a dissenting
judgment, but Sedley and Mance LJJ agreed with the principles) explained at
paragraph 22:
"The object of interpretation is to ascertain the intention of the
author, in this case the patentee. This involves examining the words of the
claim through the eyes of a person to whom the specification is directed,
in the context of the specification as a whole."
- In paragraph 23 in Wheatley at [2000] IP&T 1077, Aldous LJ went on to
say that the question of construction is to be judged objectively. He explained
that the approach to construction embodied in Article 69 of the European Patent
Convention ("the EPC") is the same as the approach adopted by Hoffmann
J in Improver Corp. -v- Remington Consumer Products Limited [1990] FSR 181
at 189. As Hoffmann J made clear in that case, his approach is directly derived
from that of Lord Diplock in Catnic [1982] RPC 183. The observation I have
referred to of Lord Diplock in Catnic [1982] RPC 183 at 243 is entirely consistent
with the approach of the English courts towards the construction of charterparties
(where "detailed semantic and syntactical analysis" must "yield
to business common sense" per Lord Diplock in The Antaios [1985] AC 191
at 210D) and leases (see e.g. Basingstoke and Deane B. C. -v- The Host Group
Ltd [1988] 1 WLR 348). Accordingly, when construing a patent, the approach
of the court should not, in my view, normally differ substantially from its
approach when construing any other legal document. Thus the approach of the
court to interpreting technical terms in a patent is the same as in other
legal documents - see Chitty on Contracts (28th Edition) Volume I paragraph
12.041, and Part 3 of Chapter 12 generally.
- It is true that a patent, unlike most documents the court is called upon
to construe, involves taking into account the principle I have mentioned of
"fair protection for the patentee [and] reasonable... certainty for third
parties" (see the Protocol). However, I believe that that is largely
reflected in the well established rule that a patent is to be construed through
the eyes of a person or persons of reasonable skill in the relevant art, who
is assumed to possess the common general knowledge available in his field.
In my view, this is substantially akin to the surrounding circumstances known
to both parties which must be taken into account when construing a commercial
contract (see for instance per Lord Hoffmann in Investors Compensation Scheme
Ltd -v- West Bromwich Building Society [1998] 1 All ER 98). The fact that
a patent, unlike a charter party or a lease, is a unilateral document does
not seem to me of itself to be a relevant point of distinction, given that
it appears that the approach to construction of notices is the same as that
of contracts: see Mannai Investment Co Ltd -v- Eagle Star Life Assurance Co
Ltd [1997] AC 749.
- As a matter of principle, questions of construction of a claim in a patent,
and questions of infringement of that claim are separate. Indeed, there are
obvious dangers in determining issues of construction of the claims of a patent
while having regard to the issues of infringement. At least on the face of
it, what the patent means should not be influenced by the existence or nature
of an alleged infringement. Apart from anything else, the alleged infringement
will normally have arisen some time after the patent has been applied for,
and will therefore be something which occurred after the date by reference
to which the patent is to be construed. However, some issues of construction
in a patent action only arise because of the nature of the alleged infringement,
and sometimes an issue of construction can hardly be understood without reference
to the alleged infringement which gives rise to the issue of construction.
- Furthermore, in many cases there is something of an overlap between construction
and infringement issues. In many infringement actions, where the alleged infringement
is not within the literal wording of a claim, it is now well established that
the court has to ask itself the three questions which Hoffmann J set out in
Improver [1990] FSR 181 at 192, and which were recently cited with approval,
as being in accordance with the Protocol, by Aldous LJ in Wheatley [2000]
IP&T 1067. The reasoning of Hoffmann J was based on the approach of Lord
Diplock in Catnic [1982] RPC 183 and that of Aldous LJ was based on the Protocol.
Accordingly, at least on the face of it, there is a powerful case for saying
that, ultimately, when considering the three questions, the court is really
posing a composite issue of interpretation. This view is supported by Hoffmann
J’s statement in Improver [1990] FSR 181 at 189 that:
"In the end..... the question is always whether the alleged infringement
is covered by the language of the claim."
- It nonetheless remains the case that the three Improver or Protocol questions
are directed to infringement, indeed to a specific alleged infringement -
note the approach of the Court in Improver. At least in this case, it seems
to me that these Improver or Protocol questions, to the extent that it is
necessary to deal with them, are more conveniently considered under infringement,
rather than under construction. It is because of the potential interrelationship
between construction, sufficiency and infringement that I will deal with these
issues in that order before turning to other matters relating to 605.
- Before turning to the specific issues of construction of 605, it is right
to mention that, as is perhaps inevitable, some of the issues of construction
are plainly connected. Thus, the point as to the meanings of "host cell"
and "securing expression" in Claim 1, and the meanings of "recombinant
polypeptide" and "an exogenous DNA sequence" in Claim 19 appear
to have a great deal in common. While it would obviously require an exceptional
case before two connected expressions of the same claim could be given inconsistent
meanings, it would be easier for connected expressions in different claims
to be given inconsistent meanings. Nonetheless, given that all the claims
have to be construed in the context of the patent as a whole, it seems to
me that, in the absence of any good reason to the contrary, one would prefer
to arrive at a conclusion whereby connected expressions in different claims
were given consistent meanings. However, I do not think that is a point of
much weight where the claims are independent of each other or cast very differently
from each other.
Claim 1: Introductory
- There are, or at least there were, four issues of construction relating
to Claim 1. The first is whether the opening words "a DNA sequence"
extends to all DNA sequences, and in particular whether it could extend to
a cDNA sequence coding for human EPO. The second issue is the meaning of "host
cell" and "securing expression". The third issue concerns the
meaning of integer (a). The fourth issue concerns the meaning of "stringent
conditions" in integers (b) and (c). This latter issue is, I think, most
conveniently dealt with when considering insufficiency. Accordingly, I propose
to deal only with the first three issues, as I have identified them, at this
stage.
Claim 1: "A DNA sequence"
- Roche initially contended that, particularly if one can take into account
605A and 605B, and what was said during the hearing before the Board in 1994,
human cDNA is not included within the scope of Claim 1. In support of this,
Mr Simon Thorley QC (who appears with Mr Michael Tappin and Miss Iona Berkeley
for Roche) pointed out in opening to the fact that the focus of the teaching
in 605 is human genomic DNA and monkey cDNA, and that any teaching relating
to human cDNA is conspicuous only by its absence. Further, in light of the
amendments made to 605B before the Board and in particular the amendment to
Claim 3, Mr Thorley argued that, even if Claim 1 on its face, in the context
of 605, appears to extend to human cDNA, it should not be so construed. However,
after further consideration, Mr Thorley abandoned these arguments, albeit
leaving the latter contention open in a higher court.
- For what it is worth, I consider Mr Thorley was right to abandon that point,
at least at first instance. As a matter of ordinary scientific language, a
"DNA sequence" is a sequence of nucleotides which can, as the patent
itself explains, be derived from any source. In particular, unless there was
reason to think that the draftsman of the patent intended a more limited use
of the expression, reference to a DNA sequence includes any genomic DNA and
any cDNA; indeed, it is perfectly apt to include synthetic or natural sequences
(or, indeed, a permutation of the two). To my mind, reading Claim 1 together
with Claim 2 and Claim 3 tends to support this conclusion. Claim 2 specifically
refers to a DNA sequence "encoding human [EPO]" which confirms that
the patent is intended to extend to human EPO (as to which there could, it
is fair to say, be no real doubt anyway). By referring expressly to "a
cDNA sequence" and by referring to Claim 1, it appears to me that Claim
3 serves to underline the fact that Claim 1 is indeed extending to cDNA.
- Further, once one concludes that Claim 1 extends to some cDNA, it is hard
to see how it can be said, as a matter of construction, that human cDNA is
not included. The fact that there is no claim specifically to a cDNA sequence
for human EPO is not, to my mind, sufficient to indicate a contrary result.
- Roche sought to support their case by reference to the apparent finding
of the Board that human cDNA was not enabled by the patent, and that, as a
result, Claim 3 of 605A had to be amended to the form as it presently appears
in 605. At least on the basis of the arguments I have heard, my view is that,
as the law in this country currently stands, when construing a patent, it
is not legitimate to have regard to the arguments raised by or before the
Board in opposition proceedings relating to the grant or amendment of the
patent in question, even though those observations may have led to the patent
being amended.
- First, I do not think that Roche’s argument would have been easily reconcilable
with Section 125 of the 1977 Act. Secondly, Roche’s approach to construction
would lead to inconvenience and expense. If, when construing a patent, one
could take into account what was said on behalf of the patentee at any opposition
proceedings, then, it seems to me, one always would have to take into account
what was said at opposition proceedings. It cannot be a matter of choice.
Accordingly, no patent agent or lawyer could sensibly advise an interested
third party as to the meaning and effect of a European patent without studying
a transcript of the opposition proceedings (if any). Thirdly, I consider that
Roche’s argument would be inconsistent with the recent rejection of the proposal
to amend Article 69 of the EPC to incorporate something along the lines of
what is known in the United States as file wrapper estoppel.
- Fourthly, it appears that authority supports my conclusion. In Glaverbel
[1995] RPC 255, the precise point was not at issue, but at 270 to 271, Staughton
LJ rejected an attempt to rely upon other documents containing statements
by the patentee relating to the alleged invention, although he accepted that,
if the facts warranted it, statements made by the patentee could give rise
to an estoppel. Of more direct relevance is Palmaz’s European Patents (UK)
[1999] RPC 47 at 73, where Pumfrey J referred to the submission that a particular
construction of the patent was "consistent with the representations made
by... the patent attorneys acting for the patentees to the European Patent
Office...", and said that "this is not a legitimate approach to
construction".
- It is true that the point was left open by Jacob J in Bristol Myers Squibb
Limited -v- Baker Norton Limited [1999] RPC 253 at 274, and it appears that
the Netherlands Supreme Court and the Stockholm City Court may well take a
different view (see Ciba Geigy AG -v- Ote Optics BV (13th January 1985), NJ
1995 391 and Spanak Aktiebolag -v- Allround-Smide Aktiebolag (6th May 1997
respectively). However, as Mr Waugh points out, the Hague District Court in
their decision dated 13th March 1993 (upheld by the Netherlands Appeal Court
on 27th January 2000) when considering the validity and meaning of the 605
patent itself, was apparently unimpressed by this argument.
- Indeed, the Dutch decision in the present case seems to me to highlight
another reason why one should, at the very least, be wary of relying on what
was said in objection proceedings before the Board. Although any decision
of the Board on an issue which this court has to decide are worthy of respect
and consideration, it is most certainly not binding on this court, as the
Dutch courts emphasised in their decisions on the 605 patent. In the Netherlands,
both the court at first instance and Appeal Court concluded, contrary to the
opinion of the Board, that human cDNA was within the scope of Claim 1 of 605
in its present form. Quite apart from this, I am not convinced of the factual
basis for the contention advanced by Roche, even if the legal basis existed.
However, as the point is not pursued, it would be inappropriate to delve into
that aspect.
Claim 1: "Host cell" and "securing expression"
- The words "host cell" in Claim 1 have to be construed as part
of the opening part of that Claim, which is:
"A DNA sequence for use in securing expression in a ... host cell of
a polypeptide product having... the structural conformation of [EPO]."
It is common ground that the words "for use in" in the context
of a patent means that the thing in question has to be suitable for the defined
role, in this case securing expression of the appropriate protein in a host
cell: see for instance Bristol Myers [2000] IP&T 908 at 917, where the
Court of Appeal said that "what is suitable is a question of fact, not
one of perception".
- There is no doubt that the teaching of the patent, involving as it does
the insertion, through recombinant DNA technology, of the human EPO gene into
a non-human cell (be it a yeast cell, an E.coli cell, a CHO cell or a COS
cell) results in the cell concerned being a "host cell". That is
because the whole of the gene encoding for human EPO does not naturally exist
in the cell concerned, and therefore the gene which is introduced for the
purpose of ultimately expressing EPO is a stranger to the cell, and the cell
is therefore accurately described as a "host cell".
- Given that the issue of construction centres on the word "host"
in the expression "host cell", the obvious question which arises
is: host to what? Two possible answers are advanced to that question. The
first is that of TKT, namely that the cell must be host to a "DNA sequence"
which encodes EPO or an analogue of EPO. The alternative answer, supported
by Amgen, is that it is a cell which is host to some "DNA sequence",
which is foreign to it, but which need not have any particular characteristics,
save that it is connected with the production of EPO or an analogue of EPO.
- Concentrating on Claim 1 on its own, there is linguistic force in the point
that the "host cell" referred to is a cell which was "host"
to that which is described in the Claim, namely "a DNA sequence",
which is then further defined at the end of the Claim by reference to integers
(a), (b) and (c). Accordingly, Amgen’s argument that it is not limited to
encoding sequences, as non-encoding sequences are included in Tables V and
VI, and hence in integer (a), has considerable attraction and logic.
- However, this interpretation would appear to exclude a cell from being a
"host cell" if it was host to DNA sequences upstream of the whole
sequence disclosed in Table VI (which DNA sequence can be used according to
molecular technology to "switch on" the endogenous encoding sequence).
That is a conclusion which seems rather arbitrary, bearing in mind how the
disclosure in Table VI would have rendered the sequencing of that further
upstream region a relatively simple exercise even as at 1984. These inconsistencies
are avoided if TKT’s more limited construction is adopted.
- I am of the view that a cell is not a "host cell" unless it is
host to exogenous DNA encoding for EPO or its analogue. Such a conclusion
is based in part on the teaching of the 605 patent. The terms "host"
and "host cell" are used consistently to describe cells which have
been transfected with exogenous or foreign DNA (i.e. DNA from outside that
particular cell) which encodes EPO, with a view to securing expression of
EPO in those host cells. That was accepted by Dr Brenner. The Examples contained
in 605 are all concerned with EPO-encoding DNA which has been isolated outside
the cell and inserted into the cell to which it is foreign. Indeed, at the
relevant time, the routine method of production of a recombinant protein was
by cloning the gene encoding the protein and the introduction of that clone
into a self-replicating organism by transfection or transformation. There
was no knowledge of the technique of "switching on" an endogenous
encoding sequence by transfecting the cell with exogenous DNA sequences as
including an artificial promoter.
- Further, in order to fall within Claim 1, a DNA sequence must be one "for
use in securing expression... of a polypeptide...". I accept that it
can be said that strands of nucleotides other than the parts which actually
encode a polypeptide (e.g. a promoter) are instrumental in securing expression.
However, it seems to me that, particularly in the context of the teaching
of 605, the notional addressee would have understood the DNA referred to as
including sequences which actually encode, i.e. which directly express, rather
than only consisting of sequences which indirectly cause or assist the encoding
parts of the gene to express (a point I expand on when considering the meaning
of "exogenous DNA" in connection with Claim 19).
- I believe that the interpretation favoured by TKT is supported by the way
in which integer (b) of Claim 1 is limited to "the protein coding regions"
of the sequences identified in integer (a). The reference to "fragments
thereof" does not take matters any further, in the sense that that must
be a reference to fragments of the encoding regions. It is true that integer
(a) itself extends to the whole sequences of Tables V and VI and therefore
includes non-encoding regions. However, that is because those two specific
sequences have been obtained in full: the centrally relevant regions are clear
from integers (b) and (c). In other words, even in Claim 1 itself the draftsman
is concentrating on the encoding regions of EPO DNA.
- Further, the wider meaning is not even foreshadowed either by the state
of the art at the relevant date or by the contents of the specification. As
I have mentioned, the specification is purely concerned with DNA which includes
the EPO-encoding regions being isolated outside a cell and then introduced
into the DNA inside that cell, the host cell, with a view ultimately to expressing
EPO. The discussion (for instance, at page 48, lines 6 to 10) in the 605 patent
about future possible developments are no more than speculation, albeit informed
speculation. More significantly, I consider that even that passage would not
have been read by the notional reader as referring to the "switching
on" of endogenous DNA. As Dr Brenner accepted, that had not been achieved,
let alone disclosed anywhere, by 1984.
- Accordingly, in order to be a host cell for the purpose of Claim 1, I consider
that the cell must have had introduced into it EPO-encoding genetic material;
which had first been isolated outside the cell. However, I do not consider
that it follows from this that the genetic material so introduced must, as
it were, be foreign material, in the sense of coming from a different species.
Thus, the fact that monkey EPO-encoding DNA is introduced into a monkey cell
would not prevent that cell becoming a host cell for the purpose of Claim
1 even though there is already monkey EPO-encoding DNA present. I reach that
conclusion for two reasons. First, as a matter of ordinary language and concept,
a cell would be a "host" to a substance artificially introduced
into it, even though there is already some of that substance naturally present.
Nothing was said in the evidence which causes me to think that the notional
addressee would think otherwise. Secondly, Example 6 involves introducing
monkey cDNA into a COS cell (which is a monkey cell). It is true that monkey
cDNA does not exist naturally, but it seems to me that it would be perverse
to construe Claim 1 as not capable of extending to monkey genomic DNA in COS
cells, in light of that Example. Further, if one considers the teaching of
the patent more generally, it seems to me that that point is reinforced. Perhaps
the most important passage for this purpose is at page 48, which refers to
"mammalian cells in culture" as being "conspicuously comprehended",
as well as the statement that:
"It will be understood that expression of e.g. monkey origin DNA in
monkey host cells in culture and human host cells in culture actually constitute
instances of "exogenous" DNA expression in as much as the EPO DNA
whose high level expression is sought would not have its origins in the genome
of the host."
- In connection with this latter passage, it seems to me important to bear
in mind that, whatever the correct construction of Claim 1 may appear to be
if one concentrates on the words used in it, the Claim must be construed in
the context of the patent as a whole. If the draftsman has specifically indicated
somewhere in the specification what he means by a particular expression, then
that must clearly be taken into account. In patents, just as in any other
documents, it is open to the parties of the draftsman "to make their
own dictionary" as Romer LJ put it in Re Sassoon [1933] 1 Ch. 858 at
890-891. Of course, the mere fact that the draftsman of a patent indicates
in the specification that a certain thing is "conspicuously comprehended...
within the contemplation of the invention" does not automatically mean
that it is in fact comprehended within a particular claim, or even any claim,
in that patent. Otherwise, one would fall foul of the fourth proposition approved
by Staughton LJ in Glaverbel [1995] RPC 255.
- However, I do not consider that anything in the teaching of the patent assists
Amgen’s contention that "host cell" in Claim 1 can extend to a cell
where it is the native DNA sequence (as opposed to a DNA sequence which had
been artificially introduced into the cell) unless the DNA sequence introduced
into the cell is a DNA sequence within Claim 1 itself, namely a DNA sequence
"selected from the group consisting of" integers (a), (b) and (c)
of the Claim. Not only do I believe that this accords with the natural meaning
of Claim 1, linking as it does "host cell" with "a DNA sequence",
but there is nothing in the teaching of the patent to call that conclusion
into question.
- I should add that this conclusion appears to me to be consistent with my
conclusion as to the meaning of "human cDNA", which I discuss when
considering that expression in the context of the alleged insufficiencies
of Claim 1.
Claim 1: "From the group consisting of"
- On behalf of Roche, Mr Thorley contends that, in order to be within Claim
1, a DNA sequence must be one which falls within one of the three integers,
(a), (b) or (c), and it is not enough if it is a sequence which is merely
part of a sequence falling within an integer. Thus, as I have mentioned, in
Table VI, the patent sets out the coding sequences (i.e. the exons) the intervening
non-coding sequences (i.e. the introns) as well as the DNA upstream of the
5’end of the first exon to the tune of nearly six hundred bases, and the DNA
downstream of the 3’end of the last exon to the tune of some five hundred
bases. Accordingly, if Mr Thorley’s argument is correct, Claim 1(a) would
not extend to a DNA sequence which, for instance, omitted the first three
bases and/or the last three bases shown in Table VI, let alone human cDNA
which would omit all the introns as well as most or all of the upstream DNA
and most or all of the downstream DNA.
- As a matter of pure language and precision, there is obvious force in this
contention. Tables V and VI contain specific DNA sequences, and the natural
language of the closing part of Claim 1 (from "said DNA sequence selected
from...") can be said with force to suggest that the draftsman intended
only those sequences, in whole, or, indeed, complementary strands of the whole
of those sequences, to be within the integer of the Claim. It can also be
said that this proposition is supported by the references to "the protein
coding regions of the DNA sequences defined in (a) and the "fragments
thereof" in Claim 1(b).
- On the other hand, at any rate at first sight, it seems almost absurd to
construe integer (a) of Claim 1 in such a limited way. At least in the absence
of integers (b) and (c), it would mean that the ambit of the Claim, while
precise, was extraordinarily limited so far as the patentee was concerned.
Indeed, in the absence of integers (b) and (c), it would be so limited as
to call into question whether it can possibly be correct, bearing in the mind
the requirement of "a purposive construction".
- In the absence of integers (b) and (c) of Claim 1, I think that it would
have been necessary to strive to give a wider meaning to the Claim than it
naturally bears. However, in light of the inclusion of integers (b) and (c),
I consider that integer (a) should be given the limited meaning for which
Mr Thorley contends. First, as already mentioned, it is the natural meaning,
in light of the words of Claim 1 immediately preceding integer (a). Secondly,
as I have also mentioned, to depart from the natural meaning would involve
implying into integer (a) the sort of additions or modifications that are
expressly contained in integer (b). Thirdly, it appears to me that integer
(b) effectively solves the apparent problem thrown up by the literal construction
of integer (a). Read literally, integer (a) covers the entire sequence of
bases set out in Table VI and the complementary sequence (i.e. A for T and
vice versa and G for C and vice versa). Integer (b) will extend not merely
to any sequence which hybridises in stringent conditions to the exons of the
DNA shown in Table VI (or the complement of those exons) but also to fragments
of those exons. Subject to any question as to the sufficiency of integer (b),
it seems to me that it was plainly intended to extend to those sequences which
would be covered by the wider and non-natural reading of integer (a), urged
on behalf of Amgen, through Mr Anthony Watson QC, Mr Andrew Waugh QC and Mr
Colin Birss.
- Fourthly, it appears to me that if one does not give integer (a) its natural
meaning, but a wider meaning as contended for by Mr Waugh, it is unclear how
wide that meaning should go. Thus, it is unclear whether one should simply
limit it to the exons, or whether one should permit it to extend to some of
the exons. If the answer is simple, then it is hard to understand why the
draftsman of the patent did not make it clear. If the answer is not simple,
then it is self-evidently unsatisfactory because one is faced with uncertainty
as to what to imply. Furthermore, it seems to me to involve a rather odd approach
to construction to hold that one integer of a claim should be interpreted
more widely than its natural meaning, where it is unclear how widely it should
be interpreted, particularly where in the immediately succeeding integer the
draftsman has identified specific criteria by which sequences, related to
those in the first integer, but representing a much wider class than the first
integer, are to be identified. If integer (b) is sufficient, and there is
no other objection to Claim 1, then that would be a satisfactory "purposive"
result. If it turns out that integer (b) is insufficient, then that is no
reason for giving integer (a) an artificially wide meaning. In other words,
although an integer of a claim can, indeed should, properly be construed bearing
in mind another integer of the same claim, it does not seem to me that the
construction of the first integer, should, at least normally, be altered if
it transpires that the second integer is insufficient.
Claim 2
- Amgen contend that the reference in Claim 2 to "a DNA sequence according
to Claim 1" effectively incorporates only the first part of Claim 1,
namely:
"A DNA sequence for use in securing expression in a prokaryotic or
eukaryotic host cell."
Roche argue that the whole of Claim 1 is, as it were, incorporated into
Claim 2.
- Amgen’s contention is that Claim 2 is limited to DNA sequences which encode
human EPO and which are suitable for the stated use. Amgen also argue that
this extends not merely to DNA sequences which do so encode, but also to DNA
sequences which include the whole of such encoding region (e.g. as exons).
In other words, to adopt Roche’s language, Amgen’s case is that "Claim
2 is a narrow claim which is not susceptible to the same attacks (hybridisation,
degeneracy and analogues) as are mounted against Claim 1". Roche, on
the other hand, argued that the whole of Claim 1 is, as it were, incorporated
into Claim 2.
- Claim 2 is not conspicuously well drafted, and, accordingly, it follows
that it is not clear, at least to me, precisely what the draftsman was getting
at. Particularly in those circumstances, it appears to me that the appropriate
approach is to seek to construe Claim 2 strictly literally, and then ask oneself
whether that construction accords with common sense and the Protocol. If it
does, then, as I see it, that construction should be adopted. If it does not,
then one may have to cast one’s eyes a little further.
- There are three components to Claim 2. The first component limits the Claim
to a DNA sequence. There is no problem about that. The second component, "according
to Claim 1" seems to me to incorporate, at least as a matter of simple
language, the whole of Claim 1. The third component "encoding human erythropoeitin"
appears to me to be introducing a factor which is intended to cut down the
wider words of Claim 1. In other words, Claim 2 extends to DNA sequences which
satisfy both of two requirements, namely that they fall within Claim 1 and
that they encode human erythropoeitin.
- As to what is meant by "human erythropoeitin" in Claim 2, there
is a difference between the parties, in that Amgen contends that it is limited
to the protein human erythropoeitin with the amino acid sequence identified
in Table VI of the 605 patent, whereas Roche argue that it extends to any
analogue of that protein, or any allelic variant of that protein, which shows
EPO-like characteristics. On this issue, I am of the view that Amgen’s argument
is correct. The expression "human erythropoeitin" means what it
says, at least on the face of it, and is limited to the amino acid sequence
identified in Table VI. Any other polypeptide which has a very similar sequence
(e.g. a change of a single amino acid residue) and which has the same biological
properties as EPO is not "human erythropoeitin". I draw support
in reaching that conclusion from the reasoning of the Court of Appeal in American
Home Products [2000] IP&T at 1308, where the Court of Appeal held that
the word "rapamycin" in a claim was limited to that particular molecule,
and not any variant thereof. Of course, decisions as to what one word means
in one patent are of very limited assistance as to what another word means
in another patent, but it appears to me that the approach of the Court of
Appeal in that case does provide support for my conclusion here. Furthermore,
there is the contrast between Claim 1, which refers to "a polypeptide
product having at least part of the primary structural confirmation of that
of erythropoeitin to allow possession of [its] biological property..."
with the simple reference to "human erythropoeitin" in Claim 2.
- To support its contrary contention, Roche referred to various references
to erythropoeitin or human erythropoeitin in the specification. It seems to
me that only references to "human erythropoeitin" would even be
capable of being of assistance on this issue. However, the more important
point, as I see it, is that this is not a case where there is real assistance
from the specification as to what is meant by a particular expression in a
claim. The meaning of the claim in question, namely Claim 2, appears to me
to be tolerably clear, particularly when compared with the immediately preceding
Claim, and in light of the fourth proposition in Glaverbel [1995] RPC 255,
I think it would be illegitimate to invoke anything in the specification to
point to a different conclusion, save in exceptional circumstances, e.g. if
the specification actually defined the term "human erythropoeitin"
for the purposes of the patent.
- In these circumstances, I conclude that the qualification effected by Claim
2 to Claim 1 effectively reduces the ambit of Claim 1 to DNA which encodes
the protein whose amino acid sequence is identified in Table VI, and does
not extend to its analogues. I do not think it would be realistic to treat
the definition as so limited that, for instance, it does not apply to the
mature protein (i.e. human erythropoeitin without the leader peptide).
- I turn to the question of the applicability of integers (a) to (c) of Claim
1 into Claim 2. As a matter of language, it seems to me, as I have already
said, that the whole of Claim 1 is incorporated into Claim 2, save in so far
as it is effectively cut out by the closing three words of Claim 2. Accordingly,
those integers would be incorporated into Claim 2, unless, as I have indicated,
it leads to an odd result. So far as integer (a) is concerned, the Table VI
sequence could be incorporated but it would be meaningless surplusage, but
the Table V sequence would not. As to integers (b) and (c), it is conceptually
possible for them to be incorporated into Claim 2. However, standing back
and looking at the matter in a practical way, I have reached the conclusion
that those three integers are not included by incorporation into Claim 2.
It appears to me to be unreal and unnecessary to include integers (b) and
(c) of Claim 1 when it comes to Claim 2, because Claim 2 has already identified
perfectly satisfactorily the DNA sequences which are claimed, namely those
which encode the specific protein, human EPO, i.e. the encoding sequence or
a larger sequence which includes the encoding sequence in such a way that
it actually can effect expression of EPO. The whole "baggage" of
the integers of Claim 1 seems to me to be redundant. The notion that the integers
are redundant can be said to be inconsistent with the natural reading of Claim
2 as I have identified, but that is also met by the fact that, on any view,
a large portion of Claim 1 does not get translated into Claim 2, namely the
reference to analogues of EPO which have the necessary biological function.
Claim 19: Introductory
- There are four issues raised in relation to Claim 19. The first issue is
the meaning of "recombinant polypeptide", the second issue concerns
the meaning of "being the product of eukaryotic expression of an exogenous
DNA sequence". The third and fourth issues relate to the expression "higher
molecular weight by SDS-PAGE" and from EPO isolated from urinary sources,
namely how one assesses whether "has a higher molecular weight by SDS-PAGE",
and the meaning of "[EPO] isolated from urinary sources". I shall
deal with those four issues in turn.
Claim 19: "Recombinant polypeptide"
- While it is common ground that a "recombinant polypeptide" must
be a polypeptide which results from recombinant DNA, TKT contend that it has
a more limited meaning than that for which Amgen argue. On Amgen’s case, a
recombinant polypeptide is a polypeptide which has been produced using any
recombinant DNA technique, including homologous recombination. In particular,
it is said to extend to a case which involves using the cell’s endogenous
encoding DNA which has been "switched on" by an inserted exogenous
construct and promoter inserted upstream of the encoding DNA. On the other
hand, on TKT’s case, it is limited to a polypeptide which is expressed in
cells which have been transformed or transfected with exogenous DNA which
encodes the polypeptide concerned (in this case EPO), and which has been isolated
outside the cell, joined to a vector sequence and transfected into the cell.
- As a matter of straightforward language, one might have thought that, in
order to be described as "recombinant", a polypeptide itself would
have to be combined in some way, but that is obviously not what is meant by
"recombinant polypeptide", and, to that extent at least, the expression
can be said to be a little misleading to the uninitiated. It is clear that
the word "recombinant" in the expression is referential to something
other than the polypeptide: it is a reference to the means by which the polypeptide
was obtained.
- In those circumstances, it appears to me that there is a powerful case for
saying that the natural meaning of "recombinant" when used to describe
a polypeptide is to indicate that the polypeptide has been produced by recombinant
means, or, to put the same point another way, by DNA technology. As is pointed
out on behalf of Amgen, the word "recombinant" derives from the
concept of cleaving (normally at least two strands of) DNA and then ligating
or combining two or more pieces of DNA thereby produced, resulting in sequences
which would not exist in nature. As a matter of ordinary language, it might
be wondered why one can describe a polypeptide as recombinant only if the
DNA which encoded that polypeptide was exogenous to the cell in which the
polypeptide was expressed, and had been isolated outside that cell. If the
polypeptide was expressed at all, or was expressed in artificially high quantities,
as a result of DNA technology involving cleaving and ligating DNA, that might
be thought to be enough to enable it to be described as "recombinant".
- However, I have reached the conclusion that, in the context of this patent,
viewed through the eyes of the appropriately skilled addressee in 1984, the
reference to "a recombinant polypeptide" would have been understood
to have a more limited meaning, namely the product of cells transformed or
transfected with exogenous DNA which encodes the polypeptide. The patent throughout
is concerned with recombinant polypeptides produced by exogenous encoding
DNA. Dr Brenner, Amgen’s witness on this topic, accepted that the term "recombinant
polypeptide" was used in that sense throughout the patent.
- However, it is right to mention that Dr Brenner also stated that he thought
that, even in 1983 or 1984, a polypeptide would have been regarded as recombinant
if it had been expressed in "cells in which there was propagated DNA
made by natural means which encoded the polypeptide". Nonetheless, he
accepted that the more limited meaning of "recombinant polypeptide",
for which TKT contend, was at the time "the main use of this term",
at least in the patent itself.
- The witness who dealt with this issue on behalf of TKT was Professor Proudfoot.
His evidence, which I found impressive on this issue, in that it was logical,
careful and consistent, was based fundamentally on the proposition that recombinant
DNA would have been understood as at 1984 to be DNA which had been isolated
by recombinant technology and then inserted into a cell. Indeed, this was
implicit in a question put to him by Mr Watson and with which he agreed. Mr
Watson described "the basic invention" of 605 as "the isolation
and sequencing of the EPO gene followed by the disclosure of a route to its
expression".
- In addition, it appears to me that the relevant academic or technical dictionaries
support the narrower construction. Thus, the 1997 edition of the Oxford Dictionary
of Biochemistry and Molecular Biology describes "recombinant protein"
as "a protein coded for by a gene... that has been cloned in a system
that supports expression of the gene...". Glick and Pasternak in "Molecular
Biotechnology" (1994) have a glossary in which "recombinant protein"
is defined as "a protein whose amino acid sequence is encoded by a cloned
gene". A very similar definition is to be found in the glossary of "Gene
Cloning: An Introduction" by Brown (1986 and 1995). The fact that some
of these books were published significantly after the priority date is a factor
which should, if anything, assist Amgen’s case because the use of endogenous
coding sequences promoted by exogenous sequences had become pretty well known
by the early 1990s.
- These dictionary definitions are consistent with the evidence of Professor
Proudfoot. Certain other dictionaries were put forward as supporting Amgen’s
construction, but it seems to me that they suffered from the fact that, although
they contained definitions of related expressions (in particular recombinant
DNA), none of them defined "recombinant polypeptide" or "recombinant
protein". Further, on analysis, even the dictionary definitions of recombinant
DNA relied on by Amgen did not assist the contention that it extended to homologous
recombination.
- Of course, the extent to which dictionaries are helpful on a question of
construction is limited. Questions as to the meaning of words in documents
can rarely, if ever, be determined conclusively by reference to dictionaries.
Not only are dictionary definitions inevitably shorn of any relevant context,
but they also represent the view of a particular person who is required to
summarise a definition in a few words. Further, where, as here, the argument
is whether a dictionary definition is too narrow, the conclusion that a wider
meaning is correct does not contradict the dictionary meaning. Also, particularly
in a new and rapidly evolving science, expressions can change their meaning
from time, and can easily have slightly different meanings to different scientists
in the field.
- It is right to mention some references to the allegedly infringing EPO produced
by TKT, which goes under the name of GA-EPO. This is produced by introducing
a targeting construct (made up of various sequences of DNA) into the genome
of the cell upstream of the endogenous coding region of the EPO gene, which
coding region is effectively "switched on" by the introduction of
the targeting construct. The EPO thereby produced would not be a "recombinant
polypeptide" within the meaning of Claim 19 on TKT’s construction, albeit
that it would be on Amgen’s construction. In a report on behalf of HMR (one
of the TKT parties) to the Food and Drug Administration ("FDA")
in the United States, Professor Kagen of Boston University referred to the
EPO thereby produced as "recombinant". GA-EPO is also referred to
by this adjective in an internal HMR document. Indeed, Professor Matsudaira
referred to GA-EPO as "recombinant" in his evidence in this case.
Dr Heartlein described the targeting construct as prepared for "recombination
EPO".
- Particularly when taken together, these references plainly assist the argument
that a polypeptide can be described as "recombinant" even though
it has been expressed by encoding regions of the DNA which are endogenous.
However, while of obvious assistance to Amgen’s case, they are all relatively
recent descriptions (the earliest being, I think, 1996) and are therefore
referable to a time when genetic engineering techniques had advanced significantly
since the filing date. In particular, they were statements made at a time
when techniques had enabled endogenous encoding regions which would not otherwise
be active to be artificially "switched on" by inserting DNA upstream,
techniques which were only dreamed of or hoped for in 1984.
- Drawing the various strands on this issue together, the position seems to
me to be as follows. Standing as at 1984, the appropriately skilled person
might have understood "recombinant polypeptide" to have the wider
meaning for which Amgen contend, but, as at that date, the more natural and
common meaning was the narrower one, as argued for by TKT. The notion that
the narrower meaning is what would have been understood by the notional reader
in the present case is reinforced once one considers that it is not only the
more common meaning, but the meaning which accords with the teaching of the
patent, and the way in which the expression is used elsewhere. On the basis
of the evidence, it seems to me likely that, as the techniques of biotechnology
have expanded over the past fifteen years, the wider meaning of the term "recombinant
polypeptide" has gained greater currency. However, even now, it appears
to me that the narrower, more limited, meaning is one which has considerable
currency, particularly in light of the evidence of Professor Proudfoot and
of the recent editions of the dictionaries.
- In reaching this conclusion, I have considered the meaning of "recombinant
polypeptide" as much in the context of the patent generally as in the
context of Claim 19 itself. If, as I consider to be correct, the meaning of
the term "an exogenous DNA sequence" is limited to encoding sequences
(a point dealt with in the next section of this part of the judgment) then
it tends to reinforce my view that the narrower meaning of "recombinant
polypeptide" is also appropriate. Having said that, it appears to me
that, in the end, the meaning of "recombinant polypeptide" is not
of central importance, if the meaning of "exogenous DNA sequence"
is to be treated as limited to the extent I have indicated. Even if "recombinant
polypeptide" on its own has the wider meaning in Claim 19, the expression
can only refer to a recombinant polypeptide within the narrower meaning if
it is limited to being the product of the expression of exogenous encoding
DNA.
Claim 19: "Expression of an exogenous DNA sequence"
- Although there was a suggestion to the contrary at one time by Amgen, it
appears clear that "expression" refers to the combined process of
transcription (by which mRNA is produced from the DNA) and translation (by
which the protein is produced from the mRNA transcript). In other words, it
means the production of the polypeptide from DNA which must be "exogenous".
It is common ground that, in order to be exogenous, DNA must be foreign to
the cell: in other words, if DNA is exogenous to a cell, the cell is a "host"
to the DNA. The exogenous nature of the DNA is the conceptual complement of
the cell concerned being a host.
- Amgen contend that a polypeptide will be expressed by "an exogenous
DNA sequence", if any part of the sequence responsible for the expression
of the polypeptide (not merely the encoding part, but the promoter or any
other part of the regulatory region) is foreign to the cell in which the expression
takes place. TKT contends that the "exogenous DNA" referred to is
effectively limited to the encoding region, and in any event it must have
been constructed outside the cell, and thereafter introduced into the cell
in which the expression of protein takes place.
- In this connection, it is the encoding regions which are directly responsible
for "expression" in the sense that they are transcribed into mRNA,
which ultimately results in the expression of the protein, whereas the non-encoding
regions enable the encoding regions to effect, or assist them in effecting,
such expression. As a matter of language, one can obviously describe the non-encoding
but enabling regions as being part of the total DNA sequence responsible for
the "expression" of the ultimate "polypeptide product".
Whether one is simply referring to the encoding regions which directly express,
or the whole of the DNA which enables expression to occur, when one refers
to the DNA which "expresses" must depend, in my view, upon the context.
- The fact that Claim 1 appears substantially to be concerned with the encoding
regions does not, to my mind, take matters any further, because, unlike many,
indeed most, of the other claims, Claim 19 does not refer back, either directly
or indirectly, to Claim 1 of 605.
- In my judgment, the contents of the specification, supports the view that
a polypeptide which is the product of "expression of an exogenous DNA
sequence" is a polypeptide which is, as it were, the direct, as opposed
to the indirect, product of such expression. As with the word "host",
the word "exogenous" is used on a number of occasions in the specification
of 605. Thus, at page 48, it is stated that "monkey origin DNA in monkey
host cells in culture and human host cells in culture actually constitute
instances of "exogenous" DNA expression" because "EPO
DNA whose high level expression is sought would not have its origins in the
genome of the host". As I have mentioned, this indicates that "exogenous
DNA" can be from the same species as the host, but, more importantly
in relation to the point at issue, it does indicate that DNA that codes for
the desired protein is introduced into the DNA in the host cell. I believe
this passage to be of particular significance, because the draftsman was there
concerned with emphasising that the teaching of the patent is intended to
extend beyond the specific Examples given on the preceding pages of the 605
patent. Even though he is concerned to indicate that the patent should extend
more widely than its specific teaching might suggest, he does not go so far
as to suggest that it extends to endogenous encoding DNA sequences. As I have
indicated, this is scarcely surprising in light of the fact that this was
unachievable as at the relevant date.
- It is fair to say that there is one passage pointing the other way. On page
2 at lines 65 to 66, when describing recombinant DNA technology, there is
reference to the fact that "selected foreign ("exogenous" or
"heterologous") DNA strands usually including sequences coding for
desired product are prepared...". This could be said to suggest that,
when referring to exogenous DNA, the draftsman of the patent not merely had
in mind the fact that such exogenous DNA was not limited to encoding sequences,
but that it might even not include encoding sequences. However, those words
are in a passage dealing with the technology very generally, and not with
the meaning of "exogenous DNA sequences" in the context of "expression"
in Claim 19. Further, there is no reference to any such exercise being relevant
to the teaching or claims of the 605 patent itself. Quite apart from this,
this passage cuts both ways: it can be said with some force that the patent
should be read as involving the sort of technique that is described as being
"usually" employed.
- I should also refer to another passage on the same page of the patent at
lines 34 to 40, in these terms:
""Promoter" DNA sequences usually "precede" a gene
in a DNA polymer and provide a site for initiation of the transcription into
mRNA. "Regulator" DNA sequences, also usually "upstream"
of... a gene in a given DNA polymer, bind proteins that determine the .. rate
... of transcriptional initiation. ...[T]hese sequences... cooperate to determine
whether the transcription (and eventual expression) of a gene will occur."
This passage suggests that "expression" is "of a gene",
and that the promoter is not part of the gene - i.e. not part of the sequence
which expresses. This approach may also be seen on the same page at lines
25 to 26 where "specific DNA nucleotide sequences (genes)" are said
to be "further "transcribed" into... mRNA".
- It is right to add that the draftsman does not appear to have been entirely
consistent in his use of the word "gene". Thus, on page 24 at lines
45 to 47, there is this:
"In Table VI, the initial continuous DNA sequence designates a top
strand of 620 bases in what is apparently an untranslated sequence immediately
preceding a translated portion of the human EPO gene. More specifically, the
sequence appears to comprise the 5’ end of the gene which leads to a translated
DNA region coding for the first four amino acids.... of a leader sequence..."
It appears to me that this under-scores the point that expressions such
as "gene" can have more than one meaning, albeit within a very limited
boundary. However, the important point on the present issue is that, in accordance
with the language used on page 2 of the patent, it is the encoding regions
which are said to "express".
- During cross examination, it became apparent that the wider construction
of "exogenous DNA sequence" supported by Amgen could lead to a conceptual
or linguistic difficulty. If an exogenous promoter is inserted upstream of
an endogenous coding sequence, thereby activating the coding sequence, it
is not entirely easy to decide whether the protein thereby expressed is the
product (on Amgen’s wider construction) of an exogenous sequence. The sequence
immediately responsible for the expression is endogenous, but if one looks
at the totality of the sequence involved in the production, it also contains
exogenous material. Dr Brenner and Professor Proudfoot, both of whom were
highly experienced and straightforward witnesses, took different views as
to whether scientists practising in this field could have referred to such
DNA as exogenous or not. No such problem arises if the DNA referred to as
" exogenous" in Claim 19 is limited to the coding sequences, because,
whether one judges the matter as at 1984 or today, there does not seem to
be any technique, at any rate referred to in the evidence in this case, whereby
part of the encoding DNA is exogenous and part endogenous.
- It is true that Professor Proudfoot accepted that if, for instance, the
encoding sequences were endogenous, but there was an exogenous promoter and
an exogenous leader sequence, this would involve the creation of a new gene
(not limiting that word to the encoding regions). However, he took the view
that, if part of the gene was exogenous and part endogenous, then it would
be wrong to regard the gene as a whole either as exogenous or as endogenous:
it was in part exogenous and in part endogenous. I do not see any inconsistency
in those views, with which I agree so far as the language of the patent is
concerned. It is true that Dr Brenner had a different opinion on the exogenous
nature of such a gene, but he appeared to me to be saying that one could call
such a hybrid sequence exogenous rather than that it would have been normal
in 1984 to refer to it as such.
Claim 19: "Higher molecular weight by SDS-PAGE"
- The evidence and arguments on the comparison on SDS-PAGE between the performances
of recombinant EPO and urinary EPO ("rEPO" and "uEPO"
respectively) took up quite a substantial proportion of the factual and expert
evidence in this case. It is an area where there is a particular danger of
letting the evidence and argument relating to insufficiency spill over illegitimately
into the area of interpretation. As I have explained, SDS-PAGE involves different
substances migrating along a gel, such that the speed of migration is directly
related to the apparent molecular weight of the substance (not the actual
molecular weight, because the shape and charge of the molecules may also influence
its speed of migration).
- If a substance loaded in a particular gel is homogenous (i.e. all its molecules
have the same apparent molecular weight) then, unless the lane is over-loaded
with the substance or there is some other problem, it will migrate to a narrow
well-defined band. On the other hand, if the substance is heterogeneous, the
band will be wider and fuzzier, because the different molecules of the same
basic substance will have different apparent (and indeed actual) molecular
weight. The molecules of a non-glycosylated protein are almost always homogenous,
and will therefore produce a tight band. However, the molecules of a glycoprotein,
even if produced from a single source (whether naturally or artificially)
will nearly always be heterogeneously glycosylated, and will include a very
large number of different glycoforms. As a result the band produced by a glycoprotein
on SDS-PAGE will normally be fuzzy.
- Roche’s contention is that, in order to give clarity to the closing part
of Claim 19, it must be interpreted as meaning that all glycoforms of rEPO
have a higher molecular weight than all the glycoforms of uEPO. In other words,
on this argument, if one was running the two substances in adjoining columns
on SDS-PAGE, the leading edge of the rEPO band (containing the molecules of
rEPO with the lowest molecular weight) would be behind the trailing edge of
the uEPO (containing the molecules of uEPO with the highest molecular weight).
- I do not accept that construction. To my mind, if the leading edge, the
trailing edge and the centre of intensity on Western blot or RIA, of the uEPO
are respectively each ahead of the leading edge, the trailing edge and the
centre of intensity on Western blot or RIA, of the rEPO, that would be enough
to enable the rEPO to satisfy the requirement of the closing words of Claim
19. Both as a matter of ordinary language, and looking at the patent through
the eyes of the notional addressee, I consider that to be the correct meaning
of the closing part of Claim 19.
- So far as ordinary language is concerned, it seems to me that one has to
bear in mind the following relevant factors. First, the bare (i.e. wholly
deglycosylated) rEPO is presumably (so far as the reader is concerned) identical
to the bare uEPO; secondly, the nature and extent of glycosylation of the
two forms of EPO is multifarious even if expressed in a single type of cell;
thirdly, this results in both types of EPO having a relatively fuzzy band
on SDS-PAGE. Taking these matters together, and the natural meaning of the
closing part of Claim 19 of the 605 patent leads one to the conclusion that,
if one can say that the start, middle and end of one band is plainly ahead
of, respectively, the start, middle and end of another band, then the material
in the latter band moves slower than the material in the former band, and
therefore has a higher apparent molecular weight than that in the former band.
Assuming that each band demonstrates a "molecular weight" in the
singular rather than a band of "molecular weights" in the plural,
then, even though there may be an overlap, one cannot say that one fuzzy band
is equal to the other. One band is ahead of the other and hence has a lower
molecular weight.
- It appears to me that that view is consistent with the evidence. When faced
with neighbouring bands of different materials which clearly overlapped, but
where there was no real doubt that the start, middle and end of one band was
ahead respectively of the start, middle and end of the second band, Professor
Matsudaira said that the former clearly had a lower apparent molecular weight
than the latter. While Professor Cummings expressed himself in slightly different
ways at different points in his evidence, I consider that he took the same
view at least in relation to some of the reported experiments. In so far as
he took a different view, it was not convincing or consistent. Although Professor
Clausen appeared to take the view supported by Roche, I was not convinced
by it, indeed, it was not clear to me that he adhered to it.
- I draw support from a number of the published papers to which I was referred,
and in which results of SDS-PAGE exercises were reported, reproduced and analysed.
Where one band, viewed as a whole, ran ahead of, but by no means completely
clear of, another band, the two bands were treated as performing differentially:
in other words, a detectable difference in performance was regarded as significant,
indeed worthy of published reproduction and report, even though there was
overlap. In such cases, the band which, viewed overall, was slower, did include
some material of lower molecular weight than some of the material in the band
which was overall faster, yet the latter was treated as having a lower molecular
weight.
- Accordingly, both as a matter of ordinary language (particularly once one
notes the technical background), and in light of the way that Claim 19 would
in any event have been understood by a reader apparently skilled in the art,
I do not consider that the "absolutist" construction favoured by
Roche is correct.
- It is said, however, that any construction other than that favoured by Roche
would lead to unacceptable uncertainty. I do not agree. As with virtually
any comparative exercise, there can sometimes be doubts as to whether there
is a significant difference between two specific bands in a gel, but that
of itself cannot be a valid objection to Amgen’s construction. Further, there
are always fields where it is impossible inconvenient or unrealistic to specify
a feature in precise quantitative terms. It is equally inevitable that expressing
something in non-quantitative terms can lead, on occasions, to uncertainties,
difficulties and differences of opinion. Those sorts of "fuzzy edges"
are inevitable in science and technology, and it would be quite unrealistic
to construe a patent which does not, for some reason or another, condescend
to precise quantification, in an unrealistic or unnatural way simply because
it would otherwise result in the odd occasion in which there could be uncertainties
or differences of opinion.
- Thus, I accept that difficulties could arise in a case where the leading
edge of one band runs ahead of the leading edge of another, but the centre
of intensity and the trailing edge of the former runs behind those, respectively,
of the latter. The large number of photocopies and photographs of different
sorts of EPO suggest that this relatively rarely occurs. However, it should
be noted that, even the construction advanced by Roche would not avoid uncertainty:
it is clear, from the conflicting evidence of the undoubted experts on the
topic in this case, that highly qualified persons who are very experienced
in SDS-PAGE can disagree about where it is right to treat a particular glycoprotein
band on SDS-PAGE as starting or ending.
- As I have just mentioned, the evidence included one or two cases where two
types of EPO were run against each other on SDS-PAGE, which resulted in one
band being substantially wider than the other, so that, for instance, although
the leading edge of each band migrated effectively identically, the trailing
edge of the first band was significantly behind the trailing edge of the second
band. In some cases, that may well have been attributable to the fact that
the first band contained substantially more material, and was overloaded.
If that is the cause, then one would simply run the experiment again, without
the overloading of the first column. Sometimes the cause may be the presence
of impurities which are included in the material in the first band for some
reason. If impurities are the cause, then the obvious answer is to improve
the degree of purity of the material in the first band, and run the test again.
- However, sometimes the cause may be that the EPO in the first band is unusually
heterogeneous, and in particular far more heterogeneous than the material
in the second band. In such a case, where there is a marked differential in
the trailing edge between two bands which have effectively identical leading
edges, there is obviously more room for argument that one cannot say that
the first band has a higher apparent molecular weight than the second band.
However, taking the evidence as a whole on this topic, and in particular that
of Professor Matsudaira, who struck me as convincing, I consider that, at
least in most cases where this occurs, the material in the first band would
be regarded as having a higher apparent molecular weight than that in the
second band. This would primarily be because, given that EPO is always heterogeneous,
and therefore will always produce a fuzzy band on SDS-PAGE, the most important
indicator of "the apparent molecular weight" of the material in
a particular band is the centre of the band or, as Professor Matsudaira put
it, the point of greatest intensity within the band. The centre of the band
is not always easy to identify, because, particularly where the trailing edge
fades gradually up the column, the precise location of the centre of the band
is, at least to some extent, a matter of opinion. That is why I am convinced
by the formulation of Professor Matsudaira, namely the point of greatest intensity:
after all, that will be the point where there is greatest concentration of
EPO of a specific molecular weight.
- In these circumstances, it seems to me that, where one is running two materials
against each other on SDS-PAGE, and what appears to be the normal situation
(i.e. the leading edge, the centre, and the trailing edge of one band are
all either substantially the same or all running ahead of their equivalents
on the other band) does not obtain, it must, to some extent, be a question
of judgment as to whether one band can be said to be displaying a higher apparent
molecular weight than the other. In the great majority of such cases, however,
I am of the view that the ordinarily skilled man in the art would have been
able to say with confidence whether one band displayed a higher apparent molecular
weight than the other. It would only be where one band was very diffuse indeed
(not due to overloading, impurity, or some other correctable problem) or where
it was impossible fairly to identify the centre of intensity of one or both
of the bands, that the test would be inconclusive.
- As already mentioned, the result of a large number of SDS-PAGE experiments
were in evidence in the present case. Virtually every experiment of relevance
to the present case was one where, with all due respect to the experts and
counsel who respectively gave evidence and advanced arguments, it appeared
to me tolerably clear whether one band was or was not running ahead of, and
therefore displaying a lower apparent molecular weight than, the other band.
However, it is right to acknowledge that, having reviewed each of the experiments,
there were one or two cases where it would not be possible to draw any safe
conclusion. However, in so far as those results were the subject of oral evidence,
it did appear to me that there was a probability that their unreliability
was due to some correctable factor of the sort that I have mentioned. Accordingly,
even taking into account the fact that there would be occasions where difficulties
could arise in carrying out the exercise indicated by the closing words of
Claim 19, I am quite satisfied that it is nearly always a relatively straight
forward exercise which would rarely lead to any difficulties, and that one
can characterise those difficulties as "puzzles set at the edge of the
Claim" (to quote from General Tire & Rubber Company -v- The Firestone
Tyre & Rubber Company Limited [1972] RPC 457 at 511, line 37).
Claim 19: "Erythropoeitin isolated from urinary sources"
- I turn to the question of the identification or source of the uEPO to which
the draftsman of the 605 patent should be taken as referring at the end of
Claim 19. It is common ground that the urinary source referred to must be
human urine, but the parties differ as to what the extent and the legitimate
method of purification of the uEPO may be. The description in 605 specifically
refers on page 5 to EPO purified from urine by Miyake in J. Biol. Chem. 252(15):5558,
but it also refers to other methods of purification of EPO from human urine
immediately before and immediately after that reference. On page 6 reference
is made to a paper by Yanagawa et al. in J.Biol Chem 259(5):2707, which describes
another method of purifying EPO from urine.
- The first issue between the parties is whether EPO "isolated"
from urinary sources carries with it the requirement that the EPO should be
pure. There was some debate as to whether the notional addressee of 605 would
have understood a requirement that a protein be "isolated" from
certain sources would carry with it the requirement that it should be 100%
pure. The evidence on this issue was not particularly satisfactory, and I
suspect this is largely because words such as "isolated" and "purified"
may depend very much on context for precisely what they mean. Having heard
the evidence of a number of witnesses on the topic, none of whom I suspect
had had to consider the point in any detail before, I incline to the view
that scientists in this field tended to use the word "isolation"
in a relative rather than an absolute sense. In other words, although the
word "isolated" could be used to describe a substance which was
100% pure, the more normal adjective for such a substance is and was "pure",
I believe that the word "isolated" was more frequently used to describe
a substance which had been obtained in higher concentrations than before or
in sufficient concentration for the purpose for which it was required. "Pure"
without qualification would mean 100% pure; "isolated" would not:
thus one might describe a substance as "isolated" to the extent
of being "X% pure".
- Although this is contrary to Amgen’s contention and contrary to what Sir
John Walker said in oral evidence, it seems to me that the clearest support
for this conclusion from the evidence is to be found in the written evidence
in chief of Sir John Walker, where he described a substance "certainly
not... pure and arguably... not... isolated". Further, at page 9 line
51 of the patent there is reference to "isolation and purification"
of polypeptides, which tends to suggest that the draftsman had in mind that
they were different concepts and that isolation comes before purification.
- To my mind, therefore, the reference in Claim 19 to EPO "isolated from
urinary sources", in the normal language of scientists in this field,
would not have been understood to require the EPO to be 100% pure. If one
considers the context in which the word "isolated" is used in Claim
19, I believe that that conclusion is reinforced. What the skilled addressee
would be led to understand from Claim 19, and indeed the teaching of the patent,
is that rEPO has a higher apparent molecular weight than uEPO (see the passage
in Example 10 at page 31 lines 10 to 14). Accordingly, I believe that he would
understood that what the closing words of Claim 19 required of him, was to
isolate EPO from urine in sufficient concentration, or to a sufficient degree
of purity, to be able to carry out a comparison of that EPO with rEPO on SDS-PAGE.
It is clear from the evidence that, for that purpose, the uEPO would not have
to be 100% pure. I see no reason to interpret the closing part of Claim 19
as imposing a greater burden on the skilled addressees seeking to implement
the teaching of the patent, or seeking to discover whether his product infringes,
than that which a reasonable person in the position, and with the knowledge,
of the skilled addressee, would consider necessary.
- Miyake and Yanagawa (both of whose papers are referred to in the specification
of 605) obtained the urine, from which they then isolated EPO, from a number
of different patients, and the urine was then "pooled". On behalf
of Amgen, Mr Watson contends that the EPO isolated from urinary sources referred
to in Claim 19 would be understood by the skilled addressee to be EPO isolated
according to the teaching of Miyake, or alternatively EPO isolated from urine
"of comparable or better purity or activity to that of Miyake".
TKT, through Mr David Kitchin QC (who appears with Mr Richard Meade), argue
that, provided EPO is purified from urine (whether from a single patient or
pooled from many patients), it is within the closing words of Claim 19.
- I prefer the construction advanced by TKT. As Mr Kitchin says, if the draftsman
had intended to refer to one type of method of purification, it would only
have been too easy for him to have done so. Indeed, by referring to the different
papers of Miyake and Yanagawa (and others) in the specification (at pages
5 and 6), he has demonstrated that he knew that he could refer to one or more
of the various methods. In my judgment, the only sensible - indeed the natural
- way of reading the closing words of Claim 19, is as a reference to all uEPO
purified from human urine, at least by any of the methods described in the
description, and irrespective of the source of the urine, and, in particular,
whether from one person or whether pooled from several people.
- This leads me to another issue, namely whether the exercise called for by
the closing words of Claim 19 should be treated as limited to EPO isolated
from urinary sources in accordance with methods taught by the patent (or within
the common general knowledge of the notional addressee as at the priority
date), or whether methods of isolation which were only published (or within
common general knowledge) after the priority date could be taken into account.
As a matter of principle, of course, the patent is to be construed as at the
priority date. On that basis, there is obviously a powerful argument for saying
that EPO isolated from urine in accordance with methods which would not have
been known of as at the priority date are simply irrelevant: they could not
have been within the mind or knowledge of the skilled man as at the date he
has to construe the patent. Further, it would be unsatisfactory if a particular
recombinant EPO appeared to infringe the patent at the date of publication
(because it had a higher molecular weight than uEPO isolated in accordance
with any method known or taught as at the priority date) but it subsequently
appeared not to infringe because it had the same, or a lower, molecular weight
than EPO isolated from urine according to a method published subsequent to
the filing date.
- However, it can be said with some force that the draftsman of the patent
appears to have proceeded on the basis that EPO isolated from urine has, in
effect, a consistent apparent molecular weight, which does not depend upon
the method by which it is isolated. If that assumption turns out to be wrong,
then it may be said that the patentee only has himself to blame. Furthermore,
it can also be said that, by limiting the EPO isolated from urinary sources
to EPO isolated in accordance with particular methods known as at the priority
date, one is effectively rewriting the patent to put right a defect which
the patentee failed to consider: after all, it would have been only too easy
for the patentee to identify the method by which the urinary EPO should be
isolated.
- I have concluded that, despite these points, the reference in Claim 19 to
EPO isolated from urinary sources is to be read as limited to EPO isolated
in accordance with methods mentioned in the 605 patent (and any other methods
which were common general knowledge as at the priority date, albeit that there
is no evidence of any such other methods) although I would not exclude minor
variations or improvements to those methods. It appears to me that such a
construction is more consistent with the principle of combining "a fair
protection for the patentee with a reasonable degree of certainty for third
parties". First, if different methods of isolating EPO from urine can
produce different results, then one can at least minimise the uncertainty
by limiting the methods of isolation to those taught in the patent. Secondly,
as I have said, it appears to be very unsatisfactory that a particular recombinant
EPO could initially appear to infringe, but would subsequently not infringe.
I do not consider that it is helpful, or indeed permissible, in this connection
to take into account the circumstances in which the reference to, and comparison
with, urinary EPO was included in Claim 19 (namely the requirement of the
Board in light of the position it takes on product-by-process claims, a point
I deal with in greater detail below).
F. PRODUCT-BY-PROCESS CLAIMS
General
- Claim 19 and Claim 26 may be characterised as "product-by-process claims".
This is because they claim a product (namely "a recombinant polypeptide..."
and "a polypeptide product..." respectively) which is described
(exclusively in the case of Claim 26) by reference to having been made by
a specific process ("the product of eukaryotic expression..." and
"[product] of the expression in a eukaryotic host cell..." respectively).
They can therefore be contrasted with most of the other Claims (including
Claim 1) which are product claims, or Claims 27, 28 and 29 which are process
claims.
- There is an issue between the parties, which could be characterised as one
of construction or of policy, in relation to Claims 19 and 26, and that issue
appears to me to raise a point of principle in relation to product-by-process
claims generally. Amgen’s position is simple. A claim to a product "produced"
or "obtained" by a particular process is limited to the identified
product in so far as, and only in so far as, it has been produced or obtained
by the identified process. It is not, and cannot as a matter of ordinary language,
be a claim to the product concerned, if it has not been obtained or produced
by the identified process. If that is right, then a recombinant polypeptide
will not fall within Claim 19 unless it has actually been obtained by "eukaryotic
expression of an exogenous DNA sequence" (the words "being the product
of" being equivalent in this connection to "obtained" or "produced"),
and any polypeptide which only satisfies the other requirements of Claim 19
would not be within its scope.
- On behalf of TKT (and indeed on behalf of Roche) Mr Kitchin (supported by
Mr Thorley) argues that Amgen’s contention is incorrect, and that product-by-process
claims, such as Claim 19 and Claim 26, should be interpreted as extending
to the product claimed, whether or not it was produced or obtained by the
identified process. The importance of this point is that, if TKT and Roche
are correct, then, even if the process claimed is novel, a product-by-process
claim will be invalid on grounds of anticipation unless the product itself
is also novel. It may be that the argument advanced by TKT and Roche as to
product-by-process claims is not so much one based on construction, but on
a policy as to the circumstances in which product-by-process claims should
be allowed.
- Whatever the basis on which the contention on behalf of TKT and Roche rests,
I consider that it is wrong. As a matter of principle, application of the
normal rules of interpretation appears to me to require one to construe a
product-by-process claim, just as any other claim, by giving the words of
the claim, read overall in the context of the patent as a whole, their normal
meaning, unless, of course, there is a good reason to the contrary. Indeed,
that is what is statutorily required by Section 125(1) of the 1977 Act. As
a matter of ordinary language, a claim to a product obtained or produced by
a specific process cannot fairly be said to extend to any product other than
one produced or obtained by the particular process. Claim 19 cannot, as a
matter of ordinary language, apply to any polypeptide unless it is "recombinant"
and it is "the product of eukaryotic expression of an exogenous DNA sequence".
To construe such a claim as extending more widely appears to me to fly in
the face of the clear meaning of the words. Further, not only does the argument
advanced by Mr Kitchin, in so far as it is one of construction, involve giving
the words of a claim an unnatural meaning; it involves giving the words an
unnatural meaning with the result that the claim is likely to be invalid,
whereas giving the words their natural meaning will be more likely to render
the claim valid. As was said by Lord Brougham LC in Langston -v- Langston
(1834) 2Cl&Fin 194, "you should lean towards that construction which
preserves, rather than towards that which destroys", which he described
as "a rule of common law and common sense".
- So far as policy is concerned, I can discern no reason in principle or in
practice why a claim to a product made by a certain process could be invalid
simply because the product is not novel, if the process is novel, so that
a claim to the process would be valid. None of the grounds for invalidity
set out in Section 72 of the 1977 Act are specifically prayed in aid on this
issue by TKT or Roche. In my view rightly so; it is difficult to justify their
case simply on that basis. They rely more on decisions of the Board.
- However, before turning to those decisions, it is perhaps not irrelevant
to note that Article 64(2) of the EPC provides:
"If the subject-matter of the European patent is a process, the protection
conferred by the patent shall extend to the products directly obtained by
such process."
This is reflected in terms in the provisions of Section 60(1)(c) of the
1977 Act. As Mr Kitchin rightly points out, these provisions are concerned
with infringements, not with claims. That is particularly relevant in the
context of a system (such as that at the EPO and in some of the EPC signatories,
such as Germany) under which issues of validity and infringement are tried
separately by different courts. Nonetheless, to my mind, Article 64 and Section
60 render it more difficult to contend that a product-by-process claim should
be invalid as a matter of principle, in circumstances where the process is
novel and the claim only purports to extend to products obtained or produced
by the process.
- I now turn to consider the arguments which point to the opposite conclusion.
At least in principle, there could be three such arguments. The first is that,
as a matter of construction, Claims 19 and 26 should in the context of 605,
be construed as TKT contends. The argument is based, on the principle that,
at least in the context of a patent which contains process claims (such as
Claim 27) product-by-process claims (such as Claims 19 and 26) should be given
a different meaning or effect from a process claim. This argument is based
on the proposition that where a draftsman of a document has expressed himself
differently in two places, there is a presumption that he did so because he
intended two different effects. In my judgment, there is nothing in this point,
and, to be fair, I do not understand Mr Kitchin to advance it. First, this
principle of construction is far too weak to justify not giving Claim 19 or
Claim 26 their natural meaning, particularly if, as a result, those Claims
would be at risk of being rendered invalid. Secondly, in the context of a
patent, such as 605, which also contains product claims (such as Claim 1)
this argument is self-defeating, because it simply would mean that a product-by-process
claim instead of being a process claim becomes a product claim, and the problem
thrown up by the principle of interpretation remains, albeit in a slightly
different form.
- Secondly, there is the argument that Article 64 and Section 60(1)(c) of
the 1977 Act only extend protection to process claims to products "directly"
obtained or produced by the process, whereas Claims 19 and 26 contain no such
limitation. I do not think there is anything in that point either, and, again,
I do not understand Mr Kitchin to press it. First, the Article and Section
are concerned with infringement, not claims. Secondly, at least in the context
of Claims 19 and 26, it appears to me that it would be difficult, if not impossible,
to conceive of circumstances where the polypeptide claimed could be anything
other than the direct result of the process referred to in the Claim. Thirdly,
in so far as a product-by-process claim does claim a product which is not
directly obtained or produced from the process, the court may have to consider
whether, in the circumstances of the particular claim, it is phrased too widely
so as to catch products which are not in fact novel or otherwise entitled
to protection, in which case the claim might be bad. However, the mere fact
that, in certain circumstances, a product-by-process claim not limited expressly
or impliedly to products "directly" obtained or produced by the
process could be too wide, does not, as I see it, mean that every product-by-process
claim which does not contain the word "directly" must be invalid.
The decisions of the Board
- The third argument in favour of TKT’s construction, which is really the
way in which Mr Kitchin puts his case, is that there is a consistent line
of decisions from the Board which unambiguously supports TKT’s argument as
to how product-by-process claims should be treated. The approach appears to
originate from a decision in February 1984, T150/82, "Claim Categories/IFF"
OJ EPO 1984, 309, where product-by-process claims were discussed in paragraphs
6 to 11. I must confess to finding the reasons for the decision a little difficult
to follow, but it ultimately appears to me to turn on semantics rather than
substantive considerations. Thus, in paragraph 10, the Board said this:
"Whilst some features of [the] end-effects may be drawn into the definition
of the process for reasons of clarity and of conciseness, the product is in
consequence of the invention, without being the invention itself, which is
rather the novel interaction represented by the process in such cases. Any
attempt to claim the in itself non-inventive product by means of product-by-process
claims is claiming the mere effects instead."
- It is true that, if the product has no novel features of itself, it can
be said to be non-inventive, but, at least as I see it, if it is only such
products as have been made by the inventive process which is claimed, there
can be no objection to the claim, as is supported (albeit only indirectly)
by the provisions of Article 64(2) which, it is fair to say, the Board considered.
- I also note from the decision in T150/82 that the Board identified a difference
of approach to product-by-process claims between the courts of some Member
States (notably Germany) and those of the United Kingdom: see paragraphs 9
and 11. In particular, in the latter paragraph, the Board appeared to accept
that English courts accept product-by-process claims as valid, provided the
process is itself patentable. Although it is, of course, desirable that there
is a common approach to issues such as this in the courts of all signatories
to the EPC, I do not believe that it is the duty of an English court to abandon
what has been the English approach to construction or policy on this issue,
and to adopt what has been the German approach to construction and policy
on this issue, merely because the Board has favoured the latter as opposed
to the former. On the contrary: unless there is a provision in the EPC or
the 1977 Act to the contrary, I believe that, at least sitting at first instance,
it is my duty, in this jurisdiction, to follow what, as the Board accepts,
has been the consistent approach of the English courts - albeit prior to the
1977 Act. This is particularly so if, as I believe to be right, that approach
is in fact consistent with the 1977 Act.
- As I have mentioned, there have been a number of subsequent decisions of
the Board which have reiterated and, indeed, somewhat developed, their approach.
They are T205/83 "Vinyl Ester/Crotonic Acid Copolymers/HOECHST"
OJ EPO 1985, 363 (see paragraphs 3.1 and 3.2), T219/83 "Zeolites/BASF"
OJ EPO 1986 211 (see paragraph 10), T248/85 "Radiation Processing/BICC"
OJ EPO 1986 261 (at paragraph 6), T130/90 "University of Texas/Recombinant
Monoclonal Anti-body" [1996] EPOR 46 at 51-52 and 54-55 and T124/93 "AMOCO/Olefin
Catalyst" [1996] EPOR 624 at 632 (and indeed the decision of the Board
on what was Claim 19 in its original form). They are all decisions of three
member Boards apart from T219/83, where the Board was composed of five members.
- At paragraph 10 of the decision in T219/83, at OJ EPO 1996, at 220, the
Board said this:
"[Product-by-process] claims... have to be interpreted in an absolute
sense, i.e. independently of the process."
If that is not what a product-by-process claim means as a matter of ordinary
language, I cannot agree with that view. I have similar difficulty with an
observation in T248/85 at OJ EPO 1986, at 266, where the Board said this of
the product-by-process claims before them:
"[T]he claims do not define the extent of protection: they define the
matter for which protection is sought."
So they do, but the matter in question is limited by the requirement that
it must be obtained from the novel process. In T124/93 at [1996] EPOR 632,
the Board referred to its previous decisions as establishing that:
"Product-by-process claims give protection for the products as such,
independent from the process by which they were made...." (paragraph
3.5).
As I have indicated, as a matter of natural language, at least if worded
as Claims 19 and 26 in the present case, I do not consider that they do so.
- I am reluctant not to follow the approach of the Board, particularly in
light of the sheer number of consistent decisions on this point. However,
I am not bound by decisions of the Board. Indeed, particularly in light of
Section 125 of the 1977 Act, I am required, in any particular case, to identify
the invention claimed by what is "specified in a claim". As a matter
of ordinary language, I find it impossible to construe a product-by-process
claim, such as Claim 19 or Claim 26 in the present case, "in an absolute
sense" as the Board apparently felt able to do in T219/83 and, in effect,
in the other decisions to which I have referred.
- I should make three further points before passing on from this issue. First,
the guidance in paragraph in 4.7b of Chapter III, The EPO Guidelines for Substantive
Examination is, as one might expect, entirely consistent with the decisions
of the Board on this issue. The first sentence is in these terms:
"Claims for products defined in terms of a process of manufacture are
admissible only if the products as such fulfil the requirements for patentability,
i.e. inter alia that they are new and inventive."
It is not suggested that these guidelines take matters any further, in the
sense that they are not binding on me, and in those circumstances I say no
more about them.
- Secondly, it is right to mention that the decisions of the Board to which
I have referred show that, if two conditions are satisfied, a product-by-process
claim will be admitted. The first, which I have been discussing, is that the
product itself must be novel. The second is that it must be impossible, or
at least difficult satisfactorily, to define the product, and in particular
the way in which the product is novel, other than by means of description
through the process by which it is produced or obtained (see for instance
paragraphs 3.3 and 4.12 in T130/90 at [1996] EPOR 46 at 52 and 55). The fact
that the Board is prepared to admit product-by-process claims, albeit in the
limited circumstances I have described, means that it cannot be said that
product-by-process claims are inherently objectionable as a matter of principle.
Otherwise, the Board would have rejected the product-by-process claim in T130/90
or have required it to be reformulated as a process claim to produce a particular
product. That very possibility of such a simple reformulation suggests, at
least to my mind, that the present approach of the Board is open to question.
- Thirdly, it is to be noted that the Board does not appear to have followed
its own jurisprudence in this very case. Until the hearing before the Board,
Claim 19, as I have mentioned, did not contain the closing words limiting
the Claim to rEPO which had a higher molecular weight by SDS-PAGE than uEPO.
Those words were inserted because, in their absence, Claim 19 would have fallen
foul of the Board’s requirement that, in a product-by-process claim, the product,
as well as the process, had to be novel: without the claimed distinction between
rEPO and uEPO, rEPO would not have appeared, at least on the face of the Claim,
to be novel. On the other hand, the Board did not require Claim 26 to be amended
in this way, or indeed in any other way. As a result, it appears to be a product-by-process
claim which, on my view of the law, would not fail for want of novelty provided
the process is inventive, but should have failed before the Board on grounds
of lack of novelty because, on the Board’s view, the product was not distinguished
on the face of the Claim from naturally occurring product.
G. INSUFFICIENCY AND BREADTH OF CLAIM: THE LAW AND THE ISSUES
Introduction
- By virtue of Section 72(1)(c) of the 1977 Act a patent must be revoked if
it "does not disclose the invention clearly enough and completely enough
for it to be performed by a person skilled in the art". It is fundamental
to the validity of a patent that it not merely discloses a novel product or
process, but that the disclosure is "enabling": in this connection
see Asahi Kasei Kogyo KK’s Application [1991] RPC 485 as explained by Lord
Hoffmann in Biogen Inc. -v- Medeva plc [1997] RPC 1 at 46 to 47, especially
at 46 lines 45 to 50. If the disclosure of a patent falls short of being enabling,
i.e. if it does not satisfy the requirements of Section 72(1)(c), then it
is invalid on grounds of insufficiency. It is convenient to distinguish between
two types of insufficiency, although there can obviously be a degree of overlap
between them, and although they both derive from the same principle. I will
call the two types "classic insufficiency" and "Biogen insufficiency".
Classic insufficiency arises where the teaching of the patent does not support
that which the teaching specifically purports to deliver: in this case, TKT
and Roche contend that Claim 1(a) fails on the ground of classic insufficiency.
A claim suffers from Biogen insufficiency if it is cast more widely than the
teaching of the patent enables: in the present case, even if the teaching
of 605 is enabling so far as the specific EPO sequence identified in Table
VI is concerned, it is said that Claim 1 as a whole is cast too wide because
it is not enabling so far as analogues of EPO are concerned.
- To adopt the expression used by Lord Hoffmann in Biogen [1997] RPC 1 at
50 line 39, a patent is insufficient on either basis if it cannot "deliver
the goods". If the claim is cast more widely than the teaching justifies,
the claim will be Biogen insufficient; if the claim on the face of it appears
to be cast narrowly enough, it may nonetheless be classically insufficient
if the teaching of the specification is not enabling.
- In the present case, as I have said, the various items of teaching in the
specification, and in particular Examples 4, 7 and 10, could be said on their
face to support Claim 1(a). However, in that connection, quite apart from
the other arguments which they raise, Roche and TKT contend that the specification
is classically insufficient on a number of grounds. Over and above that, they
contend that there is no, or very little, teaching so far as analogues of
EPO and of the EPO gene are concerned, as a result of which it is said that
the Claims that extend to those products are Biogen insufficient.
- The issue of classic insufficiency involves consideration of a number of
specific criticisms as to the inadequacy of the teaching of 605 so far as
enablement of most of the Claims is concerned, and those issues turn largely
on the contents of this particular patent and the evidence in relation thereto.
The issues on Biogen insufficiency are potentially more far reaching in the
field of biotechnology patents. I propose to deal with classic insufficiency
first, and then turn to Biogen insufficiency.
- Before doing so, it is convenient briefly to consider the interrelationship
of the two types of insufficiency in a little more detail in the present case.
It is best taken by way of an example. Now that Roche has abandoned its argument
as to the meaning of "a DNA sequence" at the opening of Claim 1,
it is common ground before me that human cDNA is within the scope of the Claim.
One of the points taken by TKT and Roche is that human cDNA is not enabled
by the teaching of 605. Roche and TKT contend that, at least to that extent,
the Claim is insufficient because, in terms of enablement, the teaching of
605 is classically insufficient so far as human cDNA is concerned. Obviously,
that argument has to be resolved on its merits. However, even if that argument
succeeds, the claim to human cDNA could still be valid in light of the reasoning
of Lord Hoffmann in Biogen [1997] RPC 1.
- Accordingly, the interrelationship between the two insufficiency arguments
is rather more complex than might first appear. It is true that the two insufficiency
arguments provide alternative bases upon which TKT and Roche could in principle
rely. Thus, Claim 1(a) may be classically insufficient and Claims 1(b) and
(c) may be Biogen insufficient. On the other hand, at least as I see it, an
argument based on Biogen [1997] RPC 1 may enable Amgen to say that, even if
human cDNA or Claims 1(b) and 1(c) are not classically enabled by the teaching
of the patent, they are nonetheless properly claimed by Claim 1 because of
the reasoning of Lord Hoffmann in Biogen. In that sense, the description of
"Biogen insufficiency" is misleading, or at least insufficient.
One is as much concerned with the permissible breadth of the Claims of the
patent bearing in mind its teaching and contribution.
Classic insufficiency
- In Mentor Corporation -v- Hollister Incorporated [1993] RPC 7 the Court
of Appeal gave guidance as to what constitutes classic insufficiency. At [1993]
RPC 12 lines 3 to 7, Lloyd LJ said this:
"On the one hand the addressee must be able to perform the invention
without any further inventive step on his part. On the other hand it is not
required that he should be able to perform the invention without any trial
or experiment at all, in particular where the subject matter is new or especially
delicate."
- On the same page at lines 50 to 52, he said this:
"In each case sufficiency will... be a question of fact and degree,
depending on the nature of the invention and the other circumstances of the
case."
- At [1993] RPC 13 lines 6 to 24, he cited with approval passages in the judgment
of Buckley LJ in Valensi -v- British Radio Corporation [1973] RPC 337, which
were to this effect:
"[T]he hypothetical addressee is not a person of exceptional skill
and knowledge, ... he is not to be expected to exercise any invention nor
any prolonged research, enquiry or experiment. He must, however, be prepared
to display a reasonable degree of skill and common knowledge of the art in
making trials and to correct obvious errors in the specification if a means
of correcting them can readily be found. ...
Further... it is not only inventive steps that cannot be required of the
addressee. While the addressee must be taken as a person with a will to make
the instructions work, he is not to be called upon to make a prolonged study
of matters which present some initial difficulty: and, in particular, if there
are actual errors in the specification - if the apparatus really will not
work without departing from what is described - then, unless both the existence
of the error and the way to correct it can quickly be discovered by an addressee
of the degree of skill and knowledge which we envisage, the description is
insufficient."
- In another passage in Mentor, at [1993] RPC 14 lines 28 to 45, Lloyd LJ
said this:
"It was at first argued that the skilled man should not have to carry
out any research, enquiry or experiment at all, whether prolonged or otherwise.
But [counsel] subsequently retreated from that extreme position. There is
no support for setting so high a standard of disclosure... When, a little
later, Aldous J came to apply the law to the facts of this case, he refers
to "routine trials" and "normal routine matters that the skilled
man would seek to do and would be able to do". [Counsel] criticises the
use of the word "routine". To require the performance of routine
trials is, he said, to ask too much of the addressee. I do not agree. "Routine"
is just the word I would have chosen myself to describe the sort of trial
and error which has always been regarded as acceptable; and "routine
trials" has the further advantage that it is a positive concept, which
is easily understood and applied. ....If the trials are unusually arduous
or prolonged, they would hardly be described as routine."
- It is to be noted that the Board takes the same view. Thus, in T694/92 Mycogen/Modifying
plant cells [1998] EPOR 114, the Board said this in paragraph 5:
"[T]he guiding principle is always that the skilled person should,
after reading of the description, be able to readily perform the invention
over the whole area claimed without undue burden and without needing inventive
skill."
- The argument as to whether 605 is insufficient on classic grounds gives
rise to three issues which it is convenient to consider at this stage. The
first issue is raised by Mr Thorley who contends on behalf of Roche that,
when considering whether following the teaching of the patent involves an
undue burden or not, one can, indeed one should, take into account the fact
that, in relation to a patent such as this, it is open to the patentee to
deposit with the ATCC a cell line of the relevant cells, as indeed Roche did
in connection with Example 10 of its 678 patent. His argument is that, if
it is open to the patentee in a particular case to deposit a cell line, thereby
enabling the reader to avoid the work which would otherwise be involved in
the preparation of a similar cell line (and in particular transfecting and
amplifying), then the court should, to put it at its lowest, be that much
more ready to conclude that the extra work resulting from the cell line not
having been deposited is more than routine.
- That argument is obviously not without its attractions, but I have come
to the conclusion that it should be rejected. As Mr Thorley rightly accepts,
there is no obligation on a patentee seeking to patent a claim involving cell
technology to deposit a cell line: it is merely an option. Accordingly, in
the absence of good reason to the contrary, it seems to me that the relevance
of the ability to deposit a cell line is merely that the court should not,
as it were, lean over backwards in favour of the patentee when considering
an argument of classic insufficiency, if the patentee could have avoided the
alleged insufficiency by depositing the cell line. However, both principle
and common sense suggest to me that one should go no further than that. So
far as principle is concerned, the guidance given in Mentor [1993] RPC 7 and
in Valensi [1973] RPC 337 lays down the general approach to an allegation
of classic insufficiency. Above all, sufficiency is to be judged by reference
to the nature of the invention and the field in which it represents a contribution
to the art. What constitutes "invention..., prolonged research, enquiry
or experiment", judged in that context, does not seem to me to involve
taking into account the fact that the relevant cell line could have been deposited.
- Quite apart from this, I find it a little difficult to see just how one
would take into account the fact that the cell line could have been deposited
when deciding whether the work involved in following the teaching was "routine"
or not. Take a rather gross example. Suppose the court formed the view, ignoring
the possibility of depositing a cell line, that six months experimentation
was too much, but three months experimentation was not too much, to be routine.
It is then difficult to see why three months should be no longer acceptable,
merely because the patentee could have deposited a cell line. To put the same
point slightly differently, it is hard to identify by how much one would reduce
the three month period to take into account the right to deposit a cell line.
I appreciate that it could be said that this point looks rather stronger when
one puts it in abstract, rather than by reference to specific facts, but I
do not think that it thereby loses its validity.
- The second issue relates to the common general knowledge which is to be
treated as available to the notional addressee. I have already explained the
concept of common general knowledge. The question which has been raised is
whether, as Mr Thorley and Mr Kitchin contend, he is to be treated as limited
to the skill and common general knowledge of the notional addressee, when
deciding whether the work required of him would be more than routine from
his point of view, or whether, as Mr Waugh contends, one is entitled to take
into account the fact that the addressee might consult an individual or a
text book in a different field, in effect to supplement the common general
knowledge which he would otherwise have. I do not think that that question
can be answered in abstract. As a matter of general principle, it appears
to me that the court should be careful before it ascribes to the notional
addressee information outside his common general knowledge, when considering
whether a claim is classically insufficient or not. After all, it may be said,
the whole point of deciding on the identity and qualifications of the notional
addressee, is to enable the court effectively to determine the common general
knowledge which is to be taken into account when determining issues of construction
and sufficiency. Furthermore, if one steps outside the common general knowledge
of the notional addressee, one is entering into a field of uncertainty. For
instance, if he is to be assumed to consult a text book in a neighbouring
field, it may depend upon which text book he consults as to what he is assumed
to have picked up; if he is to consult a colleague, it may depend on where
he is working or who his colleagues are.
- On the other hand, I would have thought that it would be inappropriate to
conclude that, as a matter of absolute principle, once one has assessed the
skill and knowledge to be attributed to the notional addressee, it is impossible
in all circumstances to assume that he would not consult someone else on a
certain point, when trying to implement the teaching of the patent. After
all, a patent is ultimately a document which is intended to have practical,
rather than theoretical, consequences, and its teaching is there for the purpose
of being worked in the commercial and technical world. It seems to me, unrealistic
in those circumstances to require the court to adopt a rigid approach to this
sort of question. For instance, suppose the expert witnesses called by each
side unequivocally agree that, although a certain fact would not be within
the scope of the knowledge of the skilled addressee, it would be obvious to
him (from the teaching of the patent or otherwise) that he should consult
a certain book which would have the information in question (or a certain
class of books all of which had that information). Even if there is no express
reference to the book (or class of books) in the patent, I would have thought
it wrong to proceed on the artificial, indeed erroneous, assumption that the
skilled addressee would not have obtained that information.
- A third question which, to my mind, is also not capable of a generalised
answer, is the extent to which the addressee should be taken to be aware of
the contents of a particular paper or other document specifically referred
to in the specification of the patent in suit. If the paper is referred to
in the specification in connection with a particular aspect of the patent,
then, even though the relevant passage in the paper is not quoted in the patent,
I would have thought that, at least in general, the information identified
in the paper should be treated as being within the knowledge of the addressee
(even if it would not be within his common general knowledge) because he is
effectively given the information, albeit indirectly, in the patent itself.
On the other hand, if the paper is referred to in the patent in connection
with one point, it will not by any means necessarily follow that the addressee
should be treated as being aware of information contained in the paper relating
to another point, which may also be relevant to the teaching of the patent.
The answer must depend upon the facts of the particular case. Sometimes, the
court would not be prepared to conclude that the addressee would pick up the
fact that the paper contained information on one point, if it was referred
to in the patent in connection with a different point, at least in the absence
of cogent expert evidence to that effect. In other cases, the court may be
prepared to conclude that it is obvious, once one appreciates the teaching
of the patent as a whole, the purpose for which the paper is referred to,
and the different information which is available in the paper, that that latter
information should be treated as being available to the addressee.
Biogen insufficiency and breadth of claim: Introductory
- The issues and arguments on Biogen insufficiency in this case highlight
a problem of some general significance in the field of biotechnology patents,
and seem to me to represent a particularly acute problem of balancing "fair
protection for the patentee" with "reasonable ... certainty for
third parties". Dr Lin was the first person to succeed in sequencing
the amino acid residues in EPO and most importantly the encoding regions (i.e.
the exons), the splice sites and the two promoters of the EPO gene. Now that
the obviousness argument has been abandoned, it is common ground that what
he did was inventive, and that, subject to questions of classic insufficiency,
discovery and lack of novelty, Amgen should therefore be entitled to a patent
which extends to such techniques (if any) which the patent enables and which
relate directly to the sequences he revealed - especially that in Table VI
of 605. An important issue between the parties which remains is whether the
disclosure of the patent justifies Amgen including in their claims (i) DNA
sequences falling within Claim 1(b) and/or (c) whose sequences are not revealed
and (ii) polypeptides which fall within Claims 1 and 19. i.e. those with similar
but different sequences from that shown in Tables V and VI, and which possess
the same biological properties as EPO, namely analogues of EPO. There is no
significant teaching as to the sequences of the further DNA claimed in Claims
1(b) and (c) and no teaching how to get them or identify them, and very little
teaching (save on page 47) as to possible analogues of EPO claimed in Claim
19 or as how to get them or identify them.
- In order to deal with the issue, it is necessary to consider in a little
detail three decisions relating to the insufficiency of biochemical patents.
They are Biogen [1997] RPC 1 itself, American Home Products [2000] IP&T
1308 and Chiron Corporation -v- Murex Diagnostics Limited [1996] FSR 153.
I propose to consider the cases in that order, although Chiron, a decision
of the Court of Appeal, was decided about a year before Biogen, a decision
of the House of Lords, and the decision of the Court of Appeal in American
Home Products is the most recent of the three decisions. Each of these cases
provides helpful guidance as to what may constitute insufficiency in the present
case. Indeed, Biogen itself goes further and lays down important principles
(which have been followed in other jurisdictions as well as in England). I
think it is nonetheless important, as with virtually any decisions, to have
in mind the particular facts of each case, when considering the guidance given
by the judgments or speeches.
Biogen insufficiency and breadth of claim: Biogen [1997] RPC1
- In Biogen [1997] RPC 1, the claim was, in effect, to any recombinant method
of making antigens possessed by the hepatitis B virus; there were two types
of antigen, core antigens and surface antigens. Lord Hoffmann started by considering
the extent to which the priority document (known as "Biogen I")
was enabling. He accepted the findings of Aldous J that core and surface antigens
(HBcAg and HBsAg) could be made by the skilled man on the basis of the disclosure
of that priority document, and that it was accordingly enabling to that extent.
What Professor Murray, the inventor, had done, was to use a particular technique
to introduce the DNA coding for the particular polypeptide into a host cell,
in which the DNA had been expressed. Aldous J had held that Professor Murray’s
technique was not obvious at the relevant date, but that the actual result,
namely the synthetic HB virus antigen, was an obvious thing to try to make.
- At [1997] RPC 43 lines 42 to 47, Lord Hoffmann said this:
"The general idea of expressing the gene for a polypeptide displaying
HBV antigen specificity in a suitable host was... fairly widely entertained.
The inventive concept was the notion that Professor Murray’s method of achieving
the goal - creating large fragments of genomic DNA, ligating them to pBR322
and introducing the hybrid molecule into E.coli - would work."
- After referring to a passage in the decision of the Board in T292/85 Genentech
I/Polypeptide Expression [1989] OJ EPO 275, Lord Hoffmann went on to say at
[1997] RPC 48, lines 41 to 48, that the approach in that case involved the
application of:
"[A] principle of patent law which has long been established in the
United Kingdom, namely that the specification must enable the invention to
be performed to the full extent of the monopoly claimed. If the invention
discloses a principle capable of general application, the claims may be in
correspondingly general terms. The patentee need not show that he has proved
its application in every individual instance. On the other hand, if the claims
include a number of discrete methods or products, the patentee must enable
the invention to be performed in respect of each of them" - [1997] RPC
at 48 lines 41 to 49.
- In this important passage, Lord Hoffmann distinguished between two types
of invention, and he then went on to expand on that aspect in these terms
at [1997] RPC at 49 lines 1 to 9:
"Thus if the patentee has hit upon a new product which has a beneficial
effect but cannot demonstrate that there is a common principle by which that
effect will be shared by other products of the same class, he will be entitled
to a patent for that product but not for the class, even though some may subsequently
turn out to have the same beneficial effect..... On the other hand, if he
has disclosed a beneficial property which is common to the class, he will
be entitled to a patent for all products of that class (assuming them to be
new) even though he has not himself made more than one or two of them."
- He then quoted with apparent approval a passage from the decision of the
Board in T409/91 Exxon/Fuel Oils [1994] OJ EPO 653, which included this:
"[T]he claims must be supported by the description, in other words,
it is the definition of the invention in the claims that needs support. In
the Board’s judgment, this requirement reflects the general legal principle
that the extent of the patent monopoly, as defined by the claims, should correspond
to the technical contribution to the art in order for it to be supported or
justified", - [1997] RPC at 49 lines 16 to 22.
- At [1997] RPC 50 lines 36 to 45, Lord Hoffmann said this:
"But the fact that the skilled man following the teaching of Biogen
I would have been able to make HBcAg and HBsAg in bacterial cells, or indeed
in any cells, does not conclude the matter. I think that in concentrating
up on the question of whether Professor Murray’s invention could, so to speak,
deliver the goods across the full width of the patent or priority document,
the courts and the EPO allowed their attention to be diverted from what seems
to me in this particular case the critical issue. It is not whether the claimed
invention could deliver the goods, but whether the claims cover other ways
in which they might be delivered: ways which owe nothing to the teaching of
the patent or any principle which it disclosed."
- At [1997] RPC 51 lines 44 to 50, Lord Hoffmann discussed "the technical
contribution to the art which Professor Murray made in 1978 and disclosed
in Biogen 1". He said that:
"[Professor Murray’s contribution] consisted in showing that despite
the uncertainties which then existed over the DNA of the Dane particle - in
particular, whether it included the antigen genes and whether it had introns
- known recombinant techniques could nevertheless be used to make the antigens
in a prokaryotic host cell."
He then went on to indicate that he was prepared to accept that "the
method was shown to be capable of making both antigens and... that it would
work in any otherwise suitable host cell".
- Having considered the problem which existed before the disclosure of Biogen
I, the nature of Professor Murray’s contribution, and the legal principles,
Lord Hoffmann went on to say this at [1997] RPC 51 line 50 to 52 line 39:
"Does this contribution justify a claim to a monopoly of any recombinant
method of making the antigens. In my view it does not. The claimed invention
is too broad. Its excessive breadth is due, not to the inability of the teaching
to produce all the promised results, but to the fact that the same results
could be produced by different means. Professor Murray had won a brilliant
Napoleonic victory in cutting through the uncertainties which existed in his
day to achieve the desired result. But his success did not in my view establish
any new principle which his successors had to follow if they were to achieve
the same results. The inventive step, as I have said, was the idea of trying
to express unsequenced eukaryotic DNA in a prokaryotic host. Biogen 1 discloses...
the way to do it.... This, if anything, was the original element in what Professor
Murray did. But once the DNA had been sequenced, no one would choose restriction
enzymes on this basis. ...The metaphor use by one of the witnesses was that
before the genome had been sequenced every one was working in the dark. Professor
Murray invented a way of working with the genome in the dark. But he did not
switch on the light and once the light was on his method was no longer needed.
...
It is said that what Professor Murray showed by his invention was that it
could be done. HBV antigens could be produced by expressing Dane particle
DNA in a host cell. Those who followed, even by different routes, could have
greater confidence by reason of his success. I do not think that that is enough
to justify a monopoly of the whole field. I suppose it could be said that
Samuel Morse had shown that electric telegraphy could be done. The Wright
brothers showed that heavier-than-air flight was possible, but that did not
entitle them to a monopoly of heavier-than-air flying machines. It is inevitable,
in a young science like electricity in the 19th century or flying at the turn
of the last century or recombinant DNA technology in the 1970s, that dramatically
new things will be done for the first time. The technical contribution made
in such cases deserves to be recognised. But care is needed not to stifle
further research and healthy competition by allowing the first person who
has found a way of achieving an obviously desirable goal to monopolise every
other way of doing so."
- Finally, I should quote a passage in Lord Hoffmann’s speech at [1997] RPC
53 lines 7 to 14, where he was considering the approach of the Board:
"[I]n arriving at [its] conclusion, the Board directed its attention
solely to the question of whether the teaching in Biogen I would enable the
man skilled in the art to achieve expression of HBsAg as well as HBcAg. Nothing
was said about whether the claims were too broad because expression could
also be achieved without the use of the teaching which it contained, by a
method of which it could not be said, in the words of the Technical Board
in Genentech I, that it was "in a manner which could not have been envisaged
without the invention"."
In a sense, the first sentence in that quotation can be said to be concerned
with classic insufficiency, and the second sentence with Biogen insufficiency.
Biogen insufficiency and breadth of claim: American Home Products [2000]
IP&T 1308
- The patent in American Home Products [2000] IP&T 1308, was concerned
with the molecule rapamycin, which is produced by the bacterium Streptomyces
hygroscopicus. As at the priority date, rapamycin was a known product, whose
detailed molecular structure was also known. Professor Sir Roy Calne discovered
that rapamycin had an immunosuppressive effect, whose mechanism was not known,
but which was particularly valuable in that it inhibited organ or tissue transplant
rejection. As Aldous LJ explained at [2000] IP&T 1310H:
"Because rapamycin was a known product at the priority date, it could
not be patented; neither could its use as a treatment, because that would
offend s. 4(2) of the Patents Act 1977. For those reasons the main claims
of the patent followed the form known as "Swiss type" which is used
to claim an invention for a second medical use."
- The first issue between the parties was whether, as a matter of construction,
the patent was limited to the particular molecule or substance rapamycin,
or whether it extended to all "derivatives thereof which exhibit the
same type of inhibition to organ rejection as rapamycin and which are suitable
for the preparation of a medicament inhibiting organ or tissue transplant
rejection in a mammal" (see at [2000] IP&T 1319a). The second issue
was, if the patent was not limited to rapamycin but extended to all such variants,
it was or would be insufficient. On the issue of construction, the Court of
Appeal held that the patent was limited to rapamycin alone, and in those circumstances
the question of sufficiency did not arise. Nonetheless the court went on to
consider that question. Aldous LJ, at [2000] IP&T 1322j to 1323a identified
"two differences of substance between the parties". The first was
"whether the disclosure has to be sufficient for the full ambit of the
claim to be performed" and the second was the "particularity of
disclosure ... necessary".
- Aldous LJ then said that the first issue had been settled by Biogen [1997] RPC 1, especially at 47 to 49. At [2000] IP&T 1325h, he said this:
"As the judge held, Professor Calne hit upon the new use for rapamycin.
The specification contains an enabling disclosure of that product. Whether
any particular molecule derived from rapamycin would work at all was impossible
to predict with certainty nor how many would have immunosuppressant activity.
Even if a rapamycin derivative were produced which had immunosuppressant activity,
it would be impossible to be certain that it did not exhibit unpredictable
defects. Discovering those defects would need in vivo tests which would take
a long time. As the judge described the claim, it covered all the molecules
which would work, but left it uncertain as to which ones do and how many of
them there are. Such a claim does not reflect a class with a unifying characteristic.
It is a claim to a number of compounds with the number and identity being
left to the skilled person to find out."
- At [2000] IP&T 1326a-b, Aldous LJ continued:
"The invention as described was the discovery that rapamycin had [immunosuppressive]
advantages. Some derivatives would be expected to have similar advantages,
but the skilled person would not be able to predict which ones would have
that actuality and, even if the right one was selected, it would take prolonged
tests to find out whether it had the appropriate qualities. It follows that,
as Lord Hoffmann pointed out in Biogen, the patent, to be sufficient, must
provide an enabling disclosure across the breadth of the claim."
- I should also quote from the judgment of Aldous LJ at [2000] IP&T 1327e-g:
"There is a difference between on the one hand a specification which
requires the skilled person to use his skill and application to perform the
invention and, on the other, a specification which requires the skilled person
to go to the expense and labour of trying to ascertain whether some product
has the required properties. When carrying out the former the skilled person
is trying to perform the invention, whereas the latter requires him to go
further and to carry out research to ascertain how the invention is to be
performed. If the latter is required the specification would appear to be
insufficient.
The patentees wish to construe claim 1 to include derivatives of rapamycin
which exhibit inhibition to organ rejection like rapamycin itself. Thus upon
the patentees’ construction, the specification must teach how to perform the
invention with such derivatives of rapamycin. Upon the judge’s findings of
fact, the specification does not contain that teaching and therefore the patent
would be insufficient, if that were the correct construction of claim 1."
- As in this case, the court was faced with an argument by the patentee that,
if such a narrow conclusion were correct, that biotechnology patent, and indeed
most biotechnology patents, would be effectively valueless. The force of that
point can be seen when one sees the relatively tiny modification to the rapamycin
molecule which resulted in the allegedly infringing product (see at [2000]
IP&T 1314b-f and 1315f-j). However, Aldous LJ said this at 1329e-f:
"I do not agree that a patent limited to the second use of rapamycin
is virtually valueless. The patent protects the second medical use and the
long and expensive work that has been carried out to obtain regulatory approval.
Thus a person who wishes to market a derivative has to make the derivative
and then carry out the long and expensive work needed to get it on the market.
Without the patent, other manufacturers could use the work of the patentees.
In any case, I do not believe that the patent system should be used to enable
a person to monopolise more than that which he has described in sufficient
detail to amount to an enabling disclosure."
It should perhaps be noted that those observations were made in the context
of a finding of fact made at first instance that there was "a strong
probability that other molecules derived from rapamycin would exhibit similar
conformation in those areas which made rapamycin efficacious and would also
exhibit similar immunosuppressant activity" (at [2000] IP&T 1316e).
Biogen insufficiency and breadth of claim: Chiron [1996] FSR 153
- In Chiron [1996] FSR 153, the patent described how particles of virus had
been isolated from a chimpanzee, called Rodney, suffering from a form of hepatitis
known as NANBH and how strands of DNA were cloned, in familiar manner, to
form a cDNA library. It went on to describe how strands of the cloned cDNA
were examined for existence of codons encoding the formation of an antigenic
determinant to bind antibodies already present in individuals who had been
infected with NANBH. Out of a large number of samples, one proved positive
in five out eight tests. The genetic sequence of that cDNA sample was determined
and set out in the patent, together with the 859 amino acid sequence of the
polypeptide thereby encoded. The virus was named HCV.
- Claim 1 of the patent in Chiron claimed:
"A polypeptide... comprising a contiguous sequence of at least 10 amino
acids encoded by the genome of .... HCV and comprising an antigenic determinant
where an HCV is characterised by:
1. A positive stranded RNA genome;
2. Said genome comprising an open reading frame [sc. the exon] encoding
a polyprotein; and
3. Said polyprotein comprising an amino acid sequence having at least
40% homology to the 859 amino acid sequence in Figure 14."
- The Court of Appeal in Chiron had to consider the question of sufficiency
about a year before the decision of the House of Lords in Biogen, but they
did have the benefit of the reasoning of the Court of Appeal in Biogen [1995]
FSR 4, to which they referred, and by which they regarded themselves bound.
At [1996] FSR 181, Morritt LJ said this:
"For the appellants it was submitted that a claim to a class of products
is a claim in respect of more than one invention if the claim does not specify
a novel common feature. If it does not, so it was contended, the individual
members of the class will only be ascertainable by empirical means so that
the invention of one member is not the invention of all the others..... This
was disputed by Chiron. They submit that the test is the much simpler one
they deduce from the decision of this court in Biogen whether in the case
of a product claim the invention of the one product is the invention of the
other or others."
- After considering guidance given by the House of Lords in May & Baker
Limited -v- Boots Pure Drug Co. Limited (1950) 67 RPC 23 (also relied on by
Lord Hoffmann in Biogen), Morritt LJ referred to the Court of Appeal’s decision
in Biogen [1995] FSR 4, and then said this at [1996] FSR 182:
"The analysis of the authorities supports the argument for Chiron.
Further the decision in Biogen is binding on us. However the proposition established
in Biogen by the adoption of the principle expressed by Lord MacDermott in
May & Baker ... provides no yardstick by which to judge whether the invention
of one product is the invention of the other. In that respect it is likely
that when it is found that the invention of the one is also the invention
of the other that part of the test formulated by the appellants which requires
a novel common feature will also be found to have been satisfied. But we do
not consider that the satisfaction of that test is indispensable to the conclusion
that both the products are comprised in one invention for that would be to
impose an unnecessary strait jacket on the ability of the law to adapt to
new circumstances."
With that principle in mind, Morritt LJ then turned to the issue of "whether
individual claims relate to more than one invention".
- At [1996] FSR 183, Morritt LJ turned to the inventive concept. He said this:
"The discovery or inventive concept as found by Aldous J was "the
identification and sequencing of the 5-1-1 clone as the cause of NANBH: in
essence, finding out the specific sequence for HCV"... Claim 1, according
to Aldous J..., is "a claim to a new class of chemicals which relate
to HCV". The appellants dispute this contention by reference to the principle
as formulated by them. They contend that chemicals comprised in the claim
do not comprise a class and will be different both chemically and biologically
from each other. They submit that the claim does not prescribe a formula by
which they may be linked. Chiron claims that the discovery lay in finding
and sequencing the virus and the invention is the chemical which that analysis
has shown to contain the antigenic determinants of the virus to which antibodies
to HCV will bind."
- Morritt LJ then stated that the Court of Appeal adopted Chiron’s approach.
He went on to say this at [1996] FSR 183:
"There is nothing in [Claim 1] as a matter of language or in the specification
as a whole to differentiate between one polypeptide falling within the claim
and any of the millions of others. At the other end of the scale there is
no doubt that it was the finding and sequencing of the Rodney virus genome
which was of the greatest importance for this discovery and analysis enabled
the antigenic determinants to be found in the protein expressed by the sequence.
In view of the fact that an antigenic determinant can only be defined by reference
to the antibody which binds to it and the further fact that the immune response
of an individual produces a whole range of antibodies to any given virus it
is not possible to define antigenic determinants by reference to any common
chemical formula. Thus the invention is the chemical comprising at least 10
amino acids in which there is an antigenic determinant to which an antibody
to HCV will bind. In our view both in substance and in form this is a single
invention properly defined by the common denominator of the existence of an
antigenic determinant of HCV, notwithstanding that the resulting polypeptides
will have divergent characteristics in other respects. The invention of one
is the invention of all of them because that which is common to all is of
the essence of the discovery and that which distinguishes one from another
is irrelevant to that discovery."
- At [1996] FSR 184, he pointed out that:
"A different conclusion was reached in Biogen because the relevant
claim required the polypeptide "to display HBV antigen specificity".
That phrase covered both HBcAg and HBsAg which were different in use and composition
and responded to different antibodies. We do not regard that decision as being
inconsistent with our conclusion in respect of the numbers of inventions comprehended
in claim 1 of the patent in this case."
This indicates that the Court of Appeal’s reasons for finding the claim
in Biogen too wide were a little different from those of the House of Lords.
To that extent, as Roche and TKT argue, the reasoning in Chiron must be approached
with circumspection.
- Importantly, because it can be said to tie in Chiron with what was said
subsequently by Lord Hoffmann in Biogen [1997] RPC 1, Morritt LJ said this
at [1996] FSR 185:
"[W]e are bound by Biogen to consider whether in this case on the facts
the invention can be performed across its whole width. But before doing so
it is useful to consider what is involved in such performance and what the
invention is; the importance of the latter point having been emphasised in
Biogen... First, the performance required is not the production of a commercial
product but rather of a workable prototype. Secondly, the man skilled in the
art is expected to display a reasonable degree of skill and common knowledge
of the art in making trials and to correct obvious errors in the specification...
In this connection it should be noted that it is not disputed that it can
be determined by routine means whether any given polypeptide falls within
claim 1 nor that out of the large number of polypeptides which do fall within
claim 1 any given polypeptide falling within the claim could be made by routine
means."
- Immediately thereafter, at [1996] FSR 185-6, Morritt LJ continued:
"[T]he appellants... contended that the real issue is the extent to
which the patent specification has identified to by one skilled in the art
which polypeptides are claim 1 polypeptides because they have at least one
HCV antigenic determinant.
In our judgment the contention of the appellants is misconceived. As we
have already held in relation to the point of construction claim 1 does not
require the mapping or identification of all the antigenic determinants or
the best of them. ....[The] claim is to a polypeptide comprising an antigenic
determinant encoded by the HCV genome as identified; such a polypeptide can
be defined in the sequence by exposure to an antibody and can be made by routine
methods of molecular biology. The effect of the issue as formulated by the
appellants is to widen the claim from what it is and then to contend that
so widened it is not enabled across its width. In our judgment the issue is
not as the appellants have formulated it. The consequence is that the invention
as actually claimed is capable of being performed by a person skilled in the
art because it is a claim to a polypeptide which can be both made and identified
by routine means. Accordingly, in our judgment claim 1 is not invalid on the
grounds of insufficiency."
The alleged insufficiencies in 605
- A number of different points were advanced on behalf of Roche and/or TKT
as to why at least some of the Claims of 605 are insufficient. When considering
those arguments, I need only consider Claims 1, 19 and 20 (although the points
impinge on virtually all the other Claims). Those arguments are as follows.
The first argument is that, at least without undue burden, no source of human
cDNA was available to work Claim 1. The second contention is that Claim 1
is insufficient owing to the defective nature of some of the Examples. The
third argument is that the 605 patent’s teaching is insufficient in relation
to Claim 1 claiming expression in prokaryotic cells generally (or human cells
in particular). Fourthly, integer (b) and integer (c) of Claim 1 are allegedly
insufficient in light of the requirement of "stringent conditions".
Fifthly, there is a contention of insufficiency so far as the claims to analogues
of EPO in Claim 1 and Claim19 are concerned. Sixthly, there is the alleged
insufficiency of the comparison of recombinant EPO with urinary EPO alleged
against Claim 19. Seventhly, there is an attack on the sufficiency of the
test in Claim 20.
- It appears to me that the first, second, third and fourth allegations of
insufficiency, which relate to Claim 1, the sixth allegation, which relates
to Claim 19, and the seventh allegation, which relates to Claim 20, are essentially
allegations of classic insufficiency. However, it may be that some of those
alleged insufficiencies (particularly the third and, possibly, the first)
could, as it were, be avoided when one considers the permissible breadth of
the claim in light of the guidance given by the House of Lords in Biogen [1997] RPC 1, and the two decisions of the Court of Appeal to which I have referred.
To the extent that it is necessary to consider that aspect of any of the six
allegations of classic insufficiency, I will go on to consider them when I
deal with Biogen insufficiency and breadth of claim.
- As to the fifth allegation of insufficiency, it relates to an issue upon
which there is very brief and limited reference in the 605 patent (at page
47) namely analogues of EPO. It appears to me hard to argue against the proposition
that the teaching of the patent in this connection is classically insufficient,
in the sense that there is no real guidance as to what substitutions and deletions
in relation to the various amino acid residues in EPO, as disclosed in Table
VI, would or might work. Accordingly, I think it right to consider this aspect
under the heading of Biogen insufficiency and breadth of claim.
- An allegation of insufficiency, which I do not need to consider at this
stage at any rate, would arise if I had accepted Amgen’s construction arguments
as to the meaning of "host cell", "recombinant polypeptide"
and "expression of exogenous DNA sequence". In that event, the claims
would, as a matter of construction, have extended to expressing EPO by homologous
recombination (i.e. transfecting with an exogenous DNA targeting construct
sequence a cell with the consequence of "switching on" an endogenous
EPO-encoding DNA sequence). TKT argues that, if any claim of the 605 patent
did extend to that technique, then any such claims would be insufficient.
I shall, in fact, have to consider that argument as a substantially similar
argument when dealing with the issue of TKT’s infringement.
- It is also right to mention that, in the light of my view as to the correct
construction of Claim 2, it raises no additional problem with regard to insufficiency.
The polypeptide coded for in that Claim is a single sequence (subject to the
leader peptide point) namely that shown in Table VI of the 605 patent. There
was no specific argument directed to the sufficiency of Claim 2, possibly
because its relevance only came to light during closing speeches. In my view,
there is no basis for concluding that Claim 2, as interpreted above, is insufficient.
H. CLASSIC INSUFFICIENCY: SOURCES OF HUMAN cDNA
Introduction
- As I have mentioned when considering the technical background, if one is
to obtain a cDNA which encodes a specific protein, one needs a library with
the appropriate DNA before one can probe for the mRNA which it encodes. Accordingly,
if the skilled addressee is to obtain cDNA which encodes a specific protein,
he has to make or find a DNA library which he can be tolerably confident will
contain the specific mRNA for which he is searching.
- Roche’s case is that if Claim 1 extends to human cDNA, then the patent is
insufficient in its teaching in that connection because it does not teach
or otherwise enable (e.g. through the medium of a deposited cell line) the
notional reader to obtain a source of human cDNA, at least without undue effort.
Amgen suggests that the reader would have appreciated that there were three
different sources from which he could have obtained cDNA as at the priority
date or the date of filing. The three types of source are tissues, cell expression,
and gene synthesis. I shall consider those various suggested sources in turn.
- The issue has an air of unreality about it in the sense that human cDNA
is not identified specifically in the 605 patent. As Mr Waugh says, the patent
is ultimately concerned only with sufficient encoding and other sequences
to enable EPO to be expressed by recombinant means. However, there is an argument
as to what human cDNA actually is. There is no doubt that it includes the
five directly encoding sequences, and that it excludes the intervening four
introns. However, Roche contend that it includes the whole of the upstream
(non-encoding) sequence from the cap and the downstream (non-encoding) sequence
to the poly A tail. Like so many terms in this field, it seems to me that
"cDNA" can have more than one meaning. It appears to me that in
some contexts, Roche’s definition (referred to for convenience as "full
length cDNA") would be appropriate as Dr Fritsch and Professor Brammar
said. On other occasions it can mean something much shorter. As Professor
Brammar accepted, "A cDNA clone can indeed be very short and still be
called a cDNA clone". Professor Wall had the same view.
- In my judgment, the human cDNA which the reader of the 605 patent would
have in mind would be a human cDNA sequence which would "deliver the
goods". One is not here concerned with abstract concepts but with an
exercise with a practical commercial and/or therapeutic aim. Accordingly,
what the reader would understand is that he needed "a cDNA suitable for
expression", "a full length coding sequence with an ATG with some
means of getting translation" (to quote Professor Brammar). If there
is "no technical reason" for including the upstream or downstream
sequences, as Professor Wall said, then they would not be regarded by the
reader as being necessary. Professor Brammar accepted that "what one
is interested with [sic] is essentially the coding sequence". As Professor
Wall said, "the other elements... necessary in order to express the protein
in a cell... [such as the Kozak box] could be added synthetically or by using...
standard recombinant DNA techniques". This is consistent with the view
of Roche at the time: they recorded that Dr Lin had "disclosed the full
sequence of human cDNA". Dr Fritsch had the same view. Indeed, Roche’s
admission as to the nature of their allegedly infringing product identifies
it as expressed through a cDNA sequence which effectively is the encoding
sequence of the EPO gene. I also rely on the evidence in relation to the so-called
Hu-13 clone discussed in the next section but one of this judgment.
Human tissue
- So far as tissue sources are concerned, although they relied primarily on
the evidence, Roche point to what is said in the 605 patent itself at page
6 line 58 to page 7 line 2. After referring to the fact that previous efforts
to isolate DNA sequences encoding for EPO have failed, the patent says this:
"This is due principally to the scarcity of tissue sources, especially
human tissue sources, enriched in mRNA such as would allow for construction
of a cDNA library from which a DNA sequence coding for erythropoeitin might
be isolated by conventional techniques."
- On the face of it, that passage, read on its own, does support Roche’s suggestion.
However, that passage, like any other part of the patent, cannot be read on
its own: it must be read in the context of the patent as a whole, and in particular
in its immediate context. If one reads the remaining part of the paragraph
in which that passage is found, one sees that reference is made to difficulties
arising from the fact that, until the disclosure of 605, the genetic sequence
of the EPO gene was unknown, and there was only limited assistance to be got
from Sue and others (who had identified, albeit not wholly accurately or completely,
the first 27 amino acids of EPO, which were rather degenerate), and that the
"genetic material coding for human erythropoeitin is likely to constitute
less than 0.0005% of total human genomic DNA". Professor Wall said in
his evidence that the position became rather different with the disclosure
of the 605 patent itself, which clearly enabled long and reliable probes,
indeed probes consisting of the whole of the encoding sequence, to be prepared.
Mr Thorley suggests that Professor Wall retreated from that view, but I did
not understand him to have done so. What he did accept, quite correctly, was
that there was no teaching in the patent as to an appropriate source for constructing
a cDNA library, which is why, of course, Amgen have to rely upon common general
knowledge.
- I incline to the view that, as a matter of language, even taken in its context,
the passage relied on by Roche does mean that the absence of a source of human
cDNA is a problem. The subsequent passage seems to me to identify additional
problems rather than connected problems. However, I accept that the point
is not clear. In any event, I do not think the point need be decided. The
issue to be determined is ultimately not what the patent suggests, but what
was revealed by the patent itself or what was common general knowledge. The
only tissue source revealed in the specification of 605 is the human kidney,
but it is accepted by Amgen that this would not be a practical source. Amgen’s
contention is that human foetal liver was a suitable source of cDNA for a
person seeking to probe for the EPO gene.
- Roche contend that the foetal liver source would not have been within the
common general knowledge as at the priority date. Roche also contend that,
even if foetal liver as a source of a cDNA library would have been known to
the notional reader, it would not have produced enough EPO mRNA for a cDNA
library to contain detectable amounts of cDNA encoding EPO. I shall first
consider the evidence relied on by Amgen to support its contention that the
human foetal liver as an appropriate source for cDNA would have been within
the common general knowledge.
- First, Amgen rely on the Lawn Library, which was of course a genomic DNA
library. It was referred to in the specification of the 605 patent, and, indeed,
in the Maniatis Manual (accepted to be common general knowledge). It was constructed
from foetal liver cells. Indeed, it appears to me from the evidence that the
foetal liver was a reasonably well established source of genetic material
for various studies. The article by Lawn (cited at page 4 line 10 of the specification)
expressly refers in more than one place to the fact that his library was prepared
from human foetal liver sources.
- Secondly, there is the evidence of what those actually working in this field
were thinking at the time. In an internal paper confidential to GI (one of
the Roche parties in this litigation) and written in August 1982 in connection
with GI’s research to seek to clone the EPO gene, Dr Fritsch wrote:
"The cloned DNA sequences to be screened by these oligonucleotides
could consist of either a cDNA library of mRNA from foetal liver cells (the
liver is the major organ which produces EPO in the foetus) or the human genomic
DNA library" (emphasis added).
In his evidence Dr Fritsch described the foetal liver as "the favourable
tissue" and "certainly a place to look", but he did not accept
that, as at 1984, it was known to be the "correct place".
- Professor Orkin of Harvard University, whose team, it may be remembered,
was embarking on the same exercise at around the same time said in his unchallenged
witness statement that he had "looked at human foetal liver tissue which
was believed to be an enriched source of EPO mRNA". However, he also
said that he and his team "did not know whether or not the human foetal
liver was an appropriate source" for mRNA encoding for EPO.
- Thirdly, by the priority date, there were a number of different publications
which disclosed the same information. Two text books, one published in the
United Kingdom and the other in the United States, support the proposition,
namely Hardisty & Weatherall on "Blood and its Disorders" (Second
Edition 1982), and Wintrobe & others "Clinical Hematology" (1981)
respectively. In the former text book, at page 121, various papers are referred
to and are said to "indicate that the major source of erythropoeitin
in foetal life is the liver and not the kidney". The latter text book
states that "the liver... appears to be the major site of erythropoeitin
production during fetal and neo natal development". The same view was
being expressed in review articles at the time. Thus in a "Mini Review"
on "Control of Erythropoeitin Production" in (1983) Proc Soc Exp.
Biol and Med at 173, 289, Dr James Fisher set out to "summarise the present
state of knowledge of the many... factors which may play a role in the control
of erythropoeitin production". At 296, he said that "the liver has
been demonstrated... to be the primary site of production of erythropoeitin
in the foetus ...". To the same effect, are articles by Thomas &
others, in Brit J of Obs and Gyn, 90 at 795 in the same year, and by Testa
and others, in Haematologica 67(1):64 in 1981.
- I was also shown a number of papers which had been published by the priority
date. Thus, Congote et al. in 1977 had published a paper entitled "Regulation
of Fetal Liver Erythropoiesis" in J. Steroid. Biochem. 8:423, whose abstract
began with the words "The liver is the main erythropoietic tissue of
the human fetus at mid term". Two papers by Zanjani et al. had described
the liver as the "primary" or "major" site of EPO "formation"
or "production" in the foetus: see J. Lab. Clin. Med. 89:640 (1977)
and J. Clin. Invest. 67:1183 (1981).
- In a paper published as one of the "Letters to Nature", in Nature,
and received in December 1984, thirteen scientists working for GI including
Dr Jacobs, Dr Miyake (who had isolated very small amounts of EPO from urine,
as mentioned in the patent) and Dr Fritsch (who gave evidence) reported on
"Isolation and Characterisation of Genomic and cDNA Clones of Human Erythropoeitin".
At the beginning of the paper ("Jacobs"), the authors mentioned
that EPO was "produced in... the liver of fetal or neo-natal mammals",
citing in support two papers, one of which was one of the Zanjani papers.
Jacobs also referred to Congote to support its statement that EPO was "released
from... human fetal liver".
- I have reached the conclusion, despite this evidence, that, as at 1984,
human foetal liver was a source of human cDNA was not within common general
knowledge. I accept that a number of people who would have been interested
in the disclosure and teaching of the 605 patent would have known that the
foetal liver was probably the most promising place to look for such DNA. However,
in the first place, in accordance with the oral evidence of Dr Fritsch and
the written evidence of Professor Orkin (whose evidence was not challenged
in cross examination) it appears to me that it was more a question of the
foetal liver being a promising place to look, as opposed to being a source
in which one could have confidence. Secondly, I am not satisfied on the evidence
that the notional addressee with the appropriate level of knowledge and skill
(not the highest or the lowest common denominator, but somewhere around the
mean) would have been aware of the fact that a foetal liver was even a promising
place to look. There was no evidence that either of the two text books was
known to the notional reader of the 605 patent. Indeed, the only evidence
about them was that of Dr Fritsch who had not heard of Wintrobe. None of the
papers to which I have been referred were, if I may put it this way, self-evidently
part of the common general knowledge. None of the articles (other than Jacobs)
were in journals read by ordinary molecular biologists; indeed, Professor
Wall said that he had no knowledge about whether they would have been known
to the skilled person in 1984. It appears that they were put before the court
as a result of one of Amgen’s advisers reading Jacobs, in which those papers
were cited, directly or indirectly.
- Further, none of these papers could be said to be conclusive in showing
that the EPO gene was expressed in the foetal liver. As Dr Fritsch said in
cross-examination, even if the papers showed or strongly suggested that EPO
was present in the foetal liver, that did not mean that it was being synthesised
from EPO mRNA in the liver: it could have been produced elsewhere, and activated
in the foetal liver. Indeed, there were papers published in or before 1984
which specifically suggested this possibility was correct (for instance Fyhrquist
et al. in a Letter to Nature published in April 1984 in Nature 308:649).
- The fact that there was reference in certain text books to the foetal liver
as being a source of EPO does not cause me to change my view. The mere fact
that the two text books I have mentioned contained such references does not
of itself necessarily establish that the contents were common general knowledge
even to haematologists. Indeed, for what it is worth, Dr Winearls, a nephrologist
who gave written evidence about the management of severely anaemic patients
before and after the ability to treat such patients with recombinant EPO,
did not suggest that the foetal liver was a source of EPO DNA known to him.
- I also draw assistance from an article published in 1986 by eight scientists
working for Amgen in the Cold Spring Harbor Symposia on Quantitative Biology
("Cold Spring Harbor") Volume 51, page 693, in which they said this:
"Isolation of a gene for human EPO proved to be particularly problematical
because there was no known source of mRNA. No cell lines had been characterised
that produced significant amounts of EPO that could provide enriched sources
of mRNA."
These scientists then went on to refer to the article by Fyhrquist (op.
cit.) as indicating that the mere fact that EPO was present in the human kidney
did not mean that the encoding DNA or mRNA was present in the human kidney.
This appears to be consistent with Dr Fritsch’s evidence that the mere fact
that EPO was or might have been known to be found in the foetal liver does
not mean that the EPO mRNA was in that organ.
- I am less impressed by Roche’s alternative argument that, even if the notional
addressee of 605 should be treated as having known of foetal liver as a source
of EPO mRNA for a cDNA library, it would not have contained detectable amounts
of EPO cDNA, as Dr Fritsch suggested in his evidence. It is true that EPO
is, and was known to be, a rare protein with correspondingly small, even tiny,
quantities of mRNA. However, I think that, on this aspect of human tissue
as a source of coding mRNA, Roche’s case, and indeed, at least to an extent,
Dr Fritsch’s evidence, involved a degree of magnifying what might have been
seen as a small potential problem into something which appeared to be, but
was not really, substantial.
- Although it was accepted by Dr Fritsch that foetal liver did not require
as low an oxygen level as an adult kidney to express EPO, he suggested that
there would be concerns about the degree of hypoxicity necessary, and that
this would depend upon the precise physiological conditions in the particular
foetus. Secondly, he suggested that the foetal liver might only be producing
EPO at certain stages of foetal growth. Thirdly, he suggested it was possible
that the foetal EPO gene was different from the human EPO gene.
- There was little, if anything, other than what was said by Dr Fritsch, in
the way of evidence to support the contention that any of these matters would
have been of concern to the notional addressee of the 605 patent, or, indeed,
that any such concerns would have been justified. For instance, there is nothing
to suggest that EPO was expressed in the liver of foetuses only for certain
periods of development, and no reason was put forward as to why that might
be so. The reason that the evidence concentrated on livers of foetuses which
were approximately 20 weeks old is obvious: the larger the liver, the better
the prospect of getting many cells in which EPO was expressed, but foetuses
more than 20 weeks old are rare, for moral and legal reasons.
- In relation to both aspects of alleged insufficiency in connection with
human tissue, Mr Thorley placed some reliance on what was done by the research
team at GI, who were engaged on the same exercise as Dr Lin. I am not convinced
that that is of a great deal of assistance on either aspect of alleged insufficiency.
The fact that one particular person did something, did not do something, found
something easy, or did not find it easy, can, of course, be of some potential
value when the court is called on to consider what the notional skilled man
might have done, and how easy he might have found it. However, the problem
with this sort of evidence is that it simply shows that a particular person
took a certain amount of time and a certain amount of effort, as a result
of which he got or did not get a particular result. If, as in the present
case, the evidence is put forward to suggest that what was involved was a
long and uncertain task, one can either take that at face value, or one can
analyse how, if one omits the wrong turnings and dead-ends, the ultimate result
could have been attained (if it was not achieved) or how it could have been
attained much more quickly (if it was eventually attained). That would then
lead to arguments as to whether the person who actually carried out the work
was unlucky, incompetent, or exaggerating his difficulties, and as to whether
the analysis which shows that he could have achieved his end much more quickly
is merely based on wisdom of hindsight. That sort of argument then brings
one straight back to the issue which the court would have to determine anyway.
Over and above this, difficulties encountered in the past may be reduced or
even avoided by the very disclosure of the patent in suit.
- It seems to me that the evidence as to what work was actually carried out
by the GI team in relation to obtaining EPO cDNA runs into just this sort
of problem. A number of steps taken by the team did not involve using a foetal
liver cell line, and that could therefore be said to be irrelevant and distracting
work. Some of their attempts to obtain encoding mRNA may have failed because
they did not have the information revealed by the 605 patent, and so they
were unable to use a long and reliable probe based on Table VI of the patent.
- In my judgment, therefore, if (contrary to my view) it had been within the
common general knowledge that EPO-encoding mRNA would be found in a DNA library
made up from foetal liver, then I am not persuaded that it would have involved
undue effort on the part of the appropriately skilled man to screen that library
with appropriate probes. While it would not have been an elementary exercise,
it certainly would not have been a "research project" as suggested
by Mr Thorley. In the context of this sort of technology, I do not consider
that that exercise would have involved undue effort.
Cell expression
- Amgen’s case is the notional reader would have appreciated that EPO cDNA
could and would be cloned by taking the following steps. First, the EPO gene
would be isolated from a genomic DNA library by a probe based on the information
contained in Table VI of 605. Secondly, the EPO gene would be inserted into
a host cell in accordance with the Examples in the patent (or indeed any other
method known to a person skilled in the art): in particular, in light of the
description in the patent, the cell would almost certainly be a COS or CHO
cell. Thirdly, the host cell transfected with the EPO gene would express EPO
mRNA, thereby providing an enriched source of this material. Fourthly, reverse
transcriptase would be used to make cDNA, from which the EPO cDNA clone can
be obtained.
- There is no specific teaching in connection with such a method in the patent,
although Amgen is able to point to a reference to this sort of exercise in
Example 5 (at page 25, lines 18 to 20 of 605), which was concerned with confirming
the presence of a lysine amino acid residues in human EPO (not found in monkey
EPO). The passage is in the following terms:
"Presence of the lysine residue in the human polypeptide sequence was
further verified by the sequencing of a cDNA human sequence clone prepared
from mRNA isolated from COS P-1 cells transformed with the human genomic DNA
in Example 7 infra."
- This reference is said by Amgen to assist the contention that cell expression
would have been in the mind of the notional addressee. However, in my judgment,
one cannot build very much on that "passing reference" to the use
of COS cells (as Professor Brammar put it). It does not purport to be a teaching
specifically directed to the obtaining of human cDNA encoding for EPO. Furthermore,
as Professor Wall accepted and Professor Brammar said in terms, all that the
notional addressee would have understood from the passage was that the patentee
had managed to obtain a clone with some human sequence in it, the sequence
in question being sufficient to identify the lysine referred to in the passage
I have quoted. In other words, in so far as the sentence implies that the
patentee had obtained anything, it was not complete EPO cDNA, but a portion
which enabled him to sequence across the lysine. I agree with Professor Brammar
when he said that "there is no encouragement whatsoever in the patent
how to make a human cDNA", and, ultimately, it does not seem to me that
anything in the evidence of Professor Wall called that view into question.
His evidence in relation to this sentence in the patent was that the notional
addressee would know of the technique of obtaining cDNA from COS cells transfected
with genomic DNA encoding for EPO, and would recognise the description of
this procedure. This, therefore, brings one to the question of whether the
notion of obtaining EPO encoding cDNA through the medium of a host cell transfected
with encoding genomic DNA would have been within the common general knowledge.
That, as I see it, is the central issue.
- Because attention had been concentrating on the sentence in Example 5 of
the patent which I have quoted above, and because some of the papers referred
to in this context involved the use of COS cells, much evidence was given
over to whether, and if so to what extent, the skilled addressee would have
a concern about using a COS cell for the purpose of producing the encoding
mRNA. Thus, Professor Brammar said that the skilled reader would have regarded
the use of COS cells as very risky, because of the inability of their splicing
machinery to cope with a high degree of copying, and their general unreliability.
On this issue, there is much force in Mr Waugh’s argument that any perceived
problem with COS cells is not really in point, because both Professor Brammar
and Professor Wall agreed that there would be no or very little such concern
if a CHO cell were used. Professor Wall specifically made that point in his
written evidence in reply, where he said that if the skilled reader was concerned
about COS cells:
"The obvious routes would be either to use a human tissue source...
or... a different host such as a transformed CHO cell which could be utilised
as a source of message."
Professor Brammar said that "I would have been certainly much happier
trying [the CHO cell] route than going via COS".
- There is no doubt that the possibility of using transfected host cells for
the purpose ultimately of expressing encoding cDNA for a particular protein
had been raised by the priority date. Thus, in a paper published by Anderson
and Kingston in 1983 in PNAS 80:6838 ("Anderson") ended in these
terms:
"[A] genomic clone for the gene of interest could be isolated and sub-cloned
into [an] expression vector; subsequent transfection of an appropriate host
cell should then produce correctly spliced transcripts of the cloned gene
from which cDNA could be prepared."
- While considerable reliance was placed on this observation in Anderson,
by Mr Waugh on behalf of Amgen, I think it is of limited value. It seems to
be a suggestion as to what might be done, and it is by no means clear that
the authors had actually carried out that exercise. It may therefore have
been nothing more than a bright idea, and there is certainly no reason to
think that, if it was not already common general knowledge, this suggestion
thereby caused it to become such. Indeed, I have no reason to think that Anderson
should be treated as part of the common general knowledge of the notional
addressee in the present case. It is true that Anderson is referred to in
three places in 605, but the relevant passage is neither quoted nor relied
on, even inferentially.
- Perhaps more importantly, in 1979, two important papers had been consecutively
published in Nature. Hamer & Leder in Nature 281:35 reported that they
had expressed the mouse globin gene in a monkey cell which was not the COS
cell, but was a predecessor cell in the art, in the sense that it was an earlier,
and less satisfactory, cell so far as transfection and expression was concerned.
The complete chromosomal beta-globin gene was inserted into a vector, and
this resulted in mRNA transcription, and the translation of the globin protein.
Mantai et al. reported in Nature 281:40 that they had carried out a similar
exercise in relation to the rabbit beta-globin gene in transformed mouse cells,
resulting in beta-globin mRNA. As "land mark" publications, I believe
that these two papers were part of the common general knowledge. Partly as
a result, I think that the basic idea of obtaining cDNA through an appropriate
host cell transfected with genomic DNA is something which would, in my judgment,
have been within the contemplation of the notional addressee of the patent
who wished to obtain cDNA which encoded for EPO.
- In this connection, it seems to me that answers given by Professor Brammar,
a fair and honest witness called on behalf of Roche, in cross examination
were revealing. He accepted that there were a number of "methods to get
a cDNA" in 1984. He accepted that the sentence I have quoted from Example
5 of the 605 patent was a "short (but for the average person skilled
in the art comprehensible)" way, but "not the only way" of
achieving that end. He also accepted that "a person would be able to
reproducibly isolate and produce a human EPO-encoding cDNA according to the
methods... just described", which at least included transfecting a host
cell with the appropriate genomic DNA. He also agreed that, based on the DNA
sequence revealed in Table VI of 605, "the possibility existed to successfully
use routinely practised techniques as they are e.g. described in Maniatis
for the isolation of... cDNA probes" (my emphasis), albeit that his agreement
was invited and obtained for this as "a technical proposition".
He also accepted that the fact that "defective clones can be obtained
by all isolations of... cDNA clones" was "known to the average person
skilled in the art and he knew that he therefore had to repeat his trials
once or several times". He also said that, although deriving cDNA from
the mRNA expressed in a host cell transfected with genomic DNA "could
be done", "it would be likely to be a difficult route because of
the caveat... fishing for the authentic cDNA, with its proper splicing etc.
amongst a complex pool of other transcripts".
- In my judgment, taking this evidence together with that of Professor Wall,
which was to much the same effect, albeit that he was less concerned about
problems, the notion of using an appropriately transfected CHO host cell for
the expression of EPO-encoding mRNA, and thereby producing EPO cDNA was something
which would have been within the common general knowledge of the notional
addressee of the 605 patent. In a paradoxical way, it might be argued that
this conclusion is called into question by the sentence I have quoted from
Example 5, in the sense that it might have put off the skilled reader, because
he would not have been happy about using a COS cell (for the reasons given
by Professor Brammar) and it might not have occurred to him to use a CHO cell
in light of that sentence. That point was not raised in evidence or argument,
and I am not persuaded that it is a good one in any event.
- Indeed, I think that the use of a COS cell would also have been
in the contemplation and common general knowledge of the skilled addressee.
I consider that the notional addressee would have had in mind the possibility
of using a COS cell line for this purpose. The concern expressed by Professor
Brammar at aberrant splicing in COS cells was based on a number of papers,
including one by Wojchowski et al in Biochim. Biophys. Acta 910:224 ("Wojchowski"),
in 1987. Professor Wall described aberrant splicing as a comparatively rare
event, and a paper by Wise et al in 1989 in Nucleic Acid Research 17(16):
6591 states that aberrant splicing would either result in poor expression
of the protein or synthesis of other protein products with different molecular
weights. Both of these, as I see it on the evidence, could be pretty easily
demonstrated and the consequences excluded. Further, other papers (such as
one by Nordstrom et al in 1986 in Biochim. Biophys. Acta 867: 152) indicate
that expression in a transfected COS cell (with an exogenous construct including
the genomic DNA and an SV40 promoter) resulted in more than 50% of the mRNA
expressed being correctly spliced, and 78% of the transcripts could express
the protein.
- Wojchowski had three contributors, one of whom was Professor Orkin. His
evidence was that the work was ultimately successful and the results were
achieved "within a few months". In cross examination, Professor
Brammar accepted that the steps involved in dealing with problems in COS cells
were "relatively routine and short". In re-examination, he described
the work which Professor Orkin had to carry out as involving "steps [which]
are not complex. They are fairly predictable but they impose a time lag. ...
My guess would be at least a few weeks to correct the problem". Further,
I draw comfort from the fact that there is no evidence of anyone using the
transfected COS cell method with a view to obtaining the entire encoding region
of the EPO gene and failing.
- In reaching my conclusion that the transfected host cell route to cDNA generally,
and in COS cells in particular, would have been within the common general
knowledge of the skilled man, I derive some comfort from the fact that patents
in the biotechnology field applied for by, and granted in the United States
to, GI (one of the Roche parties) seemed to support the view. Thus, in a patent
applied for in 1987 (PCT/US87/02005) reference is made at page 15 to "the
expression vector containing the gene [being] transfected into a mammalian
cell, e.g. monkey COS cells." The application goes on to state that the
"human gene is transcribed and the RNA correctly spliced ... mRNA is
obtained from these cells and cDNA synthesised from the mRNA." The same
sort of indication was contained in another application, PCT/US87/01537 at
page 50. Indeed, there is an application for a European patent by GI, made
in 1987, EP 314,705, which, at pages 11 and 12, refers to the construct being
"amplified in bacteria and transfected into monkey COS cells ... . ..
cDNA is synthesised from the mRNA by standard procedures." The lack of
detail in these passages tends to support the view that the sort of addressee
who would be reading patents of this type would be familiar with the transfected
host cell route to cDNA. It is fair to say that these applications were made
some three years after the application in the present case, but, at least
on the evidence I have seen, including the various papers relied on by the
parties, I am not convinced that that is a significant factor. In this connection,
it is to be noted that Roche’s case in relation to COS cells was based on
a number of papers, including Wojchowski, which were published around the
same time as, or later than, the filing of these patent applications by GI.
- Roche contends that the fact that the patent does not disclose a specific
means of obtaining human cDNA emphasises the difficulty in 1984 of obtaining
such DNA. Mr Thorley says that the obvious prize which was sought was human
EPO ("HuEPO") and cDNA is a more convenient source of expression
than genomic DNA, at least according to Roche’s case. Accordingly, the fact
that there is no teaching in relation to human cDNA in the patent Mr Thorley
suggests that such DNA could not in fact be obtained easily.
- Although this point has some attraction, I have come to the conclusion that
it should be rejected. At the relevant date, Amgen had a CHO cell transfected
with a genomic EPO gene, which was giving good levels of expression, and which,
indeed, is still giving good levels of expression, according to the evidence
of Dr Browne. It is true that cDNA has advantages over genomic cDNA in terms
of size and reliability. Indeed, I accept that cDNA would be preferable to
genomic DNA. However, the arguments are not all one way. Professor Proudfoot
explained that "having the whole gene present, or at least the gene with
some of the introns, greatly enhances the final expression of that gene".
With cDNA, of course, there would be no introns, and there would not be any
splicing, and as Professor Proudfoot went on to explain:
"[I]n a number of cases... the actual process of splicing seems to
enhance the production of messenger RNA on its transfer from the nucleus to
the cytoplasm."
- In his written statement, Dr Lin said that obtaining HuEPO cDNA for the
purpose of expressing EPO was not regarded as an urgent matter or an issue
of priority by Amgen, and this was confirmed by Dr Browne in evidence. I see
no reason to doubt that evidence. After all, Amgen’s experiments as taught
in the 605 patent were "delivering the goods" with genomic DNA.
- Furthermore, when he turned his attention to the matter, Dr Lin obtained
a cDNA sequence which at least Amgen contend is HuEPO cDNA, known as Hu13,
through the transfected COS cell route, in a matter of a few weeks. Roche
contend that the Hu13 clone is not authentic cDNA in this context, because
of the arrangement of certain nucleotide sequences within the clone. However,
it appears to me that the essential point is that the Hu13 clone contains
the whole of the natural mRNA primary transcript from the cap site at the
5’end down to the poly-A tail at the 3’end. It is only the arrangement of
the sequences significantly upstream of the transcription sites which differ
from the sequences in naturally occurring HuEPO cDNA.
- It is fair to say that it is not merely that the Hu13 clone is a little
different from HuEPO cDNA which is "naturally occurring" (to use
a word slightly inappropriate to cDNA); the different nucleotide sequences
upstream of the transcription site actually gave rise to confusion in the
minds of the Amgen scientists, and that confusion was only sorted out after
consultation with an outside expert, Dr Suggs in early 1985.
- This aspect of the evidence relating to Hu13, upon which Roche rely, does
underscore their point that, transfected COS cells are not always a reliable
or predictable source of cDNA. However, it appears to me that the essential
point is that the transfected COS cell route produced, after work which was
routine and not lengthy, a gene which contained all the relevant necessary
parts of human cDNA for the purposes of the teaching of the 605 patent. At
the time, on 6th April 1984, Dr Lin specifically recorded that "Hu13
is a true human EPO clone". Of course, that is not conclusive, and he
could be said to have been parti pris. Nonetheless, it is consistent with
what Professor Brammar accepted as being "correct" in cross examination,
namely that with the Hu13 clone "you have the whole thing at your disposal"
which enables one to "engineer it to put stronger signals up front of
the coding sequence" and to "conduct experiments on that to adjust
expression".
- Professor Brammar also accepted that "if... your desire was to get
a message that goes right the way back to the first initiation site, [the
Hu13 clone] gives it to you" and that "you have the whole thing
there". He also accepted that the Hu13 clone was not "incomplete"
and that it would be a "false impression" if one thought that the
Hu13 clone "was not complete". Professor Wall’s evidence was to
much the same effect. He said that his view that the Hu13 clone was a type
of human cDNA was correct on the basis of his own experience and use of language,
and, above all, in light of the fact that it was cDNA and it performed that
function which was required of it under the patent, namely to effect human
EPO expression when used in accordance with Examples 7 and 10.
- I agree with that view. If one was to encapsulate the purpose of the patent,
it is to obtain the expression of human EPO in relatively substantial quantities
by inserting exogenous DNA into a host cell. The identification of the DNA
appropriate for this task is not in the context of an academic exercise. The
Hu13 clone is cDNA, it contains all the coding for human EPO and in that sense
it is human cDNA. Further and above all, it "delivers the goods",
to quote Lord Hoffmann in Biogen [1997] RPC 1.
- Dr Fritsch, it is fair to record, had a different view. However, it appears
to me that that view is somewhat at variance with Jacobs, a paper to which
Dr Fritsch himself was party. In that paper a gene sequence including all
the exons, but none of the introns, of human EPO, and only a relatively small
part of the upstream sequence, and the whole of the downstream sequence, was
referred to as "the isolated cDNA [which] encodes human erythropoeitin"
and "erythropoeitin cDNA" and "erythropoeitin fetal liver cDNA".
While none of those expressions are "human cDNA", I think the distinction
is one without any relevant difference, not least because, as I have mentioned,
the expression "human cDNA" is not in the patent.
Gene synthesis
- I now turn to the third method by which Amgen contend that the notional
addressee would appreciate, through common general knowledge, that he could
obtain human cDNA, namely gene synthesis. There was what I suspect was a somewhat
arid argument between the parties as to whether a synthetic DNA sequence which
was identical to the sequence of human cDNA obtained from tissue sources or
through a transfected host cell could be called human cDNA. As with some of
the expressions used in the claims of the 605 patent (such as "host cell"
or "recombinant polypeptide"), I suspect that cDNA could be and
was used to describe such synthetic DNA, at least by some people in some circumstances.
The reason the point seems a little arid is that the question of what is meant
by "human cDNA" in this context does not arise as a matter of the
proper construction of that expression in the patent in suit. The issue really
arises in relation to infringement, because, as I will explain when dealing
with infringement, Roche’s allegedly infringing product results from the expression
of what is undoubtedly human cDNA.
- In my view, in so far as the point is relevant, the draftsman of 605 did
not use the expression "cDNA" to extend to synthetic DNA. Thus,
on page 3, the draftsman specifically defines "further "cDNA"
methods" as applying to cDNA as the complement of mRNA in transfected
host cells, and not to "the mechanical manufacture of a DNA sequence"
(see at lines 12 to 16). This is confirmed by passages later on the same page.
Further, as one goes through the first ten Examples in the patent, one sees
references to cDNA which plainly do not extend to synthesised DNA (albeit
that this is merely consistent with what is common ground, and does not exclude
the possibility of "cDNA" also referring to synthesised DNA). However,
Examples 11 and 12 deal with synthetic DNA, and it is not insignificant, to
my mind, on this issue, that there is no reference to such DNA being thought
of as cDNA. I will nonetheless proceed to refer to "synthetic cDNA",
for the sake of simplicity.
- The fact that the reader of the patent, if he bothered to think about the
point at all, would conclude that the draftsman did not treat cDNA as including
synthetic DNA has little bearing on the question of whether a person wishing
to use the teaching of the patent to make HuEPO would know that he could use
synthetic cDNA for that purpose, and that this could be done without undue
effort. The fact that the patent nowhere specifically suggests this course,
even though no reference to cDNA in the patent extends to synthetic DNA, is
of some relevance. However, the statement that "the chemical manufacture
of a DNA sequence provides a code for a polypeptide of interest" is made
early in the specification, as I have mentioned. Further, the notion of synthetic
DNA sequences encoding for EPO, albeit not specifically human cDNA, is to
be found in Example 11. However, Example 11 is concerned with DNA synthesis
as a means for making sequences suitable for expression in E.coli cells and
yeast cells.
- On the evidence, it seems clear that, as at the relevant time, even a leading
expert in the field could not have synthesised human cDNA, in the sense of
each nucleotide in the synthetic product being identical to its equivalent
in the natural product (in so far as one can have "natural" human
cDNA). Professor Gassen said that the manufacture of a coding region of a
gene with more than 500 base pairs (which is what would be involved in the
EPO cDNA gene) required changes to be made from natural sequences. The changes
would be required partly to introduce or remove restriction sites to enable
the sequence to be divided into sections, partly to avoid self hybridisation
of oligonucleotides, and partly to minimise the risk of the oligonucleotides
ligating together other than in the desired order to form the final overall
cDNA sequence.
- Dr Gait, a leading figure in this field, identified two changes which would
have to be made, although, if he had actually carried out the synthesis, it
seems possible that a number of other changes either would have had to have
been made or at least would have been desirable. In that sense, again for
what it is worth, it can be said that, even if synthetic human cDNA is human
cDNA for the purposes of 605, the synthetic cDNA which could have been made
would not have been human cDNA precisely, although it would have been very
close thereto. In terms of the nucleotide sequence, if human cDNA could have
been synthesised, it would, as I see it, have about 99% homology with naturally
occurring human cDNA.
- In his evidence, Dr Gait expressed confidence that it would have been possible
in 1984 to synthesise human cDNA, albeit with a few changes to the bases for
the reasons I have mentioned. He was an impressive witness; he was clearly
very experienced in this field, and he spoke with authority. However, at least
as at the relevant date, I am not satisfied that the notional reader of the
patent, clothed with the requisite common general knowledge, would, or could
without undue effort, have embarked on the synthetic route in order to obtain
human cDNA.
- While, as I have mentioned, Dr Gait expressed confidence about the ability
of experts in this particular field to synthesise human cDNA encoding for
EPO at the relevant date, I cannot, in light of the evidence given, hold that
it was more than a real possibility that this could have been achieved. Perhaps
more importantly, had the appropriately skilled reader considered the possibility
of expressing EPO through the indirect medium of synthesised human cDNA, he
would not, in my view, have considered that as being more than a possible
route, whose success was uncertain.
- When embarking on the exercise of synthesising genetic material, the first
stage is to design the process, and the second stage is to try and implement
it. The first stage involves a number of steps, the first of which is to divide
the desired gene into appropriate sections. Dr Gait undertook that step. However,
he did not undertake the next step, which involves considering whether, and
if so how, the sequence could be made in practice, and in particular whether,
and if so how, the sequence can be divided up into oligonucleotides which
would not self hybridise, and which could be uniquely ligated together. As
Dr Gait accepted, and as indeed published papers confirm, a so-called "gene
construction map" is prepared before the second, practical, stage is
undertaken (albeit that there will no doubt normally be amendments which have
to be made to the design process which only come to light during the practical
process).
- Professor Gassen, who was significantly less sanguine about the likelihood
of success, and the relative ease, of synthesising human cDNA than Dr Gait,
effectively challenged Dr Gait to produce a practicable gene construction
map, and no such map was produced. Dr Gait had apparently undertaken an attempt
to effect that process for the first of the three sections into which he had
divided the EPO gene for the purpose of the notional synthesis, but there
was no suggestion he had done this for the other two sections. As Mr Thorley
points out, the evidence suggested that the design process should normally
take less than a week. Although Professor Gassen did not condescend to particular
problems which might be encountered in relation to the synthesis of human
cDNA, it seems to me that it can fairly be said that, unless and until a specific
proposal was put up to him, it would not have been easy for him to identify
specific problems. Further, while this may be another way of putting the same
point, the questions he was asked in cross-examination on this were not themselves
particularly specific.
- Dr Gait estimated that it would take around twelve man months to make the
sequence of more than 500 base pairs encoding for EPO using the techniques
employed in his laboratory in 1984. First, there is no doubt that Dr Gait
was one of the top experts in the world in this comparatively small field
in 1984. Secondly, his estimate of twelve man months was mainly based on very
limited specific experience; in fact, it was substantially on the basis of
the synthesis of one protein, somatomedin C, and this succeeded first time.
Not even Dr Gait, and certainly not the averagely skilled addressee, could
have been remotely confident that the synthesis of human cDNA, if it was possible,
would be successful first time round.
- I think there is something in Mr Waugh’s point that Professor Gassen may
have been somewhat more pessimistic than the notional addressee of the patent
(assuming he considered the synthetic human cDNA route) and more pessimistic
than the facts justified in 1984. Nonetheless, his experience in 1984 was
that "the vast majority of the initial attempts" to "express
[a synthetic] sequence in a host cell and hoped to produce a biologically
active protein" would "be met with failure". He suggested that
"the creation of the synthetic sequence" could "in some cases
[be] up to a year’s work". To my mind, although a highly experienced
and reputable scientist, Professor Gassen was, on this issue, closer to the
ordinarily skilled person than was Dr Gait.
- It is right to mention that there is contemporary evidence that Dr Fritsch
of GI prepared a note in 1984 suggesting that he thought that synthesising
human cDNA would not be too arduous a task. However, he was not particularly
knowledgeable about DNA synthesis, and I think it would be wrong in any event
to make much of his note in this connection.
Conclusion
- In these circumstances, I conclude that, while the obtaining of human cDNA
through human tissues or by means of synthesis would not have been within
the common general knowledge of the notional addressee of 605, the obtaining
of such DNA through the route of a transfected host cell (and in particular
a CHO cell, but also a COS cell) would have been within the common general
knowledge.
- I draw some comfort in reaching this conclusion from what Dr Fritsch of
GI (a Roche party) wrote in January 1984, when he heard what Dr Lin had achieved:
"[W]ith this information they can certainly predict the human cDNA sequence
and synthesise it easily".
I. CLASSIC INSUFFICIENCY: OTHER ISSUES BEARING ON CLAIM 1
The Examples: Introductory
- As Mr Thorley points out, as there was no deposit of cells, the skilled
person wishing to put the teaching of 605 into effect had to carry out Example
4, then Example 7, and then Example 10. He helpfully summarises the five steps
which would be involved, as follows:
1. Obtain the Lawn library;
2. Screen it with probes and isolate and clone the EPO gene (Example4);
3. Construct the expression vector and insert the EPO genomic fragment
(Example 7);
4. Obtain the DuX-B11 CHO cells and transfect them (Example 10);
5. Amplify those cells using MTX (Example 10).
- It is not suggested on behalf of Roche that step 2 suffers from any insufficiency;
Mr Thorley fairly describes the exercises in Example 4 as "straight forward
in the sense that they all involved well known procedures". As to steps
4 and 5, relating to Example 10, Roche do not contend for any classic insufficiency
there either.
- I shall deal with the alleged insufficiencies in relation to steps 1 and
3.
Example 4: The Lawn library
- So far as step 1 is concerned, Roche’s case is that the Lawn library was
not available as at the priority date, that it would therefore have to have
been made by the notional addressee, but this was technically demanding and
time consuming, and that therefore the first step alone involved undue effort.
- In my judgment, this ground of alleged insufficiency is not made out. The
way in which to prepare a Lawn library was set out in detail in Chapter 9
of the Maniatis Manual, which extended to over 25 pages, and contained clear
directions. Professor Wall estimated that it would take no more than a couple
of months to carry out this work, and Professor Brammar agreed. Further, an
advantage for the person following the teaching of the patent making his own
Lawn library would be that, with the benefit of the disclosures of the 605
patent, and with knowledge of where the EPO gene is to be found in the genome,
he could significantly enhance the frequency with which the EPO gene was included.
Although I think Mr Thorley is right to say that the construction of a Lawn
library would not have been "trivial or quick", it seems to me that
it would have involved routine work which would not have taken an undue amount
of time, even bearing in mind that it was the first of five steps.
- It is also argued by Mr Waugh on behalf of Amgen that the notional addressee
would have been able to obtain a sample of the Lawn library from someone who
himself had obtained a sample of the original library from Dr Lawn. In this
connection, I believe that the evidence establishes that the original Lawn
library had been distributed fairly widely, and indeed had been deposited
with the ATCC. Professor Wall was not challenged on his view that he "would
expect that a sample would still be available from one of the recipients of
the [original] library" and that he thought it would be "a simple
matter for an initial recipient to grow up some of their material to provide
it to others".
- Quite apart from this, it was common ground between Professor Wall and Professor
Brammar that many laboratories had, in 1984 "constructed their own genomic
libraries". This means that there was, at the very least, a good prospect
of the notional addressee either having such a library in his laboratory,
or having indirect access to such a library through a colleague in another
laboratory. Accordingly, I see no problem so far as the sufficiency of step
1 is concerned.
Example 7: Screening, isolating and probing
- A number of insufficiencies are alleged by Roche, primarily on the basis
of Professor Brammar’s evidence, so far as step 3 is concerned. Of course,
given that Example 7 includes two Examples, namely 7A and 7B, it may well
be that if one of those was insufficient, the patent would still not fail
for insufficiency on this ground, provided the other was sufficient. However,
I do not need to decide that point, because I think that, although Professor
Brammar’s criticisms were justified, in the sense that it would have been
better if the 605 patent had been drafted so as to avoid them, I do not consider
that any of them, even if they are taken together, render Example 7 or Example
7A non-enabling. I turn first to the specific criticisms of Example 7A by
Professor Brammar.
- The first criticism of Example 7A arises out of Example 6. It is the absence
of a restriction site immediately adjacent to the particular nucleotide, numbered
2448, in the gene. In 1983, it was known that there were certain "poison
sequences" which might exist upstream of the encoding area of the gene,
and which it would be desirable to remove before transfecting the gene into
COS cells. The 605 patent teaches that fragments from 2448 to 4362 are poison
sequences, and the cleavage site at 4362 was provided by a particular restriction
enzyme commercially available and widely used in 1983. However, there was
no restriction site at 2448. Professor Wall said that:
"The skilled addressee would appreciate that the specific terminus
of this fragment did not have to be exactly 2448; any fragment within 50-100
bases would most likely have provided equivalent results."
- He then identified possible restriction sites which could have been utilised
for this purpose, and also mentioned restriction enzymes which would have
cleaved at those sites. I agree with his conclusion that "once the patent
taught the key elements of the fragment, and its length, it was a routine
matter in 1983 to generate either an identical or nearly identical fragment,
or a functional equivalent." Indeed, as I understood him, Professor Brammar
accepted that view in cross-examination.
- The second criticism of Example 7A is that the sequence of a linker to be
attached to the end of the sequence at 2448 (or, in light of the criticism
I have just been considering, a slightly different nucleotide) is not provided.
Connected with this criticism is the further criticism that directions were
not given as to how to attach a linker. However, Professor Brammar accepted
that one "could readily go and get [the appropriate] linker from a catalogue"
and that this would be "standard routine". As Mr Waugh points out,
it would appear that the only information required for a linker is a restriction
site which it provides, and this is readily available from the type of catalogue
referred to. Furthermore, I was referred to publications in journals including
Nature and the Proceedings of the National Academy of Sciences which report
expression experiments involving linkers, without giving the sequences of
those linkers (see for instance Powell et al PNAS 83: 6465, in 1986 and Mishina
et al in Nature 307:604 in 1984).
- Professor Brammar also expressed some doubt about the identity of a particular
fragment, but agreed this was "a very minor" matter. I agree, and
do not consider that it begins to justify a challenge to the sufficiency of
Example 7A.
- Example 7A identifies a small fragment comprising nucleotides from "2553"
to "2770". Professor Brammar expressed the view that "2553"
is a mistake, because it is neither on or near a convenient restriction enzyme
target site, and he assumes that "2533" was intended. In cross-examination,
he explained that he had "[drawn] attention to it simply because it is
an issue and it is the kind of error that some beginner might fall into".
He also described it as a "fairly minor matter". I would accept
that the mere fact that a mistake is a misprint, even, at least conceivably
self-evidently a misprint, does not automatically mean that it cannot amount
to an insufficiency. However, where the mistake is self-evidently a misprint
which only might mislead a beginner, that cannot amount to an insufficiency.
As I have mentioned, the notionally skilled man is not the lowest common denominator
in the field; even less is he merely a beginner. As I understood Professor
Brammar, he thought that any problem thrown up by the misprint should not
have taken the ordinarily skilled person more than 24 hours to sort out.
- The next criticism of Example 7A is the lack of information as to how two
of the DNA fragments would be ligated. It is clear that this would be achieved
through the medium of a suitable linker, and it seems to me that the failure
to identify the residual sequence of the linker between the promoter and the
inserted DNA is not relevant so far as the construction of a suitable vector
is concerned. In this connection, Professor Brammar did "not know of
a specific problem", and said he was merely identifying "a potential
risk" which he accepted amounted to a "minor criticism".
- The final matter I should mention in relation to Example 7A is the "worry"
expressed by Professor Brammar because of the transcription which apparently
took place from the SV40 late promoter upstream. I am slightly puzzled by
this point, in the sense that Professor Brammar’s concern appears to have
been based on the proposition that the skilled person might not follow the
teaching of Example 7A, and that he might fear that this would have undesirable
consequences. In the first place, it seems rather odd to found an insufficiency
in a patent on an assumption that if the notional reader would not follow
its teaching. Secondly, it seems a little difficult to found an insufficiency
on a double uncertainty, namely what the skilled person might do, and what
he would fear it might lead to. There is no evidence that, if the skilled
person did not follow the teaching of Example 7A precisely, and instead did
what Professor Brammar thought he "might" do, that would have resulted
in any problem. Quite apart from this, if such a problem had arisen, Professor
Brammar accepted that the skilled person could simply "redesign".
At worst, and assuming everything in favour of a problem in this connection,
Professor Brammar accepted that the construction of an alternative expression
vector would involve only "a few weeks".
- I turn then to the additional criticism advanced by Professor Brammar of
Example 7B. He raised a number of criticisms similar or identical to those
I have already considered and rejected in relation to Example 7A, and I do
not propose to repeat my reasons for rejecting essentially similar or identical
points that I have already disposed of. However, it is right to mention that,
even if all the criticisms were justified, Professor Brammar accepted that
"a few weeks, several weeks, but not much longer" would be involved
if one was "left to design [one’s] own version of the expression construct
using COS cells".
Example 7B: The mistake in Table VI
- The only separate criticism of Example 7B which I ought to consider arises
from a small, but potentially significant, inaccuracy in the sequence information
contained in Table VI of 605. At position -44(i.e. 44 bases upstream of the
five prime end of the first exon) Table VI shows a G instead of a C. Professor
Brammar explained this would lead to the design of a linker with a mismatch.
Based on his own view, supported to some extent by a paper published in 1987
by Wiaderkiewicz and Ruiz-Carillo in Nucleic Acid Research 15(19): 7831, he
suggested this mistake would lead to a "C/C mismatch ligation" which
was inefficient, and quite likely to lead to a failure to ligate, so that
the skilled man would have to solve the problem himself.
- While accepting that there was a problem, Dr Gait thought that the mismatch
would be tolerated to the extent that there would be significant ligation.
In this connection, it is to be noted that in his "summary of the mismatches
tested" Wiaderkiewicz stated that, at least as a generality, there would
be ligation in the case of a C/C mismatch. The evidence, essentially based
on this paper, suggests to me that there would be ligation, but the existence
of the C/C mismatch would mean that the amount of ligation would be reduced.
I accept Dr Gait’s evidence that one "would still have expected a reasonable
number of clones", in the sense that there would have been a sufficient
degree of cloning for the purpose of achieving the end and purpose of Example
7B. Although Professor Brammar, an unusually careful witness, took a slightly
more cautious view than Dr Gait, I do not think that the overall effect of
his evidence called into question the conclusion expressed by Dr Gait which
I have quoted and explained above.
Expression in human cells
- Although Professor Proudfoot appeared to suggest that Roche might be contending
that 605 did not extend to expression of EPO in human cells, I do not understand
the point to be advanced by Mr Thorley. In my view, there is no reason why
a human cell is not a "eukaryotic cell" within the meaning of Claim
1 or a "host cell" within the meaning of Claim 19. I think it would
require a pretty clear indication to the contrary in the specification before
such general expressions were held not to apply to human cells. There is nothing
in the specification to indicate that human cells were intended to be excluded.
On the contrary, on page 48, lines 33 to 35, it is stated that "expression
systems involving vectors of homogenous origins applied to a variety of ...
mammalian cells in culture" where "[c]onspicuously comprehended"
"within the contemplation of the invention". Plainly, "mammalian
cells" is a term which includes human cells.
- TKT contend, however, that the 605 patent is insufficient in this connection.
In the course of his attractive submissions, Mr Kitchin points out that the
draftsman of the patent identifies early on the desirability of obtaining
EPO "in quantity" to enable the treatment of over 1.5m patients
"in the United States alone" (page 5, lines 18 to 19) and that:
"the best prospects for... providing large quantities of [mammalian
EPO] for potential diagnostic and clinical use involve successful application
of recombinant procedures to effect large scale microbial synthesis of the
compound" (page 6, lines 54 to 56).
- He draws attention to the fact that, consistent with this, the draftsman
claims at page 9, lines 32 to 35, that:
"Vertebrate (e.g. COS-1 ... and CHO) cells provided by the present
invention comprise the first cells ever available which can be propagated
in vitro continuously and which upon growth in culture are capable of producing
in the medium of their growth in excess of a 100U (preferably in excess of
500U...) of erythropoeitin per 106 cells in 48 hours as determined
by [RIA]."
- In fact, however, once one looks at the teaching of the patent, the only
way of getting EPO in greater quantities which is specifically taught, is
by the use of DHFR- CHO cells. In particular, Mr Kitchin contends that there
is no teaching as to how to achieve the result in human cells. Accordingly,
although the essential point which TKT wish to establish is that the claims
are insufficient in so far as they seek to extend to expression of EPO in
human cells, their argument amounts to contending that, subject to any question
of common general knowledge, any claim which extends beyond DHFR- CHO cells
is invalid on the grounds of insufficiency. In this connection, there is obvious
force in the contention that an amplified level of expression is of the essence
of the patent, given that EPO was known to exist in nature, and had, indeed,
been isolated, albeit in very small quantities, from urine.
- In his evidence, Professor Proudfoot pointed out that the only Experiment
in the patent which produced EPO at the level promised on page 9 of the 605
patent was in amplified DHFR- CHO cells. In particular, Amgen failed in unamplified
CHO cells, in COS cells and in human cells. He also stated that, although
subsequent technology has enabled EPO to be produced in a DHFR+ cell, the
patent provided no way of amplifying such a cell, and that the consequent
requirement that the cell be DHFR- at the date of the patent, limited the
technique described in the patent to CHO cells, because there were no other
generally available DHFR- cells at the time (albeit that the position subsequently
changed). In effect, therefore, he stated that, even if the 605 patent enabled
the production of EPO in human cells, it did not enable it in amplified or
enhanced quantities.
- So far as using the information in the 605 patent to obtain some expression
of EPO in human cells is concerned, Professor Wall relied on the fact that,
as at the relevant date, use of certain human cells for that type of technique
was well known. Those cells were the so-called HeLa and 293 human cells. He
therefore said that it would have been within the common general knowledge
that the disclosure of the 605 patent would have enabled the expression of
EPO in such cells. I agree. His view is supported by the fact that scientists
employed by Amgen used the technology described in the 605 patent, including
a specific plasmid therein specified (the so-called pUC8-HuE plasmid - see
page 27) to achieve the expression of rEPO, apparently indistinguishable from
uEPO (on SDS-PAGE with RIA testing) in 293 cells. He accepted that this work
did not involve "high level expression", but suggested that procedures
to achieve that would have been "routine and standard practice".
- However, I do not consider that, subject to one piece of evidence he produced,
Professor Wall made that last statement good or called Professor Proudfoot’s
view as to the enablement of the expression of enhanced quantities of EPO
into question. Thus, he agreed that the reader of the patent at the relevant
date would understand that the identification of stable transformants and
amplification was essential to achieving the higher levels of expression promised,
that DHFR was the only contemporary amplification marker available, at least
as far as he could recollect, and that CHO cells were the only known DHFR-
cells at the time. He also agreed that Amgen’s experiments with human cells,
which were with one type of such cell, namely the so-called human 293 cell
line, did not produce high level expression.
- The one piece of evidence which Professor Wall did produce, was a paper
by Murray et al. published in 1983 in Molecular and Cellular Biology 3(1):32
("Murray"), before the relevant date, which described the use of
certain DHFR+ cells for amplification. However, I do not consider that that
assists Amgen on the issue of enhanced or amplified expression in cells other
than CHO cells. First, I do not consider that Murray was part of the common
general knowledge. Professor Wall, who raised it, only produced it in his
evidence in reply, and he had not come across it until it he had been instructed
in connection with these proceedings. Further, Professor Wall accepted that
the amplified genetic material reported in Murray would be unstable and could
only be maintained by continued MTX treatment. Accordingly; in my view, even
if the notional addressee of 605 would have thought of Murray, he would have
dismissed it as unreliable.
- It therefore follows that, subject to reconsidering this aspect in light
of the guidance given by the House of Lords in Biogen [1997] RPC 1, I consider
that this ground of classic insufficiency is made out, so far as enhanced
or amplified expression of EPO in human cells is concerned.
"Stringent conditions"
- Roche (with the support of TKT) contend that whether or not certain conditions
were investigating whether hybridisation is occurring are "stringent"
in Claim 1(b) is an uncertain matter upon which views could differ. The point
is perhaps well illustrated by considering an addressee who is seeking to
discover whether a certain polynucleotide sequence (not falling within integer
(a) of Claim1) falls within Claim 1(b). He would seek to investigate whether
the sequence hybridises in accordance with integer (b), and he may test it
at, say, three levels of stringency, which I will call (in ascending order)
levels 1, 2 and 3. At level 1, which he believes to be low stringency, it
does hybridise; at level 3, which he believes to be high stringency, it does
not hybridise; at level 2, which some might regard as high stringency but
others might not, it does hybridise. In those circumstances, if level 2 is
"stringent", then his sequence would appear to fall within Claim
1(b), but if it is not, it would not appear to do so. Roche contends that
there would clearly be circumstances in which such an addressee could not
by any means always be confident whether a particular hybridisation level
was "stringent" and, therefore, that Claim 1, or in the alternative
integer (b), is insufficient.
- It seems clear that it is and was common to identify in specific terms the
nature, and hence the stringency, of the conditions of hybridisation. Thus,
in Example 3B on page 14, lines 48-54 of the 605 patent, the essential features
of the conditions to enable one to determine the degree of stringency of the
hybridisation and washing conditions, namely the identity and concentration
of the salt, and the temperature and the time for hybridisation, are specifically
defined. Similarly specific identification of the hybridisation conditions
are to be found in Example 4 (page 19, lines 9 to 14). Further, on page 10
(lines 10 to 11), where the draftsman is summarising the DNA sequences to
which the patent extends, he identifies in paragraph (a) the sequences set
out in Tables V and VI - reflecting Claim 1(a) - and then refers in paragraph
(b) to:
"DNA sequences which hybridise (under hybridisation conditions such
as illustrated herein or more stringent conditions)."
The passage immediately goes on in paragraph (c) to refer to DNA sequences
which, in effect, fall within integer (c) of Claim 1.
- In these circumstances, the argument that the reference to "stringent
conditions", without any guidance as to what that expression means, is
insufficient has obvious force. However, I have come to the conclusion that
the argument should be rejected. The Courts have demonstrated a degree of
reluctance to hold a claim in a patent insufficient merely on the ground that
it purports to define its extent by reference to a qualitative requirement,
as opposed to a quantitative one. Thus, in British Thomson-Houston Co Ltd
-v- Corona Lampworks Ltd 39 RPC 49, the House of Lords unanimously held a
patent relating to an incandescent electric lamp valid despite an argument
that the stipulation that the filament be "of large diameter or cross
section" was insufficient. Lord Dunedin said this at 39 RPC 84, lines
4 to 16:
"The criticism is made, that in specifying the diameter of the filament,
"large" is not defined. Now, when any epithet is used which has
inherent in it the notion of comparison, and when no particular standard with
which to compare is given, it is, I think, consequential that the standard
which... is employed is the average. The average thickness of filaments in
vacuum lamps is well known. I think the Patentees meant anything larger than
that. ....A further definition of "large" does not seem to me to
be necessary."
- In Cleveland Graphite Bronze Co -v- Glacier Metal Co Ltd 67 RPC 149, the
House of Lords held that a claim referring to "a bearing liner of thin
and flexible metal" was valid. Lord Normand, with whom all but one member
of the House of Lords agreed, gave this analogy at 67 RPC 153, lines 27 to
31:
"A shoemaker who is ordered to make a pair of shoes in thin and flexible
leather knows that the customer wants thin and flexible shoes. It is true...
that shoes which are thin and flexible for a grown man may be thick and stiff
for a young child. But the intelligent shoemaker would appreciate this and
would choose his leather accordingly."
- Of course, the mere fact that the House of Lords has, on two separate occasions,
held a claim in a patent to be sufficient, notwithstanding the fact that the
claim has used an arguably vague adjectival test does not mean that in every
case where such a test is contained in a claim the Court will reject an insufficiency
argument. Ultimately, whether or not a claim is classically insufficient must
be a question of fact. Nonetheless, it would be wrong not to consider the
instant argument without bearing in mind the approach of these two well established
and authoritative decisions.
- In the present case, it appears to me that, unlike in the two cases to which
I have referred, there is some guidance as to the meaning of "stringent"
in the patent itself. I have already referred to the passage on page 10 of
the patent. It includes three categories of DNA which appear pretty clearly
to "track" integers (a), (b) and (c) of Claim 1. That point is reinforced
by the fact that the three categories of DNA sequences identified on page
10 are introduced by the words "Novel DNA sequences of the invention
include all sequences used in securing expression [of EPO or EPO-like products]
which are comprehended by...". In other words, the passage on page 10
has the same informal purpose as the formal function of Claim 1, "conditions
such as illustrated herein or more stringent conditions" and it appears
to me to tie in fairly clearly with integer (b) of Claim 1. The "hybridisation
conditions... illustrated herein" are the specific conditions identified
in Examples 3(b) and 4. The "more stringent conditions" are the
sort of stringent conditions which integer (b) of Claim 1 has in mind, and
therefore guidance is given within the patent itself to the reader.
- As I see it, a provision such as integer (b) of Claim 1 has to be read in
the context of the patent as a whole, and, while it may not be possible to
allow the rest of the patent in effect to contradict or even qualify the plain
words of a claim, it seems to me that it must be permissible to invoke a relevant
part of the specification as an aid to the construction of an otherwise ambiguous
or unclear aspect of a claim. It is particularly powerful in a case such as
the present, where, if the passage on page 10 does not assist, then the relevant
part of the claim is said to be insufficient. In such a case, as I have already
mentioned, the court should, to my mind at any rate, plainly lean in favour
of a construction which "saves" the document or a particular provision
therein. In my view, that is how a reasonable addressee would understand integer
(b) of Claim 1. He would also see that Claim 1 included the additional requirement
of being EPO-producing (or producing protein with EPO-like characteristics).
- It is right to mention that Professor Wall dealt with this issue in his
first report and in cross examination. He referred to the Maniatis manual,
which he explained would be within the common general knowledge, as is accepted
by Roche and TKT. In Chapter 7, entitled "Synthesis and Cloning of cDNA",
the manual, under the heading of "Hybridization of Southern Filters"
at pages 387 to 388 specifies hybridisation and washing conditions and states
that "if the homology between the probe and the DNA... is inexact, the
washing should be carried out under less stringent conditions". Professor
Wall said that the concept of stringent condition "would... not be something
that would be a great mystery to a person of skill in the art". I accept
that evidence, although I also accept the argument that there would still
be conditions which some might regard as "stringent" and others
would not (or, to put it another way, which the reader would be uncertain
whether they were "stringent" or not). However, I think these conditions
would be a comparatively small band on the spectrum of stringency.
- In order to dispel the suggestion that there was any such possibility of
uncertainty, Amgen rely on the further evidence of Professor Wall, to effect
that there would be unique optimum conditions for each probe, and that the
strength of hybridisation between two pieces of DNA would depend upon the
length, area and degree of complementarity as well as upon the GC, as opposed
to AT, content. I was unimpressed by this suggestion which amounts to saying
that, because a person skilled in this field would normally optimise the conditions
for any given system, he would know if he had achieved "stringent"
conditions by looking at the result. The point, as I understood it, was that
one would have achieved "stringent" conditions if the probe hybridised
and was not washed off. However, I agree with Mr Thorley, who suggests that
this simply defines "stringent" by reference to the conditions in
which the probe hybridises, and, as the whole point of the test in Claim 1(b)
is to see if there is hybridisation under stringent conditions, the exercise
proposed by Professor Wall is self-fulfilling or circular.
- I am thus of the view that integer (b) of Claim 1 does not suffer from insufficiency.
Even with the specific guidance on the specification and from items with common
general knowledge, such as the Maniatis manual, I accept that there could
be hybridisation conditions which might or might not be "stringent"
within the meaning of Claim 1(b). It is nonetheless the case, in light of
the evidence I heard and the contents of the specification and common general
knowledge that the great majority of hybridisation conditions will either
be of such a stringency that no reasonable reader of the 605 patent would
be in any doubt that they were not "stringent", or will be such
that the reader could not reasonably doubt but that they were "stringent".
In those circumstances, it does not appear to me that Claim 1(b) could properly
be said to be insufficient.
- If a particular piece of DNA hybridised in conditions which were on any
reasonable view "stringent", then it would fall within Claim 1(b);
if it only hybridised in conditions which on any reasonable view were not
"stringent", then it would plainly not infringe. The only problem
which could arise would be where a sequence hybridised in conditions which
were plainly not stringent, did not hybridise in conditions which were plainly
stringent, but did hybridise in conditions which were in the middle and uncertain
area of "stringency", namely which some might reasonably regard
as stringent, while others might not. It would only be in such a case that
Claim 1(b) would be unclear, and, in such a case, the issue of infringement
would clearly have to be resolved in favour of the alleged infringer and against
the patentee. I believe that view is consistent with common-sense. I also
believe that it is consistent with, indeed a fortiori, the reasoning of the
Court of Appeal in Scanvaegt International A/S -v- Pelcombe Ltd [1998] FSR
786 where at 797 Aldous LJ said that "Ambiguity is no longer a ground
of invalidity". He then went on to say:
"[L]ack of clarity is no longer a matter that it can result in a patent
being invalid, it cannot result in the patentee being unable to establish
infringement. If you cannot define the invention claimed, you cannot conclude
that it is being used."
- I think that my view is probably also consistent with the observation of
the Court of Appeal in General Tire at [1972] RPC 511 about "puzzles
set at the edge of the claim". Indeed it also ties in with what I have
referred to as "fuzzy edges" which are encountered in science and
technology. Such puzzles or fuzzy edges are inevitable or inherent on occasions.
It would be unrealistic and disproportionate if they invalidated a claim in
a patent, even in circumstances where they could be avoided. It would be inconsistent
with fair protection to the patentee; it would not be called for by certainty
for third parties. If the alleged infringement fell within the fuzzy edges
then certainty for third parties would require a conclusion of non-infringement;
again, fair protection for the patentee would not suggest otherwise.
- The conclusion that, even if it is incapable of being tied into the reference
to stringent conditions on page 10 of the patent, the reference to stringent
conditions does not invalidate Claim 1 in terms of classic insufficiency,
is consistent with the approach of the Board. In T301/87 Alpha-Interferon/Biogen
OJ EPO 1990, 335, the Board said this:
"Such macromolecular precursors may in appropriate cases be defined
as a class by the characteristics of the end products they relate to and by
some structural characteristics such as similarity based on capability of
hybridisation with available structures, without necessarily creating uncertainty"
(paragraph 4.5).
- As the Board went out to point out in paragraph 4.7:
"Unless claims with such functional connotations are allowable no worthwhile
protection is provided against a third party which faithfully repeats the
process of the patent and obtains new but equally useful variants of the invention."
- In The European Patent Office’s Case Law on the Patentability of Biotechnology
Inventions Dr Jaenichen, after discussing this case at pages 81 to 83, suggests
that a claim in the following form would be allowable:
"A DNA sequence hybridising to the DNA sequence of Claim X and encoding
polypeptide having the biological activity Z."
However, it is right to add that, on the same page, the author goes on to
suggest that "in order to be on the safe side" it would be sensible
to add something along these lines;
""Hybridisation" refers to conventional hybridisation conditions,
preferably to hybridisation conditions under which Tm value is between Tm...
to Tm... Most preferably, the term "hybridisation" refers to stringent
hybridisation conditions."
- This latter passage indicates how a patentee can get himself greater protection
on the insufficiency issue. However, even bearing that in mind, it appears
to me to cut both ways. Although Roche can fairly point out that it does require
identification of the hybridisation conditions, it is nonetheless the case
that the term "stringent hybridisation" is included in this latter
passage without giving specific guidance.
- Of course, as my conclusion as to the effectiveness of product-by-process
claims where the process is novel in this very case emphasises, I am not bound
by decisions, or even the approach, of the Board. Nonetheless, as has been
said in a number of cases, the Board’s decisions at least deserve respect.
Furthermore, I note that it is not unusual to make claims to DNA in biotechnology
patents by reference to those sequences which hybridise with the specific
sequences claimed (or their complements) "under stringent conditions",
or some other expression. Indeed, I was referred to a number of United States
patents granted to GI substantially in such terms. I also note that Claim
11 in Chiron which included the expression "selectively hybridisable"
was not rejected for lack of clarity or insufficiency, but because of the
lack of any limitation to sequences having the appropriate biological activity.
- It is also right in this connection to refer to my decision in Novo Nordisk
A/S -v- DSM NV (unreported 21st December 2000), which was said at least to
cast doubt on the view that the reference to "stringent conditions"
was sufficient. That case does not cause me to change my view. The essential
problem for the patentee in Novo Nordisk was that the relevant passage in
the claim referred to "DNA sequences hybridising at low stringency conditions"
and to washing conditions which were of lower stringency than the hybridisation
conditions. The patentee contended, in effect, that this was not to be construed
literally, and that the addressee would increase the stringency of the conditions
as a matter of routine. The effect of my decision on that issue was that the
absence of any teaching to that effect, and the inevitable uncertainties and
delays which it involved, resulted in the claim concerned being insufficient.
It is also right to say that a number of points were made on behalf of the
patentee in the present case in relation to this issue which were not made
on behalf of the patentee in Novo Nordisk (and I do not mean to imply any
criticism of the way in which the case was presented in Novo Nordisk: the
patentee would probably not have been assisted by any of the additional points
made on behalf of Amgen in relation to this issue in the present case).
- Accordingly, I reject the contention that Claim 1(b) is insufficient on
this ground. This conclusion applies equally, and for the same reasons, to
the incorporated reference to stringent conditions in Claim 1(c).
J. CLASSIC INSUFFICIENCY: CLAIMS 19 AND 20
Introductory
- Roche and TKT contend that that aspect of Claim 19 which stipulates that,
in order to be within the Claim, recombinant EPO ("rEPO") has to
have "higher molecular weight by SDS-PAGE from erythropoeitin isolated
from urinary sources" ("uEPO") suffers from insufficiency.
When considering the construction of Claim 19, I reached the conclusions that:
1. The closing words of Claim 19 require that there was a detectable
overall difference between the performance of the two types of EPO on SDS-PAGE;
2. The uEPO need only be isolated to the extent necessary to carry out
the SDS-PAGE exercise: in particular, it need not be completely pure;
3. The uEPO need not be from a pooled source;
4. The uEPO could be isolated in accordance with any technique referred
to in the patent (or within the common general knowledge at the relevant time)
with or without any workshop modification.
- The same argument is mounted against Claim 20 which incorporated Claim 19.
Additionally, Claim 20 is said to be insufficient in relation to its reference
to differential glycosylation.
Claim 19: Amgen’s contemporary experiments
- Not surprisingly, scientists at Amgen had carried out a number of experiments
testing the performance of a number of different batches of rEPO against a
number of different batches of uEPO, on SDS-PAGE. The individual who carried
out the bulk of this work during the 1984 and 1985 was Dr Joan Egrie, and
I saw extracts from her contemporary entries in laboratory notebooks, which
included results in the form of photocopies and/or originals of the SDS-PAGE
experiments, including blotting and RIAs. This work was the subject of three
publications in the name of Egrie and others (Experimental approaches for
the study of Hemoglobin Switching p339, Tenth Annual Frederic Stohlman Symposium,
and Immunobiol. 172:313) and two other published papers, one published in
1986 in the name of Browne and others (Cold Spring Harbor Symposia on Quatantitative
Biology Vol. LI, page 693) and the other in the name of Eschbach and others
in 1987 in New England Journal of Medicine 316(2):73.
- Amgen contends that one can draw adverse inferences from the fact that TKT
and Roche rely on these experiments, including what was said about them in
Dr Egrie’s notebooks and in the published papers, rather than carrying out
the same or similar experiments themselves for the purpose of these proceedings.
I reject that contention. As has often been observed, the carrying out of
experiments for the purpose of legal proceedings can be expensive and time
consuming. If one party is content to rely upon experiments carried out by
or on behalf of another party (whether or not for the purpose of the proceedings)
then it seems to me that the court should, if anything, deprecate the idea
that he should incur further cost and time in repeating, or seeking to repeat,
those experiments. Relying on an experiment carried out on behalf of another
party has a benefit and a risk. The benefit is that, while one will normally
not be able to rely upon the experiment as an admission in technical legal
terms, the fact that it was carried out by the other party may well make it
more difficult for the other party to impugn it. The risk of relying upon
the other party’s experiments is that the other party may know of special
facts, or may be able to call one of the people involved in carrying out the
experiment to cast doubt, or worse, upon it. From the point of view of the
court, a potential advantage of an experiment carried out by or on behalf
of one party, but not in the context of the proceedings, is that the obvious
ground for caution when considering the nature or the alleged result of the
experiment (namely the desire to succeed in the proceedings) does not exist.
However, there may well be other factors which could influence the perspective
of the person carrying out and analysing experiments not in the context of
proceedings.
- So far as the result of Amgen’s experiments in 1984 and 1985 are concerned,
I consider that, at the risk of appearing arrogant, the results were tolerably
clear. I express myself in this slightly diffident way, because a significant
proportion of the expert evidence, and, albeit to a lesser degree, of the
argument, was given over to this topic.
- Amgen’s work involved three types of urinary EPO and two types of recombinant
EPO. The three types of uEPO were:
1. "Goldwasser uEPO", which was uEPO isolated from pooled urinary
sources by Dr Goldwasser in accordance with the teaching of Miyake;
2. "Lot 82 uEPO" which was uEPO isolated substantially in accordance
with the teaching of Miyake, but in respect of which there was a single source
(i.e. the urine all came from one patient);
3. Alpha Therapeutics uEPO, which was uEPO from urinary sources, by a
method of isolation which was not specified.
The two types of recombinant EPO used in Amgen’s experiments were expressed
substantially in accordance with the teaching of 605, in COS and CHO cells
respectively (i.e. "COS rEPO" and "CHO rEPO").
- Dr Egrie ran a number of comparative SDS-PAGE experiments. She ran various
urinary EPOs against each other, most notably Lot 82 uEPO against Goldwasser
uEPO on a number of occasions, and also Alpha Therapeutic uEPO against Goldwasser
uEPO. She also ran CHO rEPO against Lot 82 uEPO on at least three occasions
and COS rEPO against Goldwasser uEPO on at least three occasions.
- The results of the Amgen experiments, at least as interpreted by Dr Egrie
at the time, were:
1. Lot 82 uEPO had a higher apparent molecular weight than Goldwasser
uEPO;
2. COS rEPO had the same apparent molecular weight as Goldwasser uEPO;
3. CHO rEPO had the same apparent molecular weight as Lot 82 uEPO;
4. Alpha Therapeutics uEPO had the same apparent molecular weight as
Lot 82 uEPO.
- In my judgment, Dr Egrie’s views, as I have just summarised them, were correct.
Professor Cummings (who did not agree with Dr Egrie) and Professor Matsudaira
(who did) both agreed that Dr Egrie was an experienced and careful scientist,
and her contemporary conclusions are expressed in confident terms in her notebooks.
These views were repeated in the articles to which I have referred, and those
articles were not written by Dr Egrie alone, but included more senior scientists
working for Amgen. Most of the articles were in prestigious journals or books,
and they were all peer-reviewed. Each of the papers contained an unambiguous
statement to the effect that one or other of the two types of rEPO migrated
on SDS-PAGE effectively identically to one of the types of uEPO. In addition,
in its own submissions to the FDA, Amgen stated that "the r-HuEPO migrates
identically to the pure urinary EPO".
- In the end, of course, the decision as to whether Dr Egrie’s conclusions
were correct, must depend upon the evidence as a whole. In that connection,
I have seen the results of the SDS-PAGE experiments, which are sometimes photographs
of the results after blotting (normally with antibodies), sometimes the rather
faded originals after blotting, and sometimes the autoradiograms or photocopies
of them. Further, there has been the expert evidence as to how to interpret
these results. Professor Cummings made a number of criticisms of the conclusions
reached by Dr Egrie. I am bound to say that he appeared to regard this to
be that of trying to think up as many conceivable uncertainties or problems
with Dr Egrie’s experiments and conclusions, so as to enable Amgen to contend
that, viewed as a whole, her experiments could not be relied on to draw any
of the conclusions which she identified. As an exercise in advocacy, it was
moderately impressive, particularly bearing in mind the clear contemporary
conclusions reached by Dr Egrie and, apparently, so many other experienced
scientists employed by Amgen. However, as an example of the proper approach
of an expert witness, it left much to be desired. It would be inappropriate
for me to deal with every aspect of his evidence on this aspect, and I hope
that a couple of examples suffice.
- First, Professor Cummings suggested that Dr Egrie’s conclusion that Lot
82 uEPO and Alpha Therapeutics uEPO showed a higher apparent molecular weight
than Goldwasser uEPO was based upon possible differences in the degree of
iodination between the two samples (the iodination being the attachment of
radioactive iodine to the protein so that it "shows up" on an autoradiogram).
While that, of course, could be a possible explanation in theory for the difference
in performance, it is clear from Dr Egrie’s own notes that she had compared
the X-ray film of the iodinated uEPO with un-iodinated uEPO by superimposing
the autoradiogram over the Western blot. She then specifically recorded that
"this comparison... definitively shows the difference in migration [between
Goldwasser EPO and Lot 82 EPO]". Indeed, Professor Cummings effectively
accepted that Dr Egrie had carried out "a sensible control", but
said, without giving any reason (as Mr Kitchin points out), that "she
may not have done it correctly". The notion that differential iodination
could have been the cause of the difference in the performance of the two
types of uEPO is further called into question by the fact that the two types
demonstrated the same apparent molecular weight on SDS-PAGE after they had
been deglycosylated: iodination involves attachment of iodine to the protein
backbone, and not to the glycans. Accordingly that test confirms Dr Egrie’s
conclusions and is inconsistent with Professor Cummings’s criticism.
- Furthermore, Professor Cummings was prepared to doubt the results of certain
SDS-PAGE experiments on at least one ground which appear to apply equally
to an SDS-PAGE experiment upon which he relied. He explained that a main reason
for not regarding one of Dr Egrie’s experiments as reliable was that two lanes
which she compared were not close to each other on the gel: there were several
lanes between them. However, when dealing with the one published paper which
arguably assisted Amgen’s case on this issue (Kung & Goldwasser in Protein
Struct. Func. Gen 28:94, 1997), where the two lanes on SDS-PAGE which were
to be compared were more than seven lanes apart, he said that the comparison
"clearly showed" a difference in the apparent molecular weight of
the substances in the two lanes.
- I should mention two other factors which Professor Cummings suggested might
render Dr Egrie’s conclusions wrong. First, the apparent overloading of some
of the lanes in some of the experiments, and secondly the duration for which
the SDS-PAGE experiments may have been run. The second point is not of significance,
as Professor Cummings himself accepted. In relation to one or two of the lanes
in one or two of the experiments carried out by Dr Egrie, the difference in
loading, or, to put it more accurately, the apparent overloading, was something
which, to my mind, could fairly be identified as rendering the performance
of the material in the particular lane unreliable. However, I agree with Mr
Kitchin, that one only has to look at the overwhelming majority of the results
of the experiments to see that there is nothing in this point, in that the
one or two occasions where it does apply do not in any way seriously be said
to call Dr Egrie’s conclusions into question.
Claim 19: Dr Strickland’s and TKT’s experiments
- Apart from the experiments of Dr Egrie, I should mention other experiments
of relevance to this issue. During 1995, and in connection with the current
proceedings, Dr Thomas Strickland of Amgen carried out the process of purifying
EPO from urine in accordance with the teaching of Miyake. In this connection,
it should be explained that the isolation of urinary EPO in accordance with
the teaching of Miyake involved seven stages. As is usual when carrying out
any process of purification or isolation, each stage should involve a mixture
with an increasing proportion of the substance one is seeking to isolate,
in this case EPO. At one stage in the Miyake procedure, namely DEAE-agarose
ion-exchange chromatography, three fractions are produced, known as the 5
millimolar (5mM), the 17mM and the 30mM fractions. (Under the procedure, calcium
chloride solutions of increasing concentration, measured by millimoles, is
used to wash protein off the agarose column). Dr Strickland found that 85%
of the protein was in the 30mM fraction, which was 2.6 times more pure or
concentrated than the material loaded onto the column, and the 17mM fraction
only contained 9.9% of the protein and was in fact only a quarter as concentrated
as the material loaded on to the column.
- Nonetheless, Dr Strickland proceeded to seek to isolate the uEPO by the
subsequent steps in the Miyake procedure from each of those two fractions.
He then ran the 30mM fraction on SDS-PAGE against the GA-EPO made by TKT,
which, according to Amgen infringes 605. In accordance with his conclusion,
it seems to me that the urinary EPO (the "30mM uEPO") migrated a
little faster than the GA-EPO. Accordingly, at least as against the 30mM uEPO,
GA-EPO had a somewhat higher apparent molecular weight, and this was also
found to be the case by TKT in its experiments.
- However, the uEPO obtained from the 17mM fraction (the "17mM uEPO")
performed rather differently as against GA-EPO, according to TKT’s SDS-PAGE
experiments, as analysed by Professor Matsudaira, with whose view I agree.
It seems to me that those experiments show TKT’s GA-EPO migrating to the same
point on SDS-PAGE as the 17mM uEPO, thereby suggesting that they enjoyed the
same apparent molecular weight.
- Two criticisms are made of TKT’s SDS-PAGE experiments so far as comparison
with the 17mM uEPO are concerned. First, it is suggested by Amgen that the
results are not to be relied on because, in order to identify the point to
which the EPO had travelled, TKT used a polyclonal antibody, rather than a
monoclonal antibody. I accept that it would be better normally to use a monoclonal
antibody, because it is virtually certain to be specific to a particular protein:
accordingly, one can be pretty confident that the band which appears as a
result of the antibody fixing on to a protein is the specific protein one
is looking for. Polyclonal antibodies are liable to be less specific, and
therefore there can be more uncertainty as to whether they have in fact fixed
on to the protein for which one is looking.
- However, in relation to TKT’s experiments, I am unimpressed with this criticism.
The trade literature relating to the polyclonal antibody used in TKT’s experiments
demonstrate that it is relatively specific, and Professor Matsudaira, a reliable
witness, said that he often used polyclonal antibodies if he thought they
were reliable. Further, if the apparent result of TKT’s experiments was wrong
because of the use of a polyclonal antibody, it could only arise from the
most extraordinary coincidence. The experiments showed a single band, of normal
width and character for a glycoprotein, indeed for EPO itself. Thus, if there
was any other protein on to which the antibody fixed, it would have had to
have had more or less exactly the same apparent molecular weight as EPO. Quite
apart from this, even then, Amgen’s indictment of the experiment would only
be justified if one could conclude that there was no EPO present, merely another
glycoprotein with more or less the same apparent molecular weight, which reacted
to this polyclonal antibody, which, at least judging by the literature, was
pretty specific. Thus the criticism of TKT’s experiments requires such a combination
of unlikely coincidences that I conclude that it can be confidently rejected.
- The second criticism of TKT’s experiments relating to the 17mM uEPO is,
in my judgment, more formidable. At first sight, at any rate, it would be
almost perverse to take the 17mM uEPO, as opposed to 30mM uEPO. The great
majority of the uEPO was in the 30mM fraction, and, indeed, the concentration
of EPO in the 17mM fraction was actually lower after the fractionation than
before. On the face of it, the natural course, if one had to choose between
the fractions, would be obvious: one would go for the 30mM fraction. Sir John
Walker expressed that view in robust terms.
- However, I do not think the point is quite that simple. The teaching of
Miyake in his paper (op. cit.) involves taking the 17mM fraction, and not
the 30mM fraction. Not surprisingly, that is because, as his paper reports,
Miyake obtained a much greater concentration of EPO in the 17mM fraction than
in the 30mM fraction (unlike Dr Strickland). I have accepted Amgen’s construction
of the closing words of Claim 19, in the sense that it refers to isolation
in accordance with methods referred to in the patent itself (or within the
common general knowledge). It seems to be tacit common ground that the most
satisfactory or common of these methods is that reported by Miyake. There
is thus obvious force in the contention that a person in Dr Strickland’s position
seeking to follow the teaching of Miyake in order to apply the test laid down
at the end of Claim 19, would find himself in a state of some uncertainty:
should he follow the 17mM fraction, in accordance with the literal teaching
of Miyake, or should he follow the 30mM fraction, in accordance with what
might be said to be the spirit of Miyake?
- Although alternative extremes were adopted by witnesses, it seems to me
that the correct approach was that of Professor Matsudaira, whose evidence
was to the following effect. He saw no reason why the skilled addressee should
have to choose between the two fractions: given the dilemma, he would follow
both. However, he accepted that, if one had to choose between the two fractions,
one would "follow the protein", to use Mr Watson’s expression, and
therefore one would go with the 30mM fraction. In my judgment, a careful person
carrying out the work, as Dr Strickland did, would have thought the safest
course was to continue the Miyake process in relation to both fractions. I
draw support for that conclusion from the fact that this is what Dr Strickland
of Amgen actually did. It is suggested on behalf of Amgen that he merely did
this because he was carrying out his work in the context of the present litigation,
and, in particular, on the instruction of the lawyers acting for Amgen. There
was no reliable evidence which even starts to support this contention, in
my view. Indeed, there is contemporary documentary evidence to suggest the
contrary. There is no record of any relevant discussions with any lawyer (whether
in this country or the United States); no lawyer was called to give evidence
on the point; Dr Strickland could not recall any relevant discussions with
lawyers. Following both fractions seems to have resulted from discussions
he had with Dr Egrie. The two doctors were relatively disinterested and relatively
skilled scientists (albeit working for Amgen) and not lawyers. I believe my
conclusion receives a little support from the fact that urinary EPO is so
very difficult to obtain and therefore so scarce. That would be an additional
practical reason for not discarding the 17mM fraction.
Claim 19: more recent publications
- There was further evidence about the performance of urinary EPO according
to papers which were published after the relevant date, in particular, Imai
et al. in Eur. J. Biochem. 194:457 (1990) ("Imai") and Inoue et
al. in Biol. Pharm. Bull. 17(2):180 (1994) ("Inoue"). Inoue reported
that if uEPO is purified from urine without the use of phenol (which was a
treatment included in the process taught by Miyake) then it migrated more
slowly on SDS-PAGE than if phenol was used. Inoue assessed the difference
as showing a difference in apparent molecular weight in the region of 2kDa.
Inoue also demonstrated that the in vivo performance of the uEPO isolated
without the use of phenol was somewhat greater than that of the uEPO where
phenol was used. A similar result was vouchsafed by Imai, but he also reported
that uEPO prepared without the use of phenol treatment had the same mobility
on SDS-PAGE as CHO rEPO.
- Amgen contend that this evidence is not reliable, because it merely amounts
to two reports of experiments, which have not been repeated for the purpose
of these proceedings. I accept that it can be dangerous to rely upon reports
in scientific journals, even when they were peer-reviewed and when they include
photographs of the relevant experiments (as both Imai and Inoue do). However,
particularly in light of the time and cost involved in carrying out experiments,
I am of the view that the court should be prepared to take into account the
results of experiments such as those reported in the two papers I have mentioned.
Plainly, care must obviously be taken in light of the fact that the person
seeking to challenge the experiments cannot cross examine the person who carried
them out, cannot have inspected when they were carried out, and cannot reasonably
be expected to repeat them (given that the person relying on them has not
chosen to do so). I see no reason to doubt the results reported by Imai and
Inoue, particularly as no witness seriously called into question the reliability
of the results so far as they could be judged from the contents of the papers.
- I have already referred to the paper by Kung and Goldwasser published in
1997. This paper involved a comparison between CHO rEPO and uEPO prepared
in accordance with the teaching of Miyake. The paper concluded that the recombinant
EPO was more easily iodinated than the urinary EPO, which in turn suggested
that there was a difference in conformation (i.e. three dimensional shape)
and/or glycosylation between the two types of EPO, on the basis that the amino
acid which is iodinated was perhaps more difficult for iodination access in
the urinary, than in the recombinant, EPO. I should interpose to say that
this does not call into question my conclusion that there was no difference
in the iodination of the different EPOs carried out by Dr Egrie. First, she
was comparing two types of urinary EPO; secondly, she competently carried
out an experiment which established to her contemporary satisfaction, and
indeed to my satisfaction (as well as to that of at least one of the expert
witnesses) that any difference in the apparent molecular weight between the
types of urinary EPO she was experimenting with was not attributable to differential
iodination. Indeed, I was referred to a paper by Tsuda et al. published in
1988 in Biochemistry 27(15) 5646, which supported the conclusion that uEPOs
from different pooled sources, isolated by the same procedures, can have different
apparent molecular weights.
- The experiments carried out by Dr Egrie establish the basic facts as I have
summarised them, by reference to Goldwasser uEPO and Lot 82 uEPO, one of which
was prepared in accordance with Miyake’s teaching, and the other (subject
to the urine having been obtained from the single source) also used Miyake’s
method subject to a minor workshop modification. The work carried out by Dr
Strickland and TKT in connection with these proceedings complicates matters
further, in that it indicates, at least to my mind, that following the teaching
of Miyake can result in urinary EPO being taken from two different fractions
at one of the stages of the purification process, and the two lots of uEPO
having different apparent molecular weights, and therefore producing inconsistent
results as against a sample of recombinant EPO with regard to the test in
the closing words of Claim 19. The position is further complicated by the
reports of Imai and Inoue: both of them showed that a minor workshop modification
to the Miyake process results in the uEPO thereby produced having a significantly
higher apparent molecular weight by SDS-PAGE than uEPO isolated strictly in
accordance with the teaching of Miyake, the modification being the non-use
of phenol at one of the seven stages taught by Miyake. Although I heard evidence
and arguments as to the reason and effect of using phenol, I do not consider
that it is necessary for me to go into that aspect: Miyake used phenol, and
because it was suspected that phenol might have an effect on the ultimate
isolated product, Imai and Inoue dispensed with it. As its use was unnecessary,
it seems to me, standing at the relevant date, it would have been an obvious
modification in the eyes of the skilled addressee to omit the phenol.
- There is no reason to doubt the conclusions of Imai and Inoue. Those conclusions
are particularly significant because the uEPO produced without the use of
phenol has a reported apparent molecular weight 2kDa greater than the uEPO
isolated strictly in accordance with the teaching of Miyake, and that sort
of difference is similar to, or greater than, any difference in apparent molecular
weight recorded between rEPOs and uEPOs in the experiments reported in published
papers, and conducted by Dr Egrie and by Dr Strickland. In particular, as
I have mentioned, Kung and Goldwasser, upon whom Amgen rely, suggest that
CHO rEPO has an apparent molecular weight 1.2kDa greater than uEPO purified
in accordance with the teaching of Miyake. I accept that it can be dangerous
and unsafe to compare the results of two independent experiments in this way,
particularly when they are only contained in reported papers (albeit in respected
peer-reviewed journals). However, it would seem from these two papers that,
while CHO rEPO has a higher apparent molecular weight than uEPO prepared strictly
in accordance with the teaching of Miyake, it has approximately the same,
and if anything a lower, apparent molecular weight than uEPO isolated in accordance
with the teaching of Miyake subject to a small, almost trivial, modification.
Claim 19: conclusions
- In my judgment, the aggregate effect of all the experiments and reports
to which I have referred, involving CHO rEPO and COS rEPO, and various batches
of uEPO prepared strictly or substantially (i.e. with minor workshop modifications)
in accordance with the teaching of Miyake establishes the following. First,
some rEPOs have a higher apparent molecular weight by SDS-PAGE than some uEPOs;
secondly, some rEPOs have the same apparent molecular weight as some uEPOs;
thirdly, no rEPOs have a lower apparent molecular weight than any uEPOs. However,
it is clear from the paper of Wojchowski (op. cit.). to which I have not so
far referred in the current connection, who expressed recombinant EPO in insect
cells, that recombinant EPO of a type specifically referred to in the patent,
and which otherwise would fall within Claim 19, can have a lower apparent
molecular weight than most, indeed probably all, urinary EPOs. His experiments
suggested that recombinant EPO expressed in a fruit fly cell had an apparent
molecular weight of some 23 KDa.
- In light of these conclusions, it appears to me that Claim 19 is incapable
of being infringed. According to the teaching of the 605 patent (in Example
10 on page 31), and indeed the evidence I have heard, any difference in apparent
molecular weight is small. It appears to me that the variations in apparent
molecular weight between different batches of urinary EPO, coupled with the
fact that it is clear that many recombinant EPOs do not satisfy the test,
would put the skilled addressee seeking to discover whether his product was
within Claim 19, and seeking to discover this in a reasonable way, in an unsatisfactory,
indeed, an impossible, position.
- In my judgment, it would be unreasonable to expect the skilled addressee
seeking to discover whether his product is within Claim 19, to carry out the
exercise required of him by the closing words of that Claim by running his
product against more than one sample of urinary EPO. Indeed, I do not think
anything else is contemplated by the Claim. The closing words of Claim 19
suggest that the draftsman believed that urinary EPOs have effectively the
same apparent molecular weight, irrespective of the method by which they were
isolated. Quite apart from this, it would be very onerous to expect the reader
of 605 to get more than one sample of isolated urinary EPO, in light of the
difficulty of obtaining samples of that product, a problem which would have
been clear from the patent and is clear from the evidence in this case.
- Suppose, however, the skilled addressee could be expected to run his product
on SDS-PAGE against three samples of uEPO from different sources. If his product
displays a lower apparent molecular weight than, or similar apparent molecular
weight to, one or more of the samples of urinary EPO, then his product would
not be within Claim 19, given my conclusion that Claim 19 requires the product
to have a higher molecular weight than all urinary EPOs isolated in accordance
with any teaching referred to in the patent or within common general knowledge.
If, however, his product has a higher apparent molecular weight than all three
samples of uEPO, that would not be the end of the matter. Given the different
performance of different uEPOs, depending on their source and the precise
manner of isolation (and possibly other factors), and bearing in mind the
very small difference in apparent molecular weight which would have been seen
by the skilled addressee, he could not be confident that his product was within
the Claim. He may well, for instance, not have run his product against urinary
EPO isolated in the same way as Imai and Inoue isolated their product. In
my judgment, it would be a long way away from giving "a reasonable degree
of certainty for third parties" if the closing part of Claim 19 did not
result in that claim being incapable of infringement.
- It does not seem to me that this conclusion is inconsistent with the conclusion
I would have reached in relation to the apparently similar problem thrown
up in relation to the requirement of "stringent conditions" in Claim
1(b) of the 605 patent. In order to see whether there is hybridisation in
"stringent" conditions, the skilled man would carry out a routine
series of experiments, involving increased stringency, and if hybridisation
only occurs in conditions which some might reasonably regard as not being
"stringent", then his product is not within the claim: the uncertainty
thrown up by the word "stringent" in that event is resolved in favour
of the alleged infringer, so that if the relevant conditions might be considered
by some, but not others, to be "stringent", there is no infringement.
I do not think that Amgen can say that the same result obtains in relation
to the uncertainty thrown up by the closing words of Claim 19. The position
might appear the same, in that the fact that one type of urinary EPO may have
the same apparent molecular weight as (or, indeed, a higher molecular weight
than) the reader’s recombinant EPO would, as I see it, mean that there was
no infringement, and it would only be if the alleged infringer’s recombinant
EPO had a higher apparent molecular weight than urinary EPO isolated from
any source in accordance with one of the methods described in the patent that
he would infringe. However, unlike the requirement of "stringent conditions"
in Claim 1(b), which requires a set of routine experiments which could, indeed
arguably would in any event, be carried out by the skilled man, the requirement
of the closing words of Claim 19 would involve him potentially carrying out
SDS-PAGE comparisons between his recombinant EPO and an indeterminate number
of different urinary EPOs, all of which would be pretty difficult to obtain.
The result of the comparisons would either be that he did not infringe or
that he could not be sure that he infringed.
- The more difficult question, to my mind, is whether my conclusion as to
the effect of the closing words of Claim 19 not merely renders that Claim
incapable of infringement, but renders the Claim invalid on grounds of insufficiency.
I revert to the words of Section 72(1)(c) of the 1977 Act: can it be said
that the closing words of Claim 19 result in "the invention [not being
disclosed] clearly enough and completely enough for it to be performed by
a person skilled in the art"? As I have mentioned when considering Claim
1(b), it has been held by the Court of Appeal that lack of clarity or ambiguity
do not render a claim insufficient, albeit that they may render it incapable
of infringement either in whole or to an extent. Thus if a claim was ambiguous,
in the sense that it had two meanings, it would be incapable of infringement
if an allegedly infringing product could not fall within both meanings. On
the other hand, it might nonetheless be capable of infringement if an infringing
product fell within both meanings.
- I have come to the conclusion that the problem raised by the closing words
of Claim 19, does not merely render the Claim incapable of infringement; it
renders the Claim invalid on grounds of insufficiency. It is true that, the
Claim is conceptually clear: it is a claim to all recombinant polypeptides
which satisfy the other requirements of the Claim, and which have a higher
apparent molecular weight than EPO isolated from any urinary source in accordance
with a method referred to in the patent or within the common general knowledge.
However, in so far as the Claim is or embodies the invention for the purposes
of Section 72(1) of the 1977 Act, it appears to me inescapable that the disclosure
is not at all "clear", in so far as it is "complete",
within the meaning of the section.
- The clarity of the disclosure required by Section 72(1)(c) is not merely
conceptual clarity. If it were, then, as I say , Amgen would have no problem
with insufficiency on Claim 19. The clarity and completeness have to be such
as to enable the skilled person to "perform" the invention. The
word "perform", in this context, carries the implication of work
which is non-inventive, routine, not prolonged and not involving research.
Even if the skilled addressee finds his product appears to satisfy Claim 19
when run against one sample of uEPO on SDS-PAGE, he might still have to check
it against any number of other EPOs. There is no teaching in the patent to
suggest that he would have to do this. Further, that he might have to do it
was not within common general knowledge . To obtain a number of uEPOs from
different sources (whether to find out which has the highest apparent molecular
weight or whether to run each of them against his product) would involve the
addressee in prolonged work; it would not be routine. Further, it is an exercise
which he could never be sure he had completed, unless and until he found that
he was not within the Claim (because he identified urinary EPO which had the
same or a higher apparent molecular weight than his product). His investigation
could be never ending, unless it established non-infringement. His research,
even if it ended with a conclusive result, could be time consuming and difficult.
His research would not be routine, let alone taught, by the patent.
Claim 20
- There is no specific teaching in the patent to the effect that some or all
recombinant EPOs differ in their glycosylation characteristics from some or
all EPO isolated from urinary sources. The nearest one gets to any such teaching
is in the last two paragraphs of Example 10 (page 31, lines 10 to 22) which
describes a "preliminary attempt... to characterise recombinant glycoprotein
products from... COS... and CHO cell expressions... in comparison to human
urinary isolates". The disclosure that CHO rEPO had a "somewhat
higher molecular weight" than COS rEPO, which in turn had a "slightly
larger" molecular weight than pooled urinary EPO would be understood
to suggest that the aggregate apparent molecular weight of the glycans on
the two types of recombinant EPO was greater (albeit not by much) than on
urinary EPO. Beyond that, however, the patent gives no guidance as to the
nature of the difference in the "average carbohydrate composition"
between the "glycoprotein polypeptide" and the "human erythropoeitin
isolated from urinary sources" referred to in Claim 20. Furthermore,
as I shall discuss in a little more detail when considering the issue of novelty,
there is, despite Professor Cummings’s suggestions to the contrary in his
written report, no satisfactory evidence, let alone specific teaching, even
today, as to what differences exist in the glycosylation of some or all rEPOs
and some or all uEPOs. Accordingly, I think Claim 20 is insufficient on that
ground. In any event, it is insufficient for the reasons given in relation
to Claim 19, given that it incorporates that Claim by reference.
K. BIOGEN INSUFFICIENCY & BREADTH OF CLAIM AND CONCLUSIONS
Introduction
- The two main insufficiency arguments raised by TKT and Roche which I shall
consider in this part of the judgment are as follows. First, Claim 1 (as well
as many of the other Claims) extends to amplified or enhanced expression of
EPO in eukaryotic cells generally, whereas the only teaching of the patent
is in relation to DHFR- CHO cells, a point I have already considered when
discussing classic insufficiency. Secondly, Claim 1 (again like many of the
other Claims) extends not merely to EPO but to analogues of EPO (that is any
polypeptide with possibly significant variations in the amino acid residues
of EPO, which retains EPO-like characteristics) with virtually no teaching
(other than one or two specific instances) as to what those analogues may
be.
- In terms of what I might call classic insufficiency, there is an obvious
case for saying that, in each respect, the Claims, in so far as they extend
to either or both features, are insufficient. So far as the first aspect is
concerned, the claim of the patent was not to have obtained pure EPO for the
first time: this has already been done, albeit in very small quantities indeed,
for instance by Miyake (op. cit.). What the patent purported to enable was
a method of obtaining EPO in greater quantities, in particular in quantities
sufficient for commercial and therapeutic use. The only specific way of doing
this taught by the patent was in amplified DHFR- CHO cells. Amgen did not
claim to have succeeded, and indeed had not succeeded, in obtaining amplified
expression of EPO in human cells or COS cells. Unlike, for instance, TKT’s
technology (of which more below) the patent does not provide a way of amplifying
a DHFR+ cell. Further, the only known DHFR- cells, at least at the relevant
time, were CHO, as was accepted by Professor Wall in cross examination. Although
Amgen’s experiments with a certain type of human cell, the so-called human
293 cell line, produced EPO, it was not at a high level of expression. Accordingly,
as I have already determined, the patent can be said to be classically insufficient
so far as amplified or enhanced expression in human cells is concerned.
- As to analogues, Professor Proudfoot’s unchallenged evidence was that the
specific structures and activities of the proteins coded for are not predictable.
EPO has 165 amino acids, and a change of one amino acid to another specific
amino acid could be deleterious, beneficial, or make no difference; the number
of different permutations involved in changing any two of the 165 amino acids
runs into millions. Once one contemplates the possibility of changing, say,
up to ten of the amino acids (and the evidence I heard suggested, albeit not
specifically, that over ten changes in a protein with 165 residues may well
not affect functionality, particularly if the changes were to residues not
in the active sites of the protein), the permutations are, almost literally,
approaching the infinite. Over and above this, the patent purports to cover
deletions and additions. It seems to me that investigation as to which analogues
(and therefore which encoding sequences) fall within Claim 1 would involve
work of a routine nature, but it could not possibly be said that it would
take a reasonable time. This is nicely encapsulated in an observation of Professor
Wall:
"I know scientists who have spent a career taking a protein and changing
every amino acid and seeing what its biological function is. They have long
boring careers in my opinion."
The last adjective in that passage indicates the routine nature of the work,
and the penultimate adjective shows that the time involved would not be reasonable.
- The 605 patent gives very little, if any, significant help on this aspect.
There is nothing to indicate which amino acids might be changed and/or which
amino acids could probably not be changed in the EPO sequence contained in
Table VI. If the patent had revealed the three dimensional structure of EPO,
and, perhaps even more, if it had revealed which of the internal sequences
constituted the active sites, that would have given some assistance, possibly
substantial assistance, to the reader. As I have mentioned, amino acid residues
in the active sites of a protein are generally more likely to be essential
to the functioning of the protein than residues outside the active sites.
- The evidence of Dr Browne of Amgen, indicated that Amgen had started an
analogue programme, but it was not given high priority, compared, for instance,
with expanding the effort on the development of mammalian cell lines producing
higher levels of EPO. He also said that Amgen knew very little about the three
dimensional structure of EPO or its active sites. He accepted that the investigations
necessary to give any real guidance as to which amino acid residues in EPO
could be varied without the resultant polypeptide losing its EPO-like characteristics
would have involved "a research programme", the very thing which
has been said to give rise to classic insufficiency.
- Amgen’s answer to this attack is that the disclosure of the 605 patent is
such that, even though the Claims extend to human and other cells, and are
not limited to DHFR- CHO cells, and to all analogues of EPO, and are not limited
to the natural sequence of EPO, does not amount to insufficiency.
Amgen’s argument based on Biogen [1997] RPC1
- Adopting the language of Lord Hoffmann in Biogen [1997] RPC 1 at 48, when
explaining the Board’s decision in Genentech I/Polypeptide Expression Amgen’s
argument effectively amounts to contending that its "invention discloses
a principle of general application" rather than "a number of discreet
methods or products". As Lord Hoffmann also explained at [1997] RPC 48,
if the invention is of the former quality "the claims may be in correspondingly
general terms", whereas if of the latter quality, "the patentee
must enable the invention to be performed in respect of each [discreet product
or process]".
- It appears to me that the first step in considering this argument is to
identify the technical contribution to the art made by the disclosure of the
patent in suit. In this connection, I start with the fact that it is common
ground that the disclosure of the patent was not obvious, and with the assumption
that the arguments that the disclosure was in some way anticipated have been
rejected. I can therefore proceed on the basis that the disclosure of the
patent has made a contribution, and it is therefore a question of identifying
the nature and extent of that contribution. All parties eschewed the notion
that one should take into account the degree of inventiveness, a view with
which I would agree. Obviously, in many cases the degree of inventiveness
and the contribution to the art of a particular invention have a degree of
equivalence, but in some cases they may not. It cannot be the function of
the court to decide how clever or ingenious a particular invention was. First,
it is obviously a particularly difficult and, to a significant extent, a subjective,
exercise. Secondly, it would lead to a substantial degree of unpredictability
in the law, which is always undesirable, and, I would have thought, particularly
so in the field of patents. Thirdly, it would appear to me to be contrary
to principle for the Court to consider the degree of inventiveness of a particular
contribution to the art: once it has decided that there is an inventive contribution,
then one goes on to look at the nature of the contribution, not the nature
of the inventiveness.
- So far as the nature of the contribution is concerned, Amgen’s case, in
a nutshell, is that the contribution of the 605 patent is encapsulated in
the disclosure contained in Table VI of the 605 patent. This Table identifies
the precise amino acid sequence of EPO, and the great majority of the EPO
gene (including much of the upstream sequence including the two start sites,
the whole of the encoding exons, the whole of the intervening introns, the
splice donor sites and the whole of the downstream sequence) coupled with
enabling teaching as to how enough of that DNA sequence could be isolated
and used in a cell to express EPO in far greater quantities than would be
achieved naturally. The disclosure enabled something which could not have
been achieved before, something which was plainly desirable and beneficial
in commercial and humanitarian terms, and something for which eminent groups
of scientists had been searching without success, despite substantial financial
backing, over the previous five years or so.
- So far as the last point is concerned, there was no dispute that Dr Lin
and Amgen had won a race in which they had a number of formidable competitors.
Biogen had a US$6m project between 1980 and 1984, employing some of the most
able molecular biologists of the time, who were seeking throughout that period
to do just what Dr Lin did. For three years, a group of researchers, including
Professor Stuart Orkin of the Harvard Medical School were engaged on the same
project, and, according to Professor Orkin, it was one of the few projects
on which he was not successful. He said that he regarded Dr Lin’s work as
"an outstanding achievement". It is also clear from the evidence
that GI (one of the Roche parties) was carrying out similar work between October
1982 and March 1984. Further, from the evidence given by Dr Alex Ullrich in
the United States proceedings, it is apparent that other institutions, including
Colombia University and Genentech were seeking to clone the EPO gene in the
early 1980s. Indeed, he said that to his knowledge "there were at least
five or six good molecular biology laboratories attempting to clone this gene".
- It seems clear from the evidence that these eminent researchers failed,
or at least had not succeeded by the relevant date, because of the very limited,
indeed in some respects erroneous, information regarding EPO. The only significant
available information was that published by Sue and another (op. cit.) which
purported to record the first 27 amino acid residues, but two of them were
not identified, two of them turned out to be wrong, and the sequence was degenerate;
ironically, the least degenerate area included one of the errors. As Professor
Brammar said, it was "astonishing how many people were misled by the
available erroneous information.". The contrast of this position with
that following the disclosure of Table VI, with all the coding sequences,
all the intervening introns, the whole of the 3’prime non-coding region, and
much of the 5’prime non-coding region (including the two endogenous transcription
start sites) speaks for itself.
- It is clear that the information as to the sequence of the EPO gene (and
in particular of the encoding regions, and the location of the splicing regions)
as a result of the publication of 605, facilitated (to use a neutral word)
something which had previously eluded a number of dedicated experienced and
well-financed groups of researchers. Professor Brammar accepted that, once
the EPO gene had been cloned and its sequence made available, "it was
straightforward for someone to clone and express this gene". He accepted
that, once GI and Roche had the information in Table VI of the 605 patent,
"they would have been able to clone EPO sequences". He indicated
it would have taken a matter of "a few weeks". Professor Proudfoot
expressed himself similarly, when he said that "once the EPO gene had
been cloned, it would have been a matter of course for the skilled worker
to apply each of the standard techniques described to that cloned gene".
Given the ability to make what he called "unique sequence probes"
as a result of the disclosure of 605, Professor Proudfoot also said that "the
rest of the exercise... is relatively straightforward" and it would "not
surprise" him if it took only "a few months".
- Professor Wall, for Amgen, gave evidence to much the same effect. He said
this:
"The disclosure of the 605 patent enabled skilled workers for the first
time to beneficially undertake recombinant techniques to target and manipulate
the EPO gene and cells containing the EPO gene to produce abundant quantities
of EPO in a variety of ways... The patent represented a genuine breakthrough
and its contribution to patient treatment was immense.... On the basis of
the information in the patent it became possible to clone EPO gDNA and EPO
cDNA and to express the EPO protein. This would have been possible based on
the sequence set out in Table VI, whether the particular examples given in
the patent had been followed or not."
He also said that "with the gene [in Table VI] in hand, using very
standard methods... one could obtain expression" and that any errors
or omissions in the specification of 605 "would [not] keep the skilled
person from reproducing the invention". Although Professor Wall struck
me as a mildly partisan witness, I do not consider that he was exaggerating
when he made those observations. Dr Brenner, in a characteristic turn of phrase,
said "once you have got the 605 patent disclosure, you have the blueprint
for the production of EPO".
- The characterisation of Dr Lin’s achievement abounds with metaphors. In
T223/92 Genentech/HIF-gamma the Board said this (albeit in connection with
a different patent):
"By identifying the DNA-sequence the respondents so to speak provided
a guide rope to the peak which enabled others to be certain of getting to
the same peak with much less trouble."
In relation to the Australian equivalent of the 605 patent, Counsel, in
the Australian Federal Court in Genetics Institute Inc. -v- Kirin-Amgen Inc.,
25th June 1996, likened Dr Lin’s disclosure to a map giving directions to
buried treasure. Heerey J preferred to invoke the analogy of a treasure in
a castle which had many gates, each with a combination lock, where the essential
or critical knowledge was the combination of the lock: without that knowledge,
the castle could not be entered, but once one had that knowledge, one can
obtain entry through any gate and with no more than a routine amount of time
and effort, the treasure will be discovered.
- Heerey J took the view that cDNA or genomic DNA represents the gate and
the combination sequence of the lock was to be found in Table VI. Indeed,
at page 23, Heerey J referred to Biogen [1997] RPC 1 at page 23, and said
this on the following page
"The fundamental difference which distinguishes the present case from
Biogen is that in the Amgen patent the coding sequence is defined. The patent
thus discloses a "principle capable of general application" and
discloses a beneficial property which is common to the class. It cannot be
said of it that it discloses no principle which would enable other products
[of the class] to be made."
- The Netherlands Court of Appeal took the same view, also relying on Biogen
[1997] RPC 1. At paragraph 13.5 of its judgment, the Court said this:
"In Table VI of the patent the inventor has disclosed for the first
time the complete error-free sequence of the coding regions (exons) of genomic
DNA... By demonstrating the exons the inventor therefore provided the essential
genetic information for obtaining the object aimed at: the production of EPO
by recombinant means. It is therefore reasonable that the inventor is allowed
a process claim in general terms for applying any "means" in which
use is made of (at least a part of) this genetic information. That in finding
those alternative "means" inventions with independent merit may
be involved, does not detract from the above"
- In my judgment, in agreement with the Australian and the Netherlands Courts,
Amgen’s contention is well-founded. Dr Lin delivered the goods, in the sense
of providing all the necessary teaching which thereafter enabled biotechnologists
to express EPO in cells using exogenous EPO-encoding DNA in accordance with
routine methods, as they existed at the relevant date and developed from time
to time over the life of the 605 patent. To that extent, he is entitled to
commensurate "fair protection" under the Protocol. Suppose a third
party invented and patented a new method of transfecting a human cell with
exogenous encoding DNA, for example. It would be unfair on Dr Lin if the public
could use the new technique to express EPO with the licence of the third party
alone - just as it would be unfair for the third party if that could be done
with the licence of the 605 patent alone. It would be fair on the third party
and Dr Lin, if the public could not use the third party’s technique to express
EPO without infringing the third party’s patent (in relation to use of the
particular technique) and the 605 patent (in relation to the particular product).
In such a case, although the new technique would "owe nothing to the
teaching of the [605] patent or any principle it disclosed", the ability
to express EPO by the new technique would do so. Identifying the extent of
the monopoly to the expression of EPO, but not to any particular technique,
appears to me to accord to Dr Lin a monopoly which "correspond[s] to
[his] technical contribution to the art" as embodied in the 605 patent.
- Roche rely on a passage in the speech of Lord Hoffmann in Biogen at [1997]
RPC 51 when he said this:
"[T]here is more than one way in which the breadth of a claim may exceed
the technical contribution to the art embodied in the invention. The patent
may claim results which it does not enable, such as making a wide class of
products when it enables only one of those products and discloses no principle
which would enable others to be made. Or it may claim every way of achieving
a result when it enables only one way and it is possible to envisage other
ways of achieving that result which make no use of the invention."
This passage must, I think, be read as a reference to a claim which is to
one or more of "a number of discrete methods or products" as opposed
to a claim which is to "a principle capable of general application"
- [1997] RPC 48.
- In a sense, it might be said that neither of the two alternatives embodied
in that observation apply precisely here. So far as the third sentence of
the passage, upon which Roche rely, is concerned, all I need to say is that,
even now, more than 16 years after the relevant date, nobody has suggested
a way of expressing EPO in commercially viable quantities in cells "which
makes no use of the invention". In particular, the technology used by
Roche, and the much more modern and sophisticated technology used by TKT,
both depend on information first disclosed in the 605 patent, information
which the various groups of well supported and eminent scientists were looking
for without success before Dr Lin. One can see how it could be said that there
is "no principle", as contemplated in the second sentence, in the
sense that there is no guidance as to how to express EPO in amplified quantities
other than in DHFR- CHO cells, and "no principle" as to how to identify
the analogues. However, the word "principle" should not be interpreted
too strictly. I think that Mr Waugh is correct to describe the disclosure
of the patent as being how to make recombinant EPO using its gene sequence.
That is the contribution to the art.
- It is true that, in the present case, people knew of the existence of EPO
in nature, knew that it had been isolated in small quantities, knew that the
EPO gene existed in the genome, and knew that a cDNA sequence could be made
by reverse transcription of EPO mRNA, if it could be found. They also knew
that DNA sequences could be isolated by screening libraries with probes, and
that once DNA sequences were isolated they could be expressed to produce the
encoded protein. Accordingly, as Mr Thorley puts it in his elegant argument:
"[T]he goal was known, the potential sources of DNA sequence were known,
the techniques were available. The problem was finding a way to apply the
techniques to achieve the goal."
- In so far as that is a helpful analysis, it seems to me to assist Roche
more on an argument based on obviousness, than on insufficiency. However,
as Mr Thorley’s argument continues, Amgen’s only "inventive contribution
was to decide to do so and succeed. This was the only novel aspect of the
patent". As is clear from those words, it is accepted that the patent
is inventive and novel, and that means that I am not concerned with the presence
or absence of inventiveness; what I must do is to assess "the technical
contribution" for the purpose of the present analysis. In connection
with the concession that the disclosure of the patent was novel, it is fair
to say that this view is supported by Professor Brammar who described Dr Lin’s
screening of a genomic library with mixed oligonucleotide probes as "an
unusual thing to do" viewed as at 1983, the time he did it.
- However, I do not agree with Mr Thorley, that this admittedly inventive
notion is to be equated, for the purpose of assessing its contribution, with
the idea Professor Murray had in Biogen [1997] RPC 1. His inventive idea was
how to achieve something which people have been trying to achieve, but, once
he achieved it, others could do the same thing in different ways which owed
nothing to him: he revealed nothing of general application. Dr Lin’s idea
can be said to have a similar quality, in the sense of being an inventive
way of achieving something which everyone was looking to do. However, what
he contributed to the art was information, embodied in Table VI, which enabled
other people to design methods of producing EPO through expression in cells,
which they would not otherwise have been able to do. If all that Dr Lin had
done was to achieve the expression of EPO in transfected DHFR- CHO cells,
then there would have been a strong similarity between his disclosure and
that of Professor Murray. However, albeit as part of the exercise enabling
him to achieve the expression of EPO, Dr Lin’s disclosure extended to a contribution
of general application.
- As Lord Hoffmann emphasised in Biogen, biotechnology is a field which is
rapidly expanding and developing. As a result, the law has to adapt, not in
the sense of changing the applicable principles, but more in the sense of
shaping, or even modifying, those principles to apply in a coherent and sensible
way to the evolving technology in the field. Inherent in the concept of "fair
protection for the patentee", which, together with "certainty for
third parties", can be taken as one of the guiding lights in the field
of patents, is a degree of value judgment. Although, there is inevitably an
element of value judgment, in the context of Biogen insufficiency, the principle
is better enshrined in the words of the Board as approved by Lord Hoffmann
in Biogen at [1997] RPC 49 line 20, namely "the extent of the patent
monopoly... should correspond to the technical contribution to the art in
order for it to be supported".
Discussion
- The conclusion that the invention embodied in 605 "discloses a principle
of general application" is not necessarily the end of the matter so far
as the alleged insufficiencies with regard to types of cell and analogues
are concerned. I turn first to the use of transfected cells (other than DHFR-
CHO cells) with exogenous EPO-encoding DNA for the expression or amplified
expression of EPO. It appears to me that the view I have formed must lead
to the conclusion that the patent does extend to such other cells, albeit
that achieving such expression might involve a fresh inventive step, which
could lead to a new patent in its own right, or else an improvement or nesting
patent. Whatever fresh inventive step was involved in achieving expression
of EPO in the new type of cell, it would remain the case that it could not
have been achieved without the disclosure given in the 605 patent, and in
particular in Table VI thereof.
- In particular, this is relevant to expression in human cells. Techniques
developed since the relevant date enable the disclosure of the 605 patent
to be invoked to obtain amplified or enhanced expression of EPO in human cells.
In light of my conclusion in the previous section of this Part of the judgment,
the claims of 605 can properly extend to such processes as their product (without
prejudice to the issue of whether the new process may itself also be patentable).
- I have more difficulty with the question of analogues, essentially for two
reasons. First, more could have been done by Amgen to give guidance to the
reader on this issue: in particular, as I have mentioned, the three-dimensional
conformation, and possibly the glycosylation sites, and the active regions
could all have been identified. Secondly, there is the reasoning and conclusion
of the Court of Appeal in American Home Products [2000] IP&T 1308.
- Amgen rely on the comparatively worthless nature of a patent relating to
a protein and its encoding gene if it could not extend to analogues of the
protein. A few amino acids or even just one amino acid could be substituted
with no significant change (or possibly even an improvement) to its activity;
concomitant alterations could be made to the codons in the gene. As Mr Waugh
says, it would be only too easy for someone to benefit from the teaching of
the patent by proceeding, on a trial and error basis, to substitute one amino
acid residue for another somewhere along the polypeptide chain of EPO, and
then to construct a strand of DNA with an appropriately adjusted sequence
of codons. If, as seems virtually certain, it would be possible to change,
say, ten of the 168 amino acid residues in human EPO for any one of say ten
other amino acids, without the EPO losing its biological properties, that
would mean that there were over ten billion different variants. As indicated
above, I suspect that that is a substantial under estimate, because it appears
likely that more than ten amino residues could be changed (provided that they
were not within the active sites) without the resultant polypeptide losing
its biological properties, and each such one amino acid could well be substituted
by most or even all of the other nineteen amino acids. It also appears that
some of the amino acid residues can be lost without the resultant protein
losing is biological properties. Mr Waugh, in the course of his painstaking
submissions, argues with justification that it would be impossible in these
circumstances, however great the resources available to a patentee, to test
for each of these variants, and then to ensure that there is sufficient teaching
in respect of them.
- I accept that Amgen could have carried out, and could have disclosed the
results of, further work which would have given more information and guidance
about the possible analogues. However, the result of such information would
not have been exhaustive, and it would certainly still have been the case
that the reader would have been in a state of uncertainty as to whether any
particular change would have resulted in a loss or reduction in the EPO-effectiveness
of the resultant polypeptide. He would know that there was a better chance
of a particular change having no effect or having an effect, but that is all.
Further, at least on the facts of the present case, it is unrealistic not
to have regard to the fact that the pressure on Amgen, and indeed on the other
researchers in this field, was to obtain the sequences of EPO and the EPO
gene, and to use this to effect expression of EPO in a transfected host cell.
It would have put the first person to win this particular race in an unreasonably
hard position if he had to elect between revealing his disclosure but not
being able to claim analogues, which would probably render his patent almost
worthless, or to hold off applying for his patent while he investigated analogues,
in which case he may lose out to a later competitor who applied for a patent
earlier. At least on the present facts, I do not think "fair protection
to the patentee" can fairly require that unpalatable choice of the inventor.
Certainty or even fairness to third parties or the public does not appear
to me to point the other way.
- I turn then to American Home Products [2000] IP&T 1308. There is no
doubt that many of the observations I have quoted from the judgment of Aldous
LJ in that case give considerable apparent support to the argument of Roche
and TKT that, whatever my view would have been in the absence of that decision,
605’s claims to analogues must fail on grounds of insufficiency in the present
case. In my judgment, however, that is not correct, particularly when one
compares the approach of the Court of Appeal in American Home Products to
that of the Court of Appeal in Chiron.
- First of all, the scope of the contribution of Professor Calne in American
Home Products was relatively limited: he simply discovered a new use for a
product which was not merely well known, but which was available already in
commercially viable and therapeutically valuable quantities, and its chemical
formula was well known. That is to be contrasted with the present case, where
Dr Lin’s discovery and invention enabled EPO to be produced in commercially
and therapeutically worthwhile quantities for the first time, and where he
also identified for the first time the chemical structure of EPO and (with
the exception of a part of the upstream sequences) the EPO gene.
- Secondly, the exercise involved in identifying which variations, in the
form of additions, substitutions or removals, of the rapamycin molecule would
have the same immunosuppressant activity as rapamycin was quite unpredictable
and conceptually boundless. As Aldous LJ put it at [2000] IP&T 1325, in
so far as molecules other than rapamycin were claimed, "such a claim
does not reflect a class with a unifying characteristic" and at 1326,
"it would take prolonged tests to find out whether [a variant] had the
appropriate qualities". On the other hand, in the present case, although
I accept that Claim 1, and indeed Claim 19, could extend, at least in theory,
to an almost infinite number of variants, the class of substitutions for each
amino acid residue in naturally occurring EPO would be limited, and the experiments
involved in relation to any particular analogue would be relatively short
and routine. Thus, while the number of permutations arising from the possibility
of substituting each amino acid residue with one of the other 19 amino acid
residues would lead to a virtually infinite number of different analogues
to be tested, the reader would have appreciated exactly what the possible
substitutions could be, and that the test that he would have to carry out
in order to effect the substitution and in order to see whether the substitution
produced a polypeptide which had EPO-like activity would be a routine exercise.
It would simply involve removals or substitutions of amino acid residues.
It appears to me that that is very different from the exercise required of
the reader if the patent in American Home Products [2000] IP&T 1308 extended
to variants of rapamycin, which was not a protein, and in respect of which
there was no general knowledge and experience as to the types of variants
which might be effective to the rapamycin molecule without it losing the characteristics
essential for the disclosure of the patent in that case.
- It appears to me that this view is support by the reasoning, indeed the
decision, of the Court of Appeal in Chiron [1996] FSR 153. I have already
quoted extensively from the judgment of Morritt LJ in that case. The Court
of Appeal held valid a claim which, as Morritt LJ put it, did not "differentiate
between one polypeptide falling within the claim and any of the millions of
others". However, the claim was held nonetheless to be valid essentially
on the basis that any analogue falling within the claim "can be defined
in the sequence by exposure to an antibody and can be made by routine methods
in molecular biology". In other words, approaching the question of sufficiency
on the classic basis, an analogue of EPO will only be within the claim if
the analogue has the biological properties of EPO and its gene hybridises
under stringent conditions to the coding regions of Table VI of the 605 patent.
The evidence establishes that it only takes a few days to make an analogue
and to test its biological activity. Similarly, there is no suggestion that
any difficulty in terms of time or effort, would be encountered in seeing
whether a gene sequence which encoded that analogue satisfies the hybridisation
test. Accordingly, as in Chiron [1996] FSR 153, the reader of the patent would
have no difficulty in finding out whether a particular analogue was, or was
not, within the claims. In other words, as Professor Wall said in evidence,
"making and testing such fragments and derivatives can be readily undertaken
starting with the sequence information in the patent and using the routine
tests and assays described in the patent". He also said that to make
an analogue would take a few days, and certainly would not take more than
a few weeks. There was nothing to suggest that looking for in vivo EPO-like
activity would be difficult or time consuming. The position in this connection
appears to be comparable to that in Chiron where (to quote from [1996] FSR
187) "other strains may be isolated and sequenced [by] processes... well
known to the man skilled in the art and of a routine, if time consuming, nature".
It is true that Dr Browne said that finding an analogue which had advantages
over EPO would be a research project, but I do not think that is quite to
the point.
- Dr Browne also explained that Amgen had found an analogue of EPO which they
were considering marketing under the name ARANESP, which had the advantage
over naturally occurring EPO of being metabolised from the blood less slowly
(so that it needs to be injected into patients less often) and that this,
self evidently, had taken some time to develop. The precise amounts of time
and effort involved in this development was unclear. Further, it appears that
the reason why the development of ARANESP took the time that it did is also
unclear: the evidence suggests that it could well have been not very high
on Amgen’s list of priorities, which of itself could well have been due to
the success they were encountering in relation to EPO with its naturally occurring
sequence. However, even on the limited amount of evidence available, it is
fair to say that the development of ARANESP involved, in terms of time and
effort more than enough work to take it outside the description of routine,
although it is fair to say that there is nothing to suggest the actual nature
of the work was any different from Professor Wall’s slightly contemptuous
description.
- However, essentially for the reasons given by Morritt LJ in Chiron [1996]
FSR 153, I do not think that this presents a problem for Amgen. As Professor
Wall said, after referring to the passages in the 605 patent at page 47 where
certain specific analogues and variants are referred to:
"I believe that those skilled in the art in 1983 could have designed
a variety of such derivatives and easily have tested them for activity using
standard assays available at the time."
He went on to say:
"[I]t was entirely predictable that there would be useful analogues
and variants of the EPO sequence shown in Table VI, although it would be necessary
to make and test such analogues and variants to assess the properties of these
new compounds."
- It is true that, unlike in Claim 1 of 605, the claims in Chiron [1996] FSR
153, did not involve the variants (or epitopes as they were in that case)
having to be tested in vivo. It is also true that there was a specific routine
method for testing for epitopes as well as evidence that this testing had
been carried out successfully. I do not regard those points as valid grounds
of distinction. The added ingredient of in vivo testing does not, on the evidence,
render the overall testing of analogues non-routine or lengthy. The fact that
there is no evidence of any efficacious analogue of EPO is not in point: testing
a particular analogue is not a problem.
- The disclosure of the 605 patent provided the guide rope to the peak, the
route map to the buried treasure, the keys to the castle. Following the disclosure,
it would have required routine work, not of a lengthy nature, to contemplate
an analogue to obtain it, and to test for its efficacy.
- Professor Wall’s view, in summary, was that "what is important... is
that the [605] patent has published the starting point from which such work
can proceed". I agree with that assessment. As a matter of law, applying
the reasoning in Biogen [1997] RPC 1 and in Chiron [1996] FSR 153, it seems
to me that extension of Claim 1 to biologically effective analogues of EPO
is permissible. I do not believe that there is anything in American Home Products
[2000] IP&T 1308 to call it into question.
Insufficiency: conclusions
- As I have already mentioned, six categories of insufficiency have been alleged
against the 605 patent. My conclusions on those are as follows:
1. A source of human cDNA was available, in the form of transfected cells;
2. the teaching of the 605 patent is classically insufficient so far
as human cells are concerned, but this does not render the patent invalid,
on the basis of the reasoning in Biogen [1997] RPC 1;
3. the reference to "stringent conditions" in Claim 1(b) is
not classically insufficient;
4. the claim to analogues of EPO does not render the patent insufficient
in light of the reasoning in Biogen;
5. the comparison of recombinant and urinary EPOs at the end of Claim
19 is insufficient;
6. the carbohydrate content comparison in Claim 20 is also insufficient.
- The consequence of these conclusions is that the insufficiency arguments
fail, save in relation to Claim 19 and Claim 20. However, because they are
contingent on Claim 19 and Claim 20, Claims 21, 22 and 23 also fail for insufficiency.
At least in so far as they rely on any of Claims 19 to 23 inclusive, Claims
29, 30, and 31 are also insufficient.
- The final issue I have to consider is whether the insufficiency of the claims
to which I have just referred renders any of the other claims, or indeed the
whole of the 605 patent, invalid on grounds of insufficiency. Where the court
concludes that a particular claim, upon which some but not all other claims
depend, is insufficient, it does not appear to me, at least as a matter of
principle, that one can lay down any absolute rule as to whether the patent
as a whole, and in particular, the claims which are not dependent on the insufficient
claims, can survive. Again approaching the matter as one of principle, I would
have thought that, if stripping out the insufficient claims (and any teaching
directly related to those claims) leaves, both conceptually and in terms of
the understanding of the notional reader, a valid and understandable patent,
then there is no reason in principle or theory why the remainder of the patent
should not survive.
- However, the point has to be determined by reference to the legislation.
Under Section 72(1) of the 1977 Act, the court "may... revoke a patent
for an invention" on various grounds including, in paragraph (c), "the
specification of the patent does not disclose the invention clearly enough
and completely enough...". Stopping there, the position would appear
to be "all or nothing". However, it is necessary to go on to Section
72(4), which provides:
"An order under this section may be an order for the unconditional
revocation of the patent or, where the court... determines that one of the
grounds mentioned in sub-section (1) above has been established, but only
so as to invalidate the patent to a limited extent, an order that the patent
should be revoked unless within a specified time the specification is amended
under section 75 below to the satisfaction of the court..."
- This would appear to suggest that, in a case such as this, provided I am
satisfied that it is possible to strip out Claims 19 and 20, and all other
Claims which are contingent thereon (or if some are only contingent in part,
to the extent that they are so contingent) then I can do so, at least in accordance
with the procedure set out in Section 72(4) of the 1977 Act. Such a conclusion
appears to me to be consistent with Section 125(1) of the 1977 Act which requires
the "invention for a patent for which an application has been granted"
to be taken as being that "specified in a claim of the specification
of the... patent". In other words, if one can establish that there are
a number of independent, albeit possibly conceptually closely related, claims,
the fact that one claim is insufficient does not thereby automatically invalidate
another.
- In the instant case, it seems to me that it is relevant to bear in mind
not merely that the claims other than Claims 19 and 20 and the Claims dependent
thereon are conceptually and linguistically independent of Claims 19 and 20,
but that the only reason that Claims 19 and 20 are invalid is due to a feature
which is not to be found in any of the other Claims (other than those dependent
on Claims 19 and 20), namely the SDS-PAGE comparison with urinary EPO and
the comparison of the carbohydrate content. In my judgment, at least so far
as the Claims are concerned, the Claims other than Claims 19 and 20 (and the
Claims dependent thereon) should, if possible, be permitted to stand. The
only part of the specification which may be, as it were, tainted is the two
paragraphs in Example 10 which I have quoted. I am not convinced that the
605 patent need be amended by the removal of those two paragraphs. The first
of the paragraphs seems plainly innocuous: it states at the very beginning
that it merely reports the result of a "preliminary" experiment.
Although that is not expressed in the second of the two paragraphs, I think
that the notional reader would appreciate that what is stated there is based
on the "preliminary" experiment described in the preceding paragraph.
Indeed, it is hard to see how he could have any other view in the absence
of any other experiments or figures being reported in the patent itself.
- In these circumstances, at least subject to further argument, it appears
to me that the appropriate course in this case is to make an order in accordance
with the second part of Section 72(4) of the 1977 Act, whereby the patent
can be amended by the removal of Claims 19 and 20, and any other Claims in
so far as dependant thereon or referential thereto. I should make two further
points. First, at least in relation to Claim 19, it would seem to me very
unsatisfactory if the closing passage relating to urinary EPO resulted in
the patent as a whole being revoked. Neither 605A (the application for the
patent) nor 605B (the patent as originally granted) contained any reference
to urinary EPO. It was only because of the Board’s view (which in my judgment
was an erroneous view) that Claim 19, without the closing words, was an impermissible
product-by-process claim, that the comparison with urinary EPO was added.
Secondly, my conclusion on the insufficiency issue, namely that the patent
is partly, indeed largely, valid, but that, in respect of a few claims it
is invalid, must, of course, be subject to my conclusion on the other grounds
of alleged invalidity, to which I now turn.
L. MERE DISCOVERY
- Section 1(2) of the 1977 Act provides:
"The following... are not inventions for the purposes of this Act,
that is to say, anything which consists of -
(a) a discovery...
but the foregoing provisions shall prevent anything from being treated as
an invention for the purposes of this Act only to the extent that a patent
or application for a patent relates to that thing as such."
- Roche contends that, in so far as Claim 1 of 605 claims genomic DNA (and
in particular human genomic DNA), it is not an invention: it is simply a discovery
of what existed in nature, and therefore cannot properly be claimed. While
not advancing any separate argument on this issue, TKT supports Roche’s position
on this issue.
- Clearly, it can fairly be said that it was the "discovery" of
the gene sequence for EPO which effectively provides the basis for the whole
605 patent. Indeed, it could scarcely be otherwise given the way in which
Amgen put their case on breadth of claim and Biogen insufficiency. However,
that is not the end of the matter. In Gale’s Patent Application [1991] RPC
305, Nicholls LJ cited at 324, lines 21 to 25 with approval an observation
of Whitford J in Genentech Inc’s Patents [1987] RPC 553 at 566, to the following
effect:
"It is trite law that you cannot patent a discovery, but if on the
basis of that discovery you can tell people how it can be usefully employed,
then a patentable invention may result. This in my view would be the case,
even though once you have made the discovery, the way in which it can be usefully
employed is obvious enough."
- Nicholls LJ went on to say at [1991] RPC 324, lines 31 to 36:
"Thus, a discovery as such is not patentable as an invention under
the Act. But when applied to a product or process which, in the language of
the 1977 Act, is capable of industrial application, the matter stands differently.
This was so held in Genentech Inc’s Patent [1989] RPC 147. There, this court
by a majority decision held that Section 1(2) did not depart from the established
principle mentioned above."
- The law was also considered by the Board in T208/84 Vicom/Computer Related
Invention [1987] 2 EPOR 74 and by the Court of Appeal in Fujitsu Limited’s
Application [1997] RPC 608. In the latter case, Aldous LJ said this at [1997]
RPC 614, lines 40 to 46:
"[I]t is... a principle of patent law that mere discoveries or ideas
are not patentable, but those discoveries and ideas which have technical aspect
or make a technical contribution are. Thus the concept that what is needed
to make an excluded thing patentable is a technical contribution is not surprising.
That was the basis for the decision of the Board in Vicom. It has been accepted
by this court and by the EPO and has been applied since 1987. It is a concept
at the heart of patent law."
- It is interesting to note that Nicholls LJ in Gale [1991] RPC 305 and Aldous
LJ in Fujitsu had "difficulty in identifying clearly the boundary line
between what is and what is not a technical contribution" - see per Aldous
LJ at [1997] RPC 616, lines 41 to 42.
- In the present case, in support of the contention that Claim 1 is invalid,
at least in so far as it extends to genomic DNA, because it constitutes a
mere discovery, Roche place considerable weight on the reasoning of the Court
of Appeal in Genentech Inc’s Patents [1989] RPC 147, and in particular the
statement of Mustill LJ at 269 line 2 that a particular DNA sequence was an
"existing fact of nature, newly discovered".
- Clearly, in so far as Genentech, a decision of the Court of Appeal, contains
any reasoning or conclusion which can fairly be said to apply to the facts
of this case, it is binding on me. However, I am of the view that it does
not. First, reading the judgments of Purchas and Dillon LJJ at 208ff and 239
to 240 respectively, it seems to me that they took a different view on the
point (which appears to be accurately reflected in the headnote at [1989]
RPC 152, lines 18 to 21). Secondly, while it is fair to say that Genentech
was concerned with a patent which claimed a DNA sequence, each case must to
a significant extent turn on its particular facts. If the principles are tolerably
clear, and there is no question of those principles having been altered as
a result of Genentech (and that is not suggested by Mr Thorley), then my duty
is primarily to apply the principles to the facts of the present case, rather
than delving into detailed judgments in other cases merely to see how the
principles were applied to the facts of those other cases.
- In my judgment, applying the well established principles summarised in the
passages from earlier cases I have quoted above, I conclude that, while it
is obviously the case that the essential feature of 605, and in particular
of Claim 1, is a "discovery", namely that of the DNA sequence of
the EPO gene, or at least a substantial part of that gene (including, crucially,
the encoding regions, the introns and the splice sites), it was a discovery
which clearly made a technical contribution. I have considered that contribution
during the course of this judgment, perhaps most notably in connection with
Biogen insufficiency and breadth of claim, and I do not propose to repeat
myself in what is already a regrettably lengthy judgment. Claim 1 is to a
DNA sequence which is "suitable for" the claimed purposes, and I
accept Mr Waugh’s submission that it is "plainly the application of the
discovery which is capable of industrial application (whatever the origin
of the DNA sequence)".
- I take comfort from the fact that, according to the submissions on behalf
of Amgen (and not, I think, challenged by Roche), over the past 20 years or
so, it has been the regular practice of the European Patent Office (and, I
think, of the US Patent Office) to grant claims substantially in the form
of Claim 1 of 605. Further, the sequences claimed in 605 has not been impugned
in any other European country, including Germany and the Netherlands, where,
as I have mentioned, 605 has been attacked on various other grounds.
M. LACK OF NOVELTY
General
- Roche and TKT each raise a number of arguments as to why Claim 19 of 605
is invalid for want of novelty, and TKT alleges that Claim 1 and Claim 26
also suffer from want of novelty. I do not think that I need deal with TKT’s
contention that Claim 1 suffers from want of novelty in light of my conclusion
that, on its true construction, the DNA sequences claimed by Claim 1 must
have been isolated from the cells in which they were found.
- Further, I have already dealt with one of TKT’s arguments as to why Claim
26 is invalid for want of novelty, namely that it is a product-by-process
claim, which should be interpreted, in accordance with the Board’s leaning,
as a claim to the product as such, and not merely to the product provided
that it is made by the process identified in the Claim. For the reasons already
given, I reject this argument of TKT.
- If I am correct in my view relating to product-by-process claims, then TKT’s
case as to why Claim 19 is invalid on grounds of lack of novelty fails. TKT
contend that, if the Board’s approach to product-by-process claims is correct,
Claim 19 will be invalid on grounds of lack of novelty if the recombinant
EPO it claims does not have a higher apparent molecular weight on SDS-PAGE
than urinary EPO, as the higher apparent molecular weight is the only specific
distinction which rEPO is said to have over uEPO. It is right for me to deal
with that contention on the basis that I am wrong in not adopting the Board’s
view of product-by-process claims, in part because the point has been fully
argued and in part because this case may well go further. I shall then deal
with an argument raised by Amgen if TKT’s point is otherwise correct, namely
that the recombinant EPO claimed by Claim 19 has other characteristics which
would distinguish it from urinary EPO. I shall then turn to TKT’s contention
that Claims 1, 19 and 26 are anticipated by the patent of Sugimoto referred
to at page 6 of the 605 patent ("Sugimoto"), and finally turn to
the effect of some publications. I should add that TKT’s allegation based
on Sugimoto and the published papers are only maintained if TKT’s product,
GA-EPO, infringes those Claims.
Higher molecular weight by SDS-PAGE
- This section proceeds on the assumption that I am wrong and that the Board
is right in its view of product-by-process claims, such as Claim 19.
- I have already dealt in some detail with various experiments carried out
for the purpose of these proceedings, and various papers, showing the performance
on SDS-PAGE of recombinant EPO from various sources and urinary EPO from various
sources, as well as discussing the evidence relating thereto. As I have mentioned,
certain conclusions can be drawn from the evidence. First, it does appear
that recombinant and urinary EPOs both produce relatively wide and fuzzy bands,
as one would expect of a glycoprotein. Secondly, urinary EPOs can vary depending
on their source, and even urinary EPOs from the same source, albeit from different
fractions during the purification process, can vary from each other. Thirdly,
recombinant EPOs can vary from each other, and indeed this is what one would
expect bearing in mind that recombinant EPO can be made, as 605 teaches, in
different types of cell, which effect different types of glycosylation.
- In relation to its case on lack of novelty, TKT rely primarily on the evidence
which, at least to my mind, establishes that:
1. Recombinant EPO made according to the teaching of 605 in CHO cells
("CHO rEPO") has a similar apparent molecular weight to the so-called
Lot 82 urinary EPO ("Lot 82 uEPO"); and
2. Recombinant EPO expressed in COS cells according to the teaching of
605 ("COS rEPO") has a similar apparent molecular weight as urinary
EPO obtained from Dr Goldwasser, which had apparently been obtained according
to the teaching of Miyake ("Goldwasser uEPO").
- TKT also rely upon other evidence to which I have referred when dealing
with the insufficiency arguments on Claim 19, namely the experiments of Dr
Strickland and of TKT and the papers written by Inoue and by Imai (opa. cita.).
It is not necessary to consider this evidence, nor indeed the arguments relating
to this evidence, in any detail so far as TKT’s case on novelty is concerned,
in light of the discussion on the evidence in relation to insufficiency.
- The position appears to me to be this. The closing words of Claim 19 set
a standard which, on its face, identifies the recombinant EPOs claimed by
reference to a factor which distinguishes them from naturally occurring EPOs.
However, if the evidence in this case merely demonstrates that many recombinant
EPOs do not fall within the Claim (either because they have a lower apparent
molecular weight than, or the same apparent molecular weight as, urinary EPO),
that would not mean that the limitation of the claim to recombinant EPO with
higher molecular weight is invalid on grounds of lack of novelty. Far from
it: the claim would only extend to recombinant EPOs which were different from
naturally occurring EPO - the very requirement which would, if sufficient,
bestow novelty.
- The evidence establishes that there may well be some difference between
one EPO and another. However, not only can urinary EPOs vary from each other,
but it is not sensibly possible to predict as at the relevant date (or even
today) what the differences will be. On the limited evidence I have, the apparent
molecular weight of CHO and COS rEPO would appear to be the same or higher
than uEPO prepared in accordance with the teaching of Miyake (op. cit.) (with
or without minor modifications). However, even with that difficulty (fatal
to Claim 19 on insufficiency grounds) it does not seem to me to alter the
force of Amgen’s argument on the issue of novelty. If it is otherwise valid,
Claim 19 only extends to EPOs which do differ from all natural EPOs in their
apparent molecular weight whether one takes the average or the spread of different
weights. I believe my reasoning on this aspect is consistent with the approach
of the Board in T130/90 - see at [1996] EPOR 55, paragraphs 4.10 and 4.11.
Other alleged differences between rEPO and uEPO
- In his report, Professor Cummings stated that there were numerous differences
between urinary EPO and recombinant EPO, quite apart from the fact that the
former had an apparently higher molecular weight on SDS-PAGE than the latter.
The differences he identified may be expressed in summary terms as being variations
in performance in isoelectricfocusing and electrophoresis, differences in
oligosaccharide and/or sialic acid composition, different N-glycan distribution,
different proportions of branched polysaccharides, different sialic acid and/or
glycan linkages, and different biological activity.
- In my judgment, neither as a matter of law nor as a matter of fact do any
of these contentions assist Amgen, and I am bound to say that Professor Cummings
did his credibility no favours by suggesting otherwise. As a matter of principle,
it does not seem to me that it is open to Amgen to rely upon differences between
recombinant EPO and urinary EPO which are not identified in Claim 19, or in
the specification. First, the patent would be insufficient if it relied on
a test which it did not describe, and the differences alleged by Professor
Cummings were not known to exist (assuming that they do exist) at the relevant
time. Secondly, Amgen led no evidence on these differences, other than references
to papers. Thirdly, and perhaps most importantly, the invention of a patent
is defined by its claims, as is emphasised by Section 125(1) of the 1977 Act:
it is not defined by later evidence of actual or potential differences between
the disclosure of the specification and the prior art. That, I believe, is
a fundamental feature of patent law.
- Quite apart from this, I am satisfied as a result of hearing Professor Cummings
cross examined, that (with one possible exception) none of the alleged differences
are made out. The various papers cited by Professor Cummings in his report
which were said to support the various alleged differences he was putting
forward did not appear to assist the conclusion when examined more closely.
Indeed, Professor Cummings was forced to accept this in the case of virtually
every difference he alleged. The one exception was the paper by Kung and Goldwasser
(op. cit.) which suggested that a sample of CHO rEPO and uEPO isolated in
accordance with Miyake’s teaching might have different conformations and/or
glycosylation. The basis for this view was the differential rates of iodination
of the two types of EPO. However, this evidence was recent, indirect, imprecise
and speculative.
- I thought Professor Robbins’s evidence on this issue was far more convincing,
and indeed it was not really challenged in cross examination. He said "One
can never generalise to all urinary and recombinant from any of the papers".
I agree with that. In my judgment, none of the papers cited in support of
Professor Cummings’s alleged differences between recombinant EPO and urinary
EPO bore out his case.
- There is one aspect of the alleged differences between recombinant EPO and
urinary EPO with which I should deal in perhaps a little more detail. It is
Amgen’s contention that recombinant and urinary EPO will inevitably differ
in their oligosaccharide content. It was suggested that the effect of the
evidence of Professor Clausen and Professor Robbins was that there would inevitably
be a difference in the structure of the glycans of recombinant EPO and of
urinary EPO. Thus, Professor Clausen said that, as a result of increasingly
sensitive and sophisticated techniques since the mid-1980s "it may be...
now possible to show some differences between a sample of rEPO by these techniques".
In the first place, that does not seem to me to support the contention which
Amgen are advancing: it is directed to potential differential glycosylation
of recombinant EPO. Secondly, it is a speculation, albeit informed speculation
by an expert.
- So far as Professor Robbins is concerned, he said that his "general
feeling" was that "the glycosylation pattern of erythropoeitin will
vary from cell line to cell line depending on the glycosylation machinery
available in the cell for glycosylation". He also said "one always
does find small differences based on the source, cell line, and so forth".
It seemed to me that he came nowhere near saying that, for instance, certain
types of glycosylation would only occur in recombinant EPO or urinary EPO.
On the contrary: he said that he would be "surprised to ever find that
any [oligosaccharide] structure one finds in one preparation of erythropoeitin
would be totally absent from another. It will be a matter of proportion probably".
In other words, as I understand it, Professor Robbins’s view was that each
type of EPO will contain many of the same glycans, and the normal explanation
for any differential in the apparent molecular weight is due to a difference
in the relative proportion of different types and degrees of glycosylation.
Quite apart from that, even more than 15 years after the relevant date, the
experts were unable to do more than speculate on this issue.
- In what I can only characterise as something of a last-ditch argument on
this issue, Amgen placed reliance on a test apparently used at the Sydney
Olympics, because some athletes would be tempted to take recombinant EPO in
order to increase their oxygen production. The limited information provided
on this test was scant and imprecise, and I found it of no assistance. In
any event, as Mr Kitchin contends, "technology invented 16 years after
the patent can hardly be used to construe it or render it sufficient",
a submission which I quote partly because it tends to support my view that,
when construing the reference to EPO isolated from urine in Claim 19, one
should do so by reference to methods which existed as at the priority date.
Sugimoto
- Sugimoto purports to teach the preparation of fused cells which produce
EPO. The fusion is of a cell from a particular type of tumour and a lymphoblastoid
cell. The former cell is from a tumour which produces EPO, and the latter
is a type of cell which expresses protein at a high level and will grow continuously.
In a nutshell, TKT contends that the effect of what was taught by Sugimoto
is that the cells, including their nuclei, will fuse, that this will result
in a rearrangement of the DNA in their chromosomes, and that this involves
the expression of "recombinant" EPO from "exogenous" DNA
in "host cells", at least if those expressions as used in Claims
1 and 19 of 605 have the wider meaning for which Amgen contend. I have held
that, as a matter of construction, they have the narrower meaning. Accordingly,
this point is, on my view of construction, academic. However, I assume that
Claims 1 and 19 have the wider meaning for which Amgen argue. On the basis
of that assumption, I turn to consider whether there is anything in TKT’s
contention of lack of novelty based on Sugimoto.
- I do not consider that any claim of 605 can be fairly said to have been
anticipated by Sugimoto, even on this basis. First, as a matter of fact, while
it is true that Sugimoto makes certain claims as to what has been, or could
be, achieved by its teaching, I consider, on the balance of probabilities,
that following the teaching of Sugimoto would not result in the expression
of EPO as a result of the fusion of the two cells. It appears that, in connection
with the United States proceedings, TKT tried to replicate the results of
the teaching of Sugimoto, and it appears that they failed, save to the extent
of fusing a lymphoblastoid cell line with TKT’s HT1080 cells. However, that
takes matters little further in this connection, because these HT1080 cells
are the ones used by TKT for the production of its GA-EPO, in which the EPO
gene had already been "switched on" artificially.
- Furthermore, given the pretty intensive search which was going on in a number
of laboratories around the world for an artificial way of producing EPO in
relatively substantial quantities, it is hard to understand why the teaching
of Sugimoto was not eagerly taken up and implemented, if its claims were justified.
As I have mentioned, it was filed in the United States in August 1981 (and
was filed in Japan almost exactly a year earlier) and it appears to have been
published in the United States in March 1983. Despite that fact, there is
no evidence of anyone trying to follow, let alone succeeding in following,
its teaching. The EPO production claimed in Example 6 of Sugimoto is of the
same order as Amgen’s commercial strain, which makes it more remarkable that
there appears to have been no report of EPO ever having been produced or marketed
according to the teaching of Sugimoto, given that there was such a strong
commercial incentive to produce EPO in large quantities.
- Additionally, there is no evidence that any EPO-like activity measured as
a result of the apparent expression in the fused cell described in Sugimoto
resulted from the fusion of the cells, or indeed, that any EPO or EPO-like
material was produced in vitro. According to Sugimoto, following suspension,
the cells had to be sonicated to release the protein which either was EPO
or had EPO-like activity. On the basis of the description in Sugimoto, and
the evidence and the arguments I have heard, it is at least possible, and
it may well be probable, that the protein recovered from the suspension had
been made while the tumours were growing in the animals. As Professor Wall
stated when he was being cross examined, in order to see whether the cells
which Sugimoto claimed to have fused were actually fused, and whether such
fusion resulted in the expression of EPO, would require some sort of marker
to identify the product of any such fusion. I accept his evidence that there
were simply no data to show whether there had been a successful fusion, and
whether the reported expression of EPO was coming from the fusion in any event.
- Further, even assuming that Sugimoto achieved the results it claimed, its
teaching was not enabling in any event: in other words, I consider that it
would have been classically insufficient. In this connection, I have already
referred to the fact that it appears that, in connection with the United States
proceedings, TKT tried to replicate the teaching and results of Sugimoto,
and, indeed, tried to obtain the tumour cells therein described, but were
unable to do so. In that connection, there is not only the evidence of Dr
Heartlein of TKT, but also the evidence of Amgen. On 4th December 1995, they
asked one of the alleged inventors of Sugimoto for "a sample of the erythropoeitin
producing cells referred to in this patent as well as a sample of any erythropoeitin
produced by such a cell line" and were met with the answer that "we
are not in a position to provide such a cell line to any party having nothing
to do with our research activities regarding erythropoeitin". While this
correspondence obviously does not show that no such cell line or EPO exist,
it does provide some support for Amgen’s contention that Sugimoto is in any
event insufficient, particular when one bears in mind TKT’s inability to reproduce
the teaching or results of Sugimoto.
- When considering whether any of the claims in 605 can properly be treated
as anticipated by Sugimoto, it is, I think, helpful to identify the contribution
to the art made by Sugimoto (assuming, in favour of TKT and Roche, that Sugimoto
can be taken at face value) when compared with 605’s contribution. It seems
to me that the contribution of Sugimoto (if any) is pretty similar to that
of Professor Murray as described by Lord Hoffmann in Biogen [1997] RPC 1:
Sugimoto found a way of making erythropoeitin, and, on this hypothesis, if
one followed Sugimoto, one would do just that. However, like Professor Murray,
but in contradistinction to Dr Lin the inventor of 605, he did not characterise
and sequence the EPO gene. Dr Lin’s reported sequencing could then be used
for the production of EPO in cells, whether by transfecting cells thought
to be suitable in 1984 with an exogenous EPO gene, whether carrying out the
same exercise in cells later discovered to be suitable, or whether using newer
technology (such as using exogenous promoters to "switch on" endogenous
EPO gene in a human cell). All this is what, at any rate on my view, can be
said to have been effectively enabled by the disclosure of 605. Accordingly,
I do not consider that Sugimoto could fairly be said to anticipate Claim 1
of 605, given that it claims a DNA sequence "suitable for use in securing
expression in a ... host cell".
- Quite apart from this, there are difficulties for TKT in light of the drafting
of the Claims of 605. So far as Claim 1 is concerned, while it is fair to
say that I heard little evidence or argument on the point, I incline to the
view that, assuming a protein with EPO-like characteristics was produced by
Sugimoto, it would not have been the "product of the expression in a
eukaryotic host cell of a DNA sequence", irrespective of the meaning
of that expression one adopts. As I have indicated, on any view it seems to
me that, to be a "host cell" the cell in question must have DNA
with which it has been transfected. While the fused cell in Sugimoto can be
said to be artificial in itself, it seems to me that the DNA included in it,
whether originally from the lymphoblastoid cell or the tumour cell, would
not be foreign or "exogenous" to the new fused cell, which hence
would not be a "host" to the DNA which was natural to either cell.
Otherwise one would reach the rather odd conclusion that all the DNA in the
fused cell was "exogenous", and that it had no endogenous or natural
DNA whatever. I appreciate that the fusion was effected by exogenous DNA,
namely a Sendai virus, but it was not alleged that this rendered the fused
cell a "host cell", and in any event there is no evidence that this
virus played any part in the production of EPO once the fused cell came into
existence, and therefore, in any event, it cannot be said, in my view, that
the cell was, as it were, relevantly a host cell. As to Claim 19, there is
no evidence that, assuming Sugimoto’s claims are correct, it results in EPO
which has a higher apparent molecular weight by SDS-PAGE than urinary EPO.
Cell line prior art
- Six articles in journals and a patent are also relied on by TKT as providing
sources of EPO before the priority date claimed by 605. The majority were
reported in 1983 or 1984. They are Sherwood et al in Clinical Research 31,323A,
Ascensao, reported in Blood 62,1132, Katsuoka et al reported in Gann 74,534,
Hagiwara et al, Blood 63(4), 828, Saito et al Exp Hematol 11(4) 228. There
is also a report in 1979, Toyama et al Blood 554(1), 245, and a Japanese patent
in the same year, JP-A 54-55790, Tajima being the first of its five recorded
inventors and applicants. I believe that these can be dealt with relatively
shortly.
- The possibility of reproducing the experiments reported in these papers
appears to depend on the availability of the cell lines referred to, and there
was no evidence that such cells were available. I accept that there was a
practice or policy, at least in principle, that, when papers were published,
the cells referred to in them should be available. However, as Professor Wall
pointed out in cross examination, "there are a number of interesting
ways to get around" that general rule, and there was "no way of
enforcing that policy". Indeed, in relation to the work of Dr Sherwood
(who produced the first of the papers, actually in abstract, to which I have
referred) it appears that GI did not obtain a copy of the cell line, and merely
reached an agreement that Dr Sherwood would "submit her cell line to
independent testing". I turn to consider briefly the various papers to
which I have referred.
- Sherwood is, as I have mentioned, an abstract, describing human kidney tumour
cells derived from tumours passaged in nude mice, and which were reported
as capable of producing EPO. Pursuant to the correspondence to which I have
just briefly referred, GI scientists eventually obtained Dr Sherwood’s cells,
and made cDNA libraries therefrom, but were unable to detect any EPO-encoding
mRNA. Further, despite three attempts, it appears that those carrying out
the research at GI were unable to get any reliable figures in an EPO assay.
- GI’s experience in seeking to follow the teaching of Sherwood, even after
obtaining a sample of her cell line, indicates how unsafe it is to rely upon
papers in this field, which have not been subject to independent verification
by experiment, of which direct (or some other satisfactory form of) evidence
is available at trial. At first sight, it might be said that it is unsafe
to draw this conclusion in relation to other papers simply from what happened
in relation to Sherwood, not least because Sherwood is an abstract. However,
in this connection, it is important to bear in mind that Dr Sherwood and her
colleague subsequently published their work in a peer-reviewed article in
the prestigious Proceedings of the National Academy of Sciences - PNAS 83:165
(1986).
- Ascensao describes a human testicular germ cell line which apparently produced
EPO-like activity, but this only occurred after the cultures had been starved
for some ten days. Katsuoka reported production of small amounts of EPO in
fairly similar circumstances to those described by Sherwood, as did Hagiwara.
Saito is a short abstract reporting two experiments, one of which again is
similar to Sherwood, and the other described the injection of mRNA derived
from tumour cells into frog oocyte cells, which produced something with EPO-like
activity. Toyama is another example of work similar to that of Sherwood (albeit
earlier) and Tajima also describes a similar activity. I do not consider that,
without further ado, any of these reports can be fairly relied on as producing
what they allege, particularly in light of GI’s experience with Dr Sherwood’s
cell line, and, indeed, the fact that no one appears to have taken any of
this work further, despite the clear desirability of obtaining EPO in appropriate
quantities.
- Quite apart from this, it appears to me that, even if any of these papers
could be relied on by TKT in principle as being novelty-destroying, they would
run into the difficulty in relation to Claims 1, 19 and 26 as would Sugimoto.
N. ADDED MATTER
- By virtue of Section 72(1)(d) of the 1977 Act, if the matter disclosed in
the specification of a patent extends beyond that disclosed in the application
for the patent as filed, then the patent is invalid. The principles applicable
to the determination of whether a patent is invalid on the grounds of added
matter are not in dispute. The court must decide whether, when viewed through
the eyes of the relevantly skilled addressee, any subject matter relevant
to the invention has been added to the disclosure afforded by the application.
Although an allegation of added matter, as its name suggests, normally involves
the addition of fresh material of some sort, it can apply to deletion. The
threefold exercise laid down in Bonzel -v- Intervention Limited (No. 3) [1991]
RPC 553 at 574, helpfully explains the approach the court should adopt. In
that case, Aldous J said this:
"The task of the Court is threefold:
(1) To ascertain through the eyes of the skilled addressee what is disclosed,
both explicitly and implicitly in the application.
(2) To do the same in respect of the patent as granted.
(3) To compare the two disclosures and decide whether any subject matter
relevant to the invention has been added whether by deletion or addition.
The comparison is strict in the sense that subject matter will be added unless
such matter is clearly and unambiguously disclosed in the application either
explicitly or implicitly."
- In the present case, the contention that the 605 patent is invalid because
of added matter is advanced by Roche (with TKT’s support) on the basis of
what I have called the deleted matter, namely the paragraph included in Example
10 in 605A and 605B, but deleted as a result of argument and evidence before
the Board, and consequently not in 605. The argument is based on the contention
that the effect of the inclusion of the deleted matter in Example 10 affected
the construction of Claim 19 so as to cut down the scope of protection afforded
to the patentee by that Claim, and, accordingly, the subsequent deletion of
the deleted matter has resulted in Claim 19 (and indeed the claims depending
on Claim 19) being broader in scope in 605, the patent, than in 605A, the
application for the patent and 605B, the patent as originally granted. Accordingly,
references in this part of the judgment to 605A also extend to 605B .
- As I have explained, when construing Claim 19, it appears to me that, particularly
when one reads the Claim through the eyes of the appropriately skilled man,
the requirement, that the rEPO has "higher molecular weight by SDS-PAGE"
than uEPO, is satisfied if, on SDS-PAGE, the uEPO band, viewed as a whole,
runs ahead of the rEPO band, even if there is a substantial degree of overlap
between the two bands. Mr Thorley on behalf of Roche (with the support of
Mr Kitchin on behalf of TKT) contends that, with the benefit of the deleted
matter in Example 10 in 605A, the skilled addressee would have read the patent
as indicating a much more substantial difference between the respective apparent
molecular weights by SDS-PAGE of uEPO and rEPO, so that, in particular, he
would expect there to be no overlap between the bands. In other words, with
the benefit of the deleted matter in Example 10, he would expect the uEPO
band to be running so much faster than the rEPO band that there would be no
overlap between the trailing edge of the uEPO band and the leading edge of
the rEPO band.
- This argument is entirely based on the proposition that the skilled man,
reading 605A, and in particular the deleted matter in Example 10, would appreciate
that the high hexose ratio reported for rEPO, when compared with that reported
for uEPO (namely 15.09 against 1.73), meant that there was a substantial difference
in the actual, and therefore the apparent, respective molecular weights of
rEPO and uEPO. This would have been on the basis that they would both have
the same amino acid sequence (and therefore the same "bare" protein
molecular weight) but the rEPO would be, to put it simply, more heavily glycosylated,
and hence would have a much higher molecular weight.
- In my judgment, the argument that 605 is invalid on the grounds of added
matter should be rejected. I consider that the appropriately skilled team
(and in particular the post doctoral biochemist with experience of glycoproteins)
would have appreciated that the analysis reported in the deleted matter was
inaccurate. The suggestion of a hexose ratio of 15.9 (using the N-acetylglucosamine
- GlcNAc - as the base 1 level) for rEPO would have been far too high to be
believable. In this connection, the evidence of the expert witnesses was virtually
unanimous. In the US proceedings, Dr Fritsch described "the carbohydrate
composition" described in the deleted matter as "plainly inaccurate".
In his evidence before me, Dr Robbins said that one "could really give...
no weight at all" to what was reported in the deleted matter. He also
confirmed what he said in his deposition in the US proceedings, namely that
"any person of ordinary skill in the art of glycobiology in 1984 would
understand [the information in the deleted matter] to be grossly inaccurate".
Professor Cummings stated that he thought that he "would have probably
found it difficult to convince anybody in the field, who [had] analysed glycoproteins,
that [he] had found one [sc. a glycoprotein] that had that ratio [sc. namely
hexose 15.09] even if I had repeated the analyses". Professor Clausen
said that he would have been highly suspicious of the 15.09 figure, and I
infer from his evidence that he would not have given the contents of the deleted
matter any significant weight. Accordingly, at least if the notional addressee
is to be equated with any or all of these witnesses, he would not have believed
this figure, and would therefore have effectively discounted the results contained
in the deleted matter.
- However, Mr Thorley contends that Dr Fritsch, Professor Robbins, Professor
Cummings and Professor Clausen were substantially more skilled, and indeed
more specialised in the field of glycosylation of proteins, than any member
of the notional team of ordinarily skilled people to whom 605 would have been
addressed. He suggests that the notionally skilled team of addressees would
not have included someone sufficiently well informed about glycoproteins in
1984 to take this view. He draws support from what was said by Professor Clausen
and by Professor Cummings, and also by the reaction of those working for Amgen
who commissioned and reported on the work which resulted in the information
contained in the deleted matter. Professor Clausen said that he would have
had problems with the deleted matter because, as at 1984, he had had two years
of training in the world’s best carbohydrate laboratory, but he would not
expect someone with experience in cell biology, as opposed to an expert in
carbohydrate biochemistry, to spot the difference. Professor Cummings accepted
that expression of proteins in mammalian cells was in its infancy in 1984
and the kind of glycans that one might see on proteins was unpredictable and
had not been the subject of substantial publication. It also is apparent from
Amgen’s disclosure that none of the people working for Amgen on this project,
including Dr Yu, who was accepted by Professor Cummings as a "reasonably
respectable carbohydrate chemist", and who performed the analysis which
resulted in the information in the deleted matter, raised any question about
the 15.09 hexose figure.
- These points all have force, but in the end I am not persuaded by them.
Resolving an argument as to whether or not the notional skilled team includes
someone with a particular expertise is difficult, not least because most of
the arguments appear to me to involve a degree of circularity. In my judgment,
one of the members of the notional team to whom 605 was addressed would have
had sufficient knowledge of glycoproteins to have serious concerns about the
accuracy of the contents of the deleted matter, and that concern would have
been sufficiently great to discount its effect. There is no reason to think
that Dr Yu, who carried out, and reported to Amgen on, the experiments which
resulted in the information contained in the deleted matter, was asked to
advise on or consider, the effect of the evidence that he apparently obtained.
- In any event, it appears to me that Roche’s argument on added matter faces
a number of difficulties. First, subject to one possible point, such a high
figure as 15.09 for hexose ratio in rEPO (compared with the unexceptionable
level of 1.73 in the case of uEPO) would have resulted in the rEPO having
a much larger molecular weight than the uEPO. Professor Cummings estimated
that such a high hexose level would roughly double what would otherwise be
the molecular weight of the EPO: he said it would increase it by over 30kDa;
this can be compared to its actual molecular weight of around 36 kDa. Yet
at the end of the immediately preceding paragraph of 605A the rEPO is described
as having a "slightly larger" molecular weight than the uEPO. Mr
Thorley’s argument involves assuming that, while the addressee of 605A will
not be sufficiently skilled in glycosylation of proteins to appreciate that
the deleted matter is inaccurate, he will be sufficiently skilled in glycosylation
of proteins to appreciate that the reported hexose ratio of 15.09 means that
rEPO has a substantially greater molecular weight than uEPO, as otherwise
he will merely note what is in the preceding passage, and conclude that the
difference in apparent molecular weight is not very great. In my view, Mr
Thorley’s argument therefore faces a squeeze. If the addressee is sufficiently
well informed to appreciate that the figure of 15.09 in the deleted matter
results in rEPO having a very much higher molecular weight, then he will also
have sufficient knowledge to appreciate from his general knowledge and from
the previous paragraph that the figure is unreliable. On the other hand, if
he does not appreciate that the figure is unreliable, he will not be sufficiently
skilled to appreciate that the 15.09 means that rEPO has a much higher molecular
weight than uEPO, and will therefore rely on the reference to the difference
being "slight". I do not think that Mr Thorley’s argument is sustainable
in light of this squeeze. In any event, as I have indicated, it appears to
me that this notional addressee will appreciate the inaccuracy of the contents
of the deleted matter.
- Quite apart from this, even if Mr Thorley’s argument can avoid this "squeeze",
and the addressee thinks that the deleted matter results in rEPO having a
substantially higher molecular weight than uEPO, he will appreciate that there
is a clear inconsistency between the two successive paragraphs of Example
10 in 605A. The first expressly states that there is a "slight"
difference between the two molecular weights, whereas the second merely implies
that there is a large difference between the two molecular weights. Faced
with an inconsistency between express and an implied teaching, I would have
thought that the reader would either assume that the express teaching is correct,
or would regard both statements as being unreliable for obvious reasons. Whichever
view he took, the deleted matter could not affect his interpretation of Claim
19.
- That is not the end of the difficulties faced by Roche in its added matter
argument. First, it appears to me that the whole basis of the argument falls
foul of the fourth principle identified by Staughton LJ in Glaverbel. The
added matter argument involves invoking the deleted matter, which is contained
in a paragraph in an example in the specification, to cut down Claim 19, which,
in this connection, I regard as "expressed in clear language", at
least once one understands the heterogeneity of the glycans in glycoproteins,
and the consequence on SDS-PAGE.
- Quite apart from this, the whole of Mr Thorley’s argument in relation to
added matter (and indeed the discussion in this judgment so far) proceeds
on the assumption that the hexose ratio of 15.09 reported in the deleted matter
in relation to rEPO would inevitably result in the rEPO having a much higher
molecular weight. Although that was the primary evidence of Professor Cummings,
he said at one point in his evidence that there was one possible (albeit,
as I understood his evidence, unlikely) way in which a skilled person who
read and understood the implications of the deleted matter could nonetheless
conclude that the reported hexose ratio of 15.09 was accurate. This would
be on the assumption that there was only one N-glycan in rEPO. As I say, I
do not think that is what a reader of 605A who understood the implications
of the deleted matter would have concluded, not merely because it did not
convince Professor Cummings, but also because it was scarcely consistent with
the evidence of the other experts as to the view they would have taken on
the deleted matter in 1984. However, if, contrary to my view, that is the
conclusion which would have been reached by the addressee, then the consequence
would have been, as Professor Cummings explained, that the molecular weight
of rEPO, with only one N-glycosylation site, would not have been perceived
as likely to be very much greater than that of uEPO with a hexose ratio of
1.7.
- Accordingly, my primary conclusion is that the deleted matter would have
been discounted by the notional addressee of 605A, because it was simply not
believable and was inconsistent with other passages in the patent, so it would
have been given no effective weight. If it would have had no effective weight
in the mind of the reader of the patent in question, then its removal cannot
by definition, have any effect on the construction and teaching of the patent.
- Even if I am wrong in the view that the deleted matter would simply be rejected
by the notional addressee, when reading 605A, I would still reach the same
conclusion on the argument that 605 is invalid on the ground of added matter.
Claim 19, whether in 605 or in 605A, seeks to distinguish the performance
of uEPO from that of rEPO by reference to their apparent molecular weights
on SDS-PAGE, not by reference to any difference in the nature or extent of
their respective glycosylations. Accordingly, construing that aspect of Claim
19 by reference to the rest of the patent, it appears to me that the essential
aspect of Example 10 of 605A is to be found in its reference to rEPO having
a "somewhat higher" apparent molecular weight than uEPO, and not
in the passage relating to the apparent differences in glycosylation.
- In these circumstances, the exercise laid down in Bonzel appears to me to
be tolerably easy, because, although, through the medium of the deleted paragraph,
information is disclosed in the application which is not disclosed in the
patent as granted, the effect of that information on the skilled addressee
is such that the meaning of Claim 19 (and of Claim 20) in 605A is identical
to the meaning of those Claims in 605, and therefore no real question of added
matter arises.
O. DO ROCHE INFRINGE 605?
- Amgen contends that Roche infringes by disposing a product which had been
obtained by means of the processes of Claims 27 to 29, and/or by disposing
a product within Claims 19 to 21, 23, 26, 30 and 31, of 605.
- So far as Amgen’s case based on Claim 26 is concerned, the issue between
the parties really relates to Claim 1 and Claim 2, which are, of course, incorporated
by reference into Claim 26. In light of the nature of the dispute between
Roche and Amgen in this connection, it is unnecessary for me to describe in
any detail the process carried out by Roche. Suffice it to say that the dispute
between the parties arises from the HuEPO cDNA sequence used by Roche. The
encoding regions of that sequence are identical to those shown in Tables VI
of 605. The downstream 3’ untranslated region is also identical; however there
are changes in some of the untranslated upstream 5’ region.
- Accordingly, Amgen’s primary case is that Roche infringe because the DNA
used in that process falls within integer (a) of Claim 1 as a matter of construction.
I determine that issue against Amgen, essentially for the reasons given in
this judgment for favouring the narrow, at first sight perhaps startlingly
narrow, construction of that integer of Claim 1. I have concluded that integer
(a) is limited to DNA sequences which are specifically identified in that
integer, namely only those sequences set out in Tables V and VI of 605. Roche
use a DNA sequence which, while it has complete identity with the corresponding
protein encoding region and the downstream sequence shown in Table VI (with
the exception of the misprint to which I have already referred), has differences
in the sequences which are upstream of the first exon. Accordingly, the DNA
sequence used by Roche does not fall within the strict words, as I have construed
them, of integer (a) of Claim 1.
- If integer (b) and integer (c) were not included in Claim 1, so that it
was, in effect, limited to integer (a) alone, and if Amgen had included the
point in their opening, I would have thought it right to go on to consider
whether the application of the three Improver or Protocol questions would
nonetheless lead to the conclusion that Roche infringed. It is unnecessary
(and arguably inappropriate) to embark upon that exercise, but it is right
to say that there would have been an obviously attractive argument in favour
of infringement in such circumstances. As Mr Waugh says, at least in the context
of Roche’s technology, the essential ingredient for the purpose of expression,
whether one is using cDNA or genomic DNA, are the encoding regions, and Roche
uses precisely the encoding sequence disclosed in Table VI, nucleotide for
nucleotide.
- However, consideration of the three Protocol questions is, in my judgment,
unnecessary in this context. It seems to me quite clear that, in conditions
which anyone skilled in the art would regard, and would have regarded, as
stringent, the DNA used by Roche would hybridise in accordance with the requirements
of integer (b). As I have said, the encoding regions identified in Table VI
and the encoding regions of the DNA used by Roche are identical, and extend
to around 500 nucleotides. The idea that one of these DNA strands would not
hybridise in stringent conditions with the complement of the other seems to
me fanciful. Accordingly, even if (as I believe is the case) there is room
for argument as to whether some conditions are "stringent", it appears
to me that integer (b) of Claim 1 is infringed by Roche, as a result of which
Roche’s defence to the contention that it infringes Claim 26 must fail, even
if I am wrong on integer (a).
- In these circumstances, it is unnecessary for me to consider the same argument
in relation to Claim 2. However, it is right to add that, in my judgment,
Amgen would also succeed on Claim 26 in so far as it incorporates Claim 2:
the DNA used by Roche seems clearly be a DNA "encoding for human erythropoeitin".
Mr Thorley suggests that that expression is unclear, but I cannot see why
that should be. I have discussed the meaning of Claim 2 when dealing with
construction. It appears to me to contain a perfectly satisfactory description
of any DNA sequence, such as that used by Roche, which, if inserted into an
appropriate cell in appropriate conditions, will cause the expression of the
protein, human erythropoeitin.
- In light of this conclusion, I believe that it follows that Roche’s process
also infringes Claim 27, in so far as it is based on Claim 1 or Claim 2. Similarly,
I believe that Roche infringes Claim 28, in so far as it based on Claims 12,
13, 14 and 16, in so far as those Claims in turn are based on Claims 1 and
2.
- In so far as Amgen
contends that Roche infringes Claim 29, the allegation is only to the extent
that Claim 29 is based on Claim 19, 20, 21, 23 and 26. So far as the first
of those four Claims are concerned, it appears to me that they are invalid
on grounds of insufficiency, and, even if that is wrong, they are incapable
of infringement. However, in light of my reasoning, I believe Roche infringes
Claim 29 but only in so far as it is based on Claim 26. Roche also infringes
Claims 30 and 31, but only in so far as they are based on Claim 26.
P. DO TKT INFRINGE 605?
Introductory
- Amgen contend that TKT infringe Claims 19, 20 and 22. They also contend
that TKT infringe Claim 26, in so far as it is based on Claim 1, 2, 5, 6 and
7. The claim against TKT based on Claims 19, 20 and 22, it must fail. Even
if I am wrong in my view that Claim 19 is invalid, it appears that the findings
of fact I have made when considering the insufficiency of Claim 19 would render
it incapable of infringement. Given that Claims 20 and 22 are each based on
Claim 19, it must follow that the most important claim for infringement against
TKT is under Claim 26.
The issues raised by the allegation of infringement against TKT involve a
closer understanding of the technology used by TKT, and, in light of my conclusions
as to the proper construction of Claim 1 (being the principally relevant claim
upon which Claim 26 is based), consideration also has to be given to the Improver
or Protocol questions. Further, although I have gone over much of the ground
when considering the permissible breadth of the claims of the patent, I believe
that it is also appropriate to consider the guidance given by the House of
Lords in Biogen [1997] RPC 1 in this connection. I propose, therefore, first
to explain what is involved in TKT’s technology, being the technology whose
product is said by Amgen to infringe Claim 26 of 605. I will then turn to
the application of the Protocol questions to that technology and its product.
I will then discuss the consequences, including consideration of the impact
of the reasoning in Biogen [1997] RPC 1.
TKT’s technology
- In summary terms, TKT’s activity involves gene activation technology, which
I have briefly explained when considering common general knowledge, and in
particular homologous recombination. In most human cells, the EPO gene (like
almost any other gene) is "switched off" by a negative regulatory
element ("NRE"). TKT introduce into the genome of a human cell,
upstream of the EPO gene disclosed in Table VI of 605, a nucleotide sequence
which effectively overrides the NRE, and "switches on" the EPO gene.
This nucleotide sequence is a DNA "targeting construct" which does
not include the encoding region. This construct contains a powerful viral
promoter, called the CMV promoter, which is more effective than the SV40 promoter
referred to in the 605 patent, and in particular in Examples 7A and 7B. Thus,
after this treatment, TKT’s cell line contains endogenous EPO DNA so far as
the coding regions are concerned, but it also contains an exogenous promoter
construct inserted upstream of that endogenous DNA.
- What I have just described is a somewhat over-simplified version of TKT’s
technology whereby they produce their product, known as GA-EPO. It involves
the process known as homologous recombination, which I have already briefly
mentioned. As explained by Dr Brenner, it is "the process whereby two
DNA sequences which have a region of identity can exchange material at that
region." As he explained, it is a natural process used by all living
systems to generate new combinations of genetic material. Targeting of mammalian
genes using homologous recombination, i.e. adapting this natural process to
enable genes to express proteins artificially, was first disclosed in 1985
by Smithies et al in Nature 317:230. Before that time, and therefore before
the relevant date for the purpose of the 605 patent, (as I have already indicated)
it was a procedure which had not been used.
- It is necessary to describe TKT’s process in a little more detail. The targeting
construct is a piece of DNA which is constructed outside the cell in which
the EPO is to be produced. The targeting construct can conveniently be divided
up into seven sequences. First, a so-called targeting sequence of some 3,000
nucleotides upstream of the EPO gene (-5787 to -2482). Secondly, a DHFR gene,
whose function is the same as in Amgen’s technology. Thirdly, a CMV gene promoter
for activation of the endogenous coding regions. Fourthly, a sequence encoding
the first three and a third codons of the human growth hormone ("hGH")
peptide. Fifthly, a selectable marker gene, neomycin phosphotransferase ("neo")
to allow selection of stably transfected mammalian cells. Sixthly, an EPO
splice donor site, to enable correct processing of the primary transcript
following transcription. Seventhly, another targeting sequence of some 1800
nucleotides upstream of the EPO gene (-2481 to -675).
- This targeting construct consisting of these seven components is known as
pREPO 22. TKT’s technology involves introducing it into a tumour cell line
known as HT-1080. As the targeting construct contains sequences at each end
of more than 1500 nucleotides in length which are precisely homologous to
sequences upstream of the natural EPO gene, the genome will recombine with
these sequences by homologous recombination. Ideally, therefore, the targeting
construct is effectively inserted into the genome a few hundreds of bases
upstream of the EPO encoding sequences in chromosome 7. In other words, the
targeting construct is inserted just upstream of the beginning of the sequence
disclosed in Table VI of the 605 patent. The insertion is effected by the
DNA in the first and seventh components being wholly homologous with these
endogenous upstream sequences and therefore combining with them. The "switching
on" of the endogenous DNA encoding sequences is achieved by the CMV promoter.
The function of the other components of the construct has already been briefly
described.
- Although the targeting construct is intended to be inserted into chromosome
7 (being the chromosome in which the EPO gene is located), homologous recombination
in mammalian cells is not efficient or reliable, and there will be insertions
at sites in other chromosomes. The neo can be used to separate out those cells
which have taken up the targeting construct, and TKT then screens those transfected
cells for EPO production, because it will only be those cells where the construct
has been inserted upstream of the EPO coding sequences where this will occur.
Thereafter, TKT treat the cells with MTX, a standard procedure which I have
already described and, indeed, is part of the 605 patent’s teaching, given
that it was a standard technique in 1983.
- As I have already explained, the cell will amplify the inserted DHFR gene,
and, because of its proximity thereto, the EPO gene will similarly multiply
(again, this is described in the 605 patent, in Example 10). The normal type
of cell used in this procedure was the DuX-B11 CHO cells, also referred to
in Example 10. Only those cells which contain sufficient copies of the DHFR
gene, and, therefore, also multiple copies of the EPO gene, will survive the
MTX treatment. In TKT’s technology, those cells were designated as R223 cells.
- After homologous recombination of the exogenous pREPO 22 construct and the
endogenous DNA, the CMV promoter and hGH fragment are integrated into the
genomic DNA upstream of the natural promoter of the EPO gene. Subsequent thereto,
the following steps occur in the R223 cell line:
1. Transcription of the EPO gene is initiated by the CMV promoter and
proceeds along to the hGH and EPO splice donor site sequences upstream of
the natural promoter, and along the five exons of the endogenous EPO gene,
thereby producing the primary transcript;
2. The primary transcript is then spliced resulting in a variant of natural
EPO mRNA. The splicing involves the exogenous hGH sequence being spliced to
the next available downstream splice acceptor site. This is so designed as
to be the sequence flanking the second exon of the endogenous EPO gene. Accordingly,
the first encoding exon is not present in TKT’s EPO mRNA: it is spliced out.
It is not required, because it is part of the leader peptide (the rest of
the leader peptide being the upstream part of the second encoding exon) which,
as I have explained, is cleaved at an early stage, resulting in relatively
"mature" EPO;
3. Translation of the EPO mRNA produces immature EPO whose leader peptide
sequence is a hybrid between the first three and a third codons translated
from the hGH fragment and the first twenty two and two thirds codons translated
from the second encoding exon of the endogenous gene;
4. Finally, the leader peptide is removed, and mature EPO is secreted
from the cell.
Differences in TKT’s technology
- Mr Kitchin says that there are a number of differences between TKT’s technique,
and the teaching of the 605 patent, so far as the production of EPO is concerned.
First, as I have already mentioned, Amgen’s process involves the isolation
and cloning of an exogenous DNA sequence encoding EPO, which is then used
to transform or transfect a host cell. On the other hand, TKT’s technique
does not involve the isolation or cloning of any EPO-encoding sequence: they
use the endogenous encoding sequence in human cells. Dr Brenner described
this as "the fundamental difference" between the two techniques,
and Professor Proudfoot considered that it was "too big a difference
to just dismiss as being an improvement". Whether or not Professor Proudfoot
is right, this is clearly a significant and marked difference.
- Secondly, TKT’s technique is of general application, in the sense that it
can be applied to any endogenous gene. On the other hand, the traditional
cloning approach of Amgen requires transformation of a cell with a gene of
interest, and this can only be done with genes which could be inserted into
cloning vectors, which is a limiting factor, in that the transformation of
a cell with an exogenous gene of more than 10,000 bases is difficult, and
even more difficult with genes of more than 20,000 bases. I do not consider
that this is a particularly telling point, in the sense that it does not seem
to me to take the argument much further than the first point takes it. I suppose
it can be said to emphasise the existence and extent of the difference between
the two techniques.
- Thirdly, TKT’s technique enables the promoter to be placed at a range of
positions upstream of the endogenous gene, so that, as the evidence suggested,
its position can be varied with a view to finding the optimum location for
ultimate maximum expression. The technique described in the patent requires
the promoter to be relatively close to the coding sequence, to avoid the possibility
of a false translation initiation or an intermediate stop codon. The evidence
as to the real benefit of being able to change the position of the promoter
using TKT’s technology appeared to me to be a bit dubious, in practice, but
it is a feature of difference. However, it seems to me that this third factor
is of little weight. Like the second factor, it can be said to underline the
difference between the two techniques, but once one understands the two techniques,
it does not seem to me that this is a factor which takes matters much further:
it is a potential advantage arising from the nature of one of the techniques.
Mr Kitchin accepts, quite rightly in my view, on behalf of TKT that if, for
instance, TKT was to use the technology described in the 605 patent, but using
the more powerful CMV promoter instead of the SV40 promoter described in the
Examples of 605, that would involve infringing the patent. This underlines
the point that the mere fact that an improvement, or possible improvement
to the process disclosed by the patent, such as the ability to relocate the
promoter, does not of itself render a new process non-infringing.
- I think this point also casts doubt on the fourth factor relied on by Mr
Kitchin. Amgen’s teaching involves the removal of the natural EPO promoter
regulatory sequences from the exogenous gene and coupling that gene to an
exogenous promoter, which is then integrated randomly into the chromosomes
of transformed cells. As against this, TKT activate the EPO gene in its natural
environment by targeting an exogenous promoter to a specific location upstream
of the endogenous encoding region. In any event, it appears to me that this
is not really a new difference, but is a combination of the first and third
differences.
- The fifth difference identified by Mr Kitchin is that Amgen’s technology,
at least as taught in the 605 patent, could only be successfully undertaken
in DHFR- CHO cells, whereas TKT’s technology appears to allow one to select
from a virtually limitless number of cell lines, provided they contain the
endogenous EPO gene. This appears to me to be a difference which, at least
in the main, is really inherent in the nature of the two techniques. Quite
apart from this, as I have already mentioned, I believe that the 605 patent
is entitled to extend to all eukaryotic cells.
- Sixthly, it is argued on behalf of TKT that there is a difference in the
EPO produced by the two techniques and, indeed, that the DNA which indirectly
expresses the EPO is also somewhat different under the two techniques. The
evidence on this point went little further than speculation. In the United
States proceedings, the TKT witnesses stated that they were not aware of any
advantages of TKT’s product over Amgen’s product, and in these proceedings
Professor Proudfoot could not point to any advantage. According to their own
internal documentation, TKT regarded the product as "me too" and
they described there being "nothing new here".
- I accept that it is possible that the nature and degree of glycosylation
between the two types of EPO could vary. I have already referred to experimental
evidence, papers in journals, and opinions of witnesses given in this case,
which relate to that issue. Thus, there appears to be a small difference in
apparent molecular weight between CHO rEPO and COS rEPO, which suggests differences
in the aggregate molecular weights of the glycans attached in the two types
of cells. There is plainly far less glycosylation of recombinant EPO produced
in at least insect cells (according to the 1987 paper of Wojchowski (op.cit.)).
However, it is fair to say that the SDS-PAGE experiments carried out on TKT’s
GA-EPO against urinary EPO suggests that TKT’s product differs very little,
if at all, in apparent molecular weight from COS or CHO rEPO produced in accordance
with the teaching of 605.
- On the basis of the evidence I have seen, it appears to me that any difference
in glycosylation between GA-EPO, and COS or CHO rEPO produced in accordance
with the teaching of the 605 patent, is non-existent in biochemical and therapeutic
terms, and any such difference is speculative and, if it does exist, of no
apparent significance in chemical terms. So far as therapy is concerned, GA-EPO
has the same effect as EPO produced in accordance with the teaching of 605.
On the evidence I have heard, there is nothing to suggest that the difference
between GA-EPO and COS rEPO or CHO rEPO is any more significant than the difference
between rEPO produced from COS cells and rEPO produced from CHO cells, both
in accordance with the teaching of 605. Chemically speaking, in light of the
evidence of Professor Robbins, to which I have referred when discussing the
insufficiency of Claim 19 of 605, it seems to me quite possible that the heterogeneous
nature of their glycosylation of GA-EPO is no different, or at any rate little
different, from that of recombinant EPO produced in accordance with the teaching
of 605.
- So far as the difference in the EPO gene is concerned, Professor Proudfoot
suggested that in TKT’s R223 cells, the EPO gene would be methylated, whereas
in the cells containing exogenous DNA expressing EPO in accordance with Amgen’s
teaching, the gene would not be methylated. As Mr Watson submits, this may
be of interest to academic scientists, but there was no suggestion in the
evidence that methylation has any relevant effect. Indeed, Dr Brenner stated
that it would have no effect, and I do not consider that there are any grounds
for doubting that.
- Seventhly, it is contended on behalf of TKT that its technique has miscellaneous
advantages over that described by the 605 patent. Those advantages may be
summarised as follows. First, there may be advantages in having a protein
expressed from an endogenous gene in its local chromosomal environment: the
evidence on this was vague, and not supported by any specific facts or features,
even though the two techniques have been used for some time. Secondly, the
level of expression per gene copy in TKT’s R223 cells is significantly higher
than that recorded in the patent. However, this does not result in any change
in the nature of the final product, and there is little difference in the
production of EPO per cell under the two systems. Thirdly, there is the advantage
of being able to move the exogenous promoter in TKT’s system; I have said,
the evidence on this was not satisfactory or clear, but I accept that there
is a potential benefit in this connection. Fourthly, TKT suggest that there
was some advantage in their system in that they did not have to amplify to
the extent described in Example 10 in the 605 patent. I think that is a matter
of little significance; on the basis of Professor Proudfoot’s evidence, it
seems to me that, at best from the viewpoint of TKT, the difference between
the two processes could be no more than a month if Amgen’s process required
an extra amplification step.
- Quite apart from the fact that these advantages do not seem to me to be
of much significance in themselves, it is right to say that I am not convinced
that advantages of this sort can make any difference to the question of whether
the process by which GA-EPO is produced, or GA-EPO itself, infringes 605.
It appears to me that, having considered the various points raised by Mr Kitchin,
the important and essential difference, and I can well see how it could be
called a fundamental difference, between the process used and taught by the
605 patent, and the process undertaken by TKT, is encapsulated in the first
difference I have identified. That distinction, "the fundamental difference"
as Dr Brenner put it, is between isolating and cloning an encoding exogenous
sequence and transfecting a host cell with it, and inserting an exogenous
promoter and facilitating sequences into a host cell to "switch on"
the endogenous coding sequences.
Does TKT infringe Claim 26: the Protocol questions
- In light of my conclusions on the issues of construction relating to Claim
1, TKT do not infringe Claim 26, on a literal construction of the patent.
Although it can be said that the targeting construct is a "DNA sequence
for use in securing expression [of EPO] in a .... eukaryotic host cell"
in the sense that the targeting construct is "a DNA sequence" and
it is "used in securing expression" of EPO in what is to the targeting
sequence "a eukaryotic host cell", I do not think that it falls
within the composite expression contained in the first part of Claim 1 of
the 605 patent. As explained when discussing questions of construction, any
set of words has to be construed in its context. What the 605 patent is concerned
with, and what it teaches in its specification, is the expression of EPO by
means of exogenous EPO-encoding DNA, and, equally, a cell which is host to
that exogenous encoding DNA. It is inappropriate to give the words "for
use" the wider meaning for which Amgen contend, and without which TKT’s
technology would be outside the scope of Claim 1 as a matter of literal interpretation.
The patent contains no teaching whatsoever so far as using exogenous non-encoding
DNA to "switch on" endogenous EPO-encoding DNA. It makes no reference
to such technology; indeed, this is scarcely surprising as, although it may
have been hoped for at some time in the future, it was at that time simply
not part of the state of the art. It would not have been in the mind of the
skilled addressee, and he would not have read the claim as extending thereto.
- However, that does not automatically mean that TKT do not infringe. As is
clear from the discussion in American Home Products [2000] IP&T 1308,
it is then necessary, in accordance with the requirements of the Protocol,
for the Court to pose itself the question characterised by Hoffmann J in Improver
[1990] FSR 181.
- The three questions which have to be asked were set out by Hoffmann J in
Improver at [1990] FSR 189. Basing himself on the reasoning of the House of
Lords, in Catnic [1982] RPC 183, Hoffmann J said that the proper approach
is as follows:
"If the issue was whether a feature embodied in an alleged infringement
which fell outside the primary, literal or acontextual meaning of a descriptive
word or phrase in the claim ("a variant") was nevertheless within
its language as properly interpreted, the Court should ask itself the following
three questions:
1. Does the variant have a material effect upon the way the invention
works? If yes, the variant is outside the claim. If no -
2. Would this (i.e. that the variant had no material effect) have been
obvious at the date of publication of the patent to a reader skilled in the
art? If no, the variant is outside the claim. If yes, -
3. Would the reader skilled in the art nevertheless have understood from
the language of the claim that the patentee intended that strict compliance
with the primary meaning was an essential requirement of the invention. If
yes, the variant is outside the claim."
- It may be that the way in which these questions were expressed would seem
to be a little narrow to those who practice in jurisdictions where there is
a sharp demarcation between construction and infringement (for instance in
Germany, where those issues are tried separately, indeed by different Courts).
In a sense, by tying oneself down to construction, it might be said that one
was concentrating more on form than on substance. I suspect that, free of
the binding constituents of Catnic [1982] RPC 183, the questions might not
have been expressed in terms of construction. After all, the claim in Improver
[1990] FSR 183 referred to a "helical spring": as a matter of language
that could scarcely include a "rubber rod", as Hoffmann J recognised
at [1990] FSR 187. Yet Catnic [1982] RPC 183 enabled him to conclude that
the rubber rod could be within the claim. It may be that, shorn of authority,
the question should be characterised as whether the rubber rod infringed the
claim bearing in mind the technical contribution of the patent and not merely
the words of the claim.
- However, this is perhaps playing with legal categorisation. There is no
doubt that the three questions are useful, important and authoritative (having
been approved and applied by the Court of Appeal on a number of occasions,
most recently, perhaps, in American Home Products, as I have mentioned). However,
it is worth remembering that they are based upon Lord Diplock’s observation
in Catnic [1982] RPC 183 at 242 that the language of a claim "should
be given a "purposive" and not necessarily a literal construction"
(per Hoffmann J in Improver at [1990] FSR 188 to 189). While, particularly
at first instance, it would be brave or worse to depart from the three questions,
I do not find it entirely easy to accept that it can be right that, where
there is no infringement on a literal construction, the Court is in every
case to be forced into the straightjacket of answering the three specific
questions in order to decide issues of construction or even issues of infringement.
- Before answering the three questions, it is, of course, necessary to identify
what Hoffmann J called "the variant". This, involves, I think, a
three part exercise, namely analysing what the patent in suit claims, identifying
the alleged infringement, and then distilling the essential variation or variations
between the two techniques or products. Earlier in this judgment, and in the
preceding section of this part, I have tried to undertake the first two parts
of the exercise. I shall concentrate on Claim 26, because, unlike the other
Claims which TKT are said to infringe, it is, at least in my view, valid and
capable of being infringed. Claim 26 really takes one back to Claim 1.
- The nature of the variant on Claim 1 in TKT’s technology is that the EPO-encoding
DNA has not been isolated and the encoding DNA is not in a "host cell"
(these two features being, at least to an extent, different ways of putting
the same point). The "fundamental difference" between the two techniques
has been identified by Dr Brenner, as I have mentioned. Amgen’s teaching involves
transfecting a cell with exogenous encoding DNA (together with its natural
exogenous promoter or an artificial promoter) and this exogenous DNA is then
incorporated into the endogenous genome, where it serves to express EPO. TKT’s
technology involves constructing a DNA sequence with various components, including
an artificial promoter, but not including any EPO-encoding sequence, and inserting
the construct into a human cell with a view to the construct being incorporated
into the genome upstream of the EPO-encoding sequence, whereupon that sequence
is "switched on" and results in the expression of the EPO. It is
accepted by TKT, as I have mentioned, that the identity or location of the
exogenous promoter is not a relevant variant.
- I turn then to the first question. As Hoffmann J pointed out in Improver
at [1990] FSR 191, the answer to the first question "depends upon the
level of generality at which one describes the way the invention works."
He went on to say, on the following page, that "the right approach is
to describe the working of the invention at the level of generality with which
it is described in the claim of the patent." In this context, it appears
to me that Claim 1, consistently with the whole thrust of the specification,
and, indeed with commercial common sense, indicates that the patentee is getting
at the production of EPO. The obtaining of the amino acid sequence of EPO
and of the sequence of nucleotides in the EPO gene is, in the context of the
patent, a means to an end, even if, to an academic scientist, it could be
said to be an end in itself. Claim 1 does not merely identify the DNA sequences
claimed, but it identifies those which are suitable for a certain purpose,
namely the production of EPO. That is even clearer when one goes to Claim
26, which is concerned to claim the EPO produced in this way.
- In my judgment, the variant involved in TKT’s technology does not have a
"material effect on the way the invention works". In each case,
one has what was referred to in the evidence as an "identical string
of DNA", namely the encoding regions of the EPO gene, expressing EPO
in the conventional and natural (albeit artificially massaged) way.
- Mr Kitchin in his effective submissions, contends that the variant does
have a material effect on the way the invention works and relies on the contention
that "an important part of [Amgen’s] invention is the disclosure of a
route to the expression of EPO" and that that route "is fundamentally
different to that used by TKT". That point obviously has attractions,
but I do not accept it. First, it seems to me to concentrate more on the teaching
of the patent in the specification, and not on what the relevant claims assert.
In this connection, it is true, of course, that, as a matter of literal construction,
the claims do not extend to TKT’s technique, but that cannot be the determinative
factor when considering the first question. If it were, then the answer to
the first question would always be in the negative, and the whole exercise
of going through the three questions would be pointless.
- My broader reason for rejecting Mr Kitchin’s contention in this connection
is, at least to an extent, substantially along the same lines as my reasoning
for favouring Amgen’s arguments on the issues of Biogen insufficiency and
breadth of claim. The essence of the invention embodied in 605, its contribution
to the art or what one might call its inventive concept, is the disclosure
encapsulated in Table VI, which contains the whole of the encoding sequences,
the whole of the intervening introns, and a large proportion of the upstream
and downstream sequences. It enabled that to be done which was previously
impossible, namely the production of EPO in accordance with biotechnological
methods, as they existed at the relevant date as they would have been expected
to develop and improve over the ensuing years. It seems to me that, in a fast
developing technology such as that involved here, it would have been inconceivable
to the notional reader of the 605 patent at the relevant date that there would
not be significant developments and changes in the technology of genetic engineering
over the life of the 605 patent. What TKT have done is to use a new technique,
homologous recombination, to achieve EPO expression by the natural EPO-encoding
sequences.
- Indeed, this is consistent with the evidence of Professor Proudfoot who
said there was nothing new about "an SV40 promoter, the gene of interest,
DHFR for amplification placed in a CHO cell, that was all standard in 1984".
He accepted that "the basic invention was the isolation and sequencing
of... the EPO gene followed by the disclosure of a route to its expression."
He said that TKT "certainly uses newer technology to achieve that result".
While he immediately went on to say that he did not think that was the only
difference, it appeared to me that the other differences he identified were
either inherent in TKT’s technology (e.g. the ability to target the promoter)
or were features admitted on behalf of TKT not to assist on the issue of infringement
(e.g. the stronger promoter). In other words, the only significant variant
is the use of newer technology, which did not exist in 1984
- The teaching of the 605 patent and TKT’s technology involve many of the
same essential features. They employ the same EPO encoding sequences; they
involve expressing the same EPO artificially; the do so in a eukaryotic cell;
they employ an exogenous promoter; the biochemical/chemical way in which they
express the EPO is substantially the same. Neither could be achieved without
the essential disclosure - the contribution to the art - of the 605 patent
itself (as I shall explain in a little more detail below).
- I turn to the second Protocol question. In Improver, at [1990] FSR 192,
Hoffmann J emphasised that this question did not involve limiting possible
infringement to a variant "which would have suggested itself to the skilled
man as an obvious alternative to the thing denoted by the literal meaning."
He went on to say:
"In my view the question supposes that the skilled man is told of both
the invention and the variant and asked whether the variant would obviously
work in the same way. An affirmative answer would not be inconsistent with
the variant being an inventive step."
Accordingly, the fact that TKT’s technology would not have been known to
the notional addressee of the 605 patent, and, indeed, the fact that the technology
involved in TKT’s technique was inventive as at the relevant date (as I strongly
suspect it to be) does not go to the determination of the second question.
- TKT contend that the answer to the second question is no, because the reader
of the 605, skilled in the art as at the relevant date, would not know that
the technique employed by TKT would work, and, even if one is to assume that
he believed that it could work, he would not know that it would have no material
effect upon the way in which the invention claimed in 605 would work. Thus,
Mr Kitchin points out that the evidence supports the view that a person skilled
in the art as at the relevant date would not know that splicing would work.
He also says that there is nothing to suggest that he would appreciate that
the introduction of a targeting construct such as pREPO 22 would have no material
effect upon the level of or manner of expression of the endogenous encoding
EPO gene in a human cell, when compared with the level and manner of expression
of an exogenous encoding gene and associated promoter introduced in to a CHO
cell.
- Mr Kitchin’s first point raises an issue of principle in relation to the
second Protocol question. It is whether one should assume that the reader
of the patent is not merely told of the variant, but, if it is necessary,
he is also to be told that it works. In my view, it should be assumed that
the notional reader is so informed. The point did not arise in Improver, and
it was not suggested that any other authority in which the questions were
considered (including American Home Products at [2000] IP&T 1320 to 1322)
dealt with this particular issue.
- In my judgment, it is to be assumed that the reader of the patent is told
that the variant works, at least in a case such as this, if he would not in
fact have known. The point is not an entirely easy one, not least because,
if my conclusion is right, it could be a matter of argument as to quite how
much the notional reader is told. It can be said with some force that the
more he is told, the more likely the second question is to be answered in
favour of the patentee, on the basis that, in the ultimate analysis, he will
be told everything including the answer to the first of the three questions.
However, I do not regard that as a particular difficulty, because it seems
to me that all that the notional reader need know is the nature of the variant
and the fact that the variant works, i.e., in the present case that it results
in the expression of EPO in the human cell by virtue of the endogenous EPO-encoding
DNA being "switched on".
- I believe that the opposite view would be inconsistent with the underlying
intention of the Protocol, particularly in the context of fast moving technology,
such as that involved in the present case. If I am right in the present case
in holding that 605 can validly extend to analogues of EPO and variants of
the natural EPO gene, it would seem somewhat inconsistent if the Claims were
incapable of extending to subsequent inventive techniques, or even to inventive
new versions of existing techniques, subsequent to the date of the patent,
simply because the notional reader skilled in the art at the relevant date
would not have known whether they would have worked or not. That seems inconsistent
with "fair protection for the patentee". Obviously, there must also
be "fair protection" for any subsequent inventor. However, if his
invention involves a new way of doing that which could not be done without
the disclosure of the patent, it is not apparent to me that the new inventor
should be able to "scoop the pool", thereby obtaining the benefit
of the old invention, which properly belongs to the original patentee, as
well as obtaining the benefit of the new invention, which does properly belong
to him, and which can be protected by way of a new patent.
- The second point raised in relation to the second question is whether, in
this case, the reader skilled (albeit non-inventive) in the art at the relevant
date, on being told of the nature and feasibility of TKT’s technology, would
have thought it obvious that it would not affect the way in with the invention
disclosed by 605 works.
- While I accept that Mr Kitchin is right in his argument that the reader
would have expected, or at least suspected, that there might well be differences
in details, such as rate of expression, and nature and extent of glycosylation
of the EPO expressed, I do not consider that he would have had doubts about
the existence of any variation in what I might call the essential features
of the invention embodied in the 605 patent (and Claim 1 in particular), or
the essential features of the way in which that invention works. As with the
first question, it appears to me that, in order to identify "the invention"
in the context of the second question, one must go to the claim or claims
or the patent in suit. In the present case, Claim 1 does not condescend to
the sort of detail which Mr Kitchin raises as a ground for answering the second
question in the negative. Even if that is too narrow a basis for considering
the second question, I would still answer it in the affirmative. The way in
which the invention works in this case (whether one looks at the patent in
suit or at TKT’s technology) is the use of the natural EPO-encoding DNA sequence
resulting in the expression of EPO in a cell where the genome has been artificially
manipulated. It is the nature of the artificial manipulation which is the
difference between the two systems: in the teaching of the patent, the traditional
method of inserting the encoding sequence (possibly plus introns and an artificial
promoter) is used, whereas TKT’s newer technology involves switching on the
endogenous encoding sequence by means of an inserted artificial exogenous
sequence including an artificial promoter. If this latter technology were
explained to the notional reader at the relevant date, and he was also told
that it worked, I consider that he would have concluded that it was obvious
that it worked in the same way as the more traditional technique described
in the patent. The essential point, as I see it, is that EPO is expressed
in a eukaryotic cell through the medium of a DNA sequence which is in each
case identical, being the naturally occurring EPO-encoding DNA sequence.
- While the reader may well certainly have had doubts as to whether the glycosylation
of the EPO produced by the two techniques was the same, that does not seem
to me to be relevant. While the patent in suit only teaches a technique in
relation to two specific cell lines, namely the COS cell and the CHO cell,
only the latter of which can be described as wholly successful, it is clear
that the patent envisages (and the notional reader would have expected) that,
in accordance with advances in biotechnology, it would be possible to use
its disclosure to express EPO in other types of cell. If, after the relevant
date, a naturally occurring cell line, not previously known to be suitable
for the sort of technology described in the patent, had been discovered as
being suitable for that purpose, it seems to me that a person following the
teaching of the patent, in all respects, save that he uses the new cell rather
than the CHO cell, would infringe the patent. I find the argument that he
would not do so because the glycosylation of the EPO expressed in the new
cell was different from that of the EPO expressed in the CHO cell or COS cell
unconvincing. First, apart from the rather vague guidance in the two paragraphs
in Example 10 (which amount to no more than the result of a preliminary experiment)
coupled with the closing words of Claim 19, there is nothing in the patent
to suggest that the nature of the glycosylation of the EPO is part of the
invention, or that it is a necessary feature of the EPO produced in accordance
with its teaching. Secondly, it is clear that the nature and extent of the
glycosylation varies from one type of cell to another, and, indeed, can vary
within cell lines. Thirdly, as the passage in Example 10 shows, there is a
variation in the glycosylation of the EPO produced in the two types of cell
specifically referred to in the patent, namely the COS cell and the CHO cell.
Fourthly, apart from the reference to the results of preliminary experiments
in Example 10 and the closing words of Claim 19, there is nothing, particularly
in Claim 26, to suggest that the glycosylation of the resultant EPO is significant.
- I turn, then, to the third question, namely whether "strict compliance
with the primary meaning [of Claims 1 and 26] was an essential requirement
of the invention". In this connection, as Professor Proudfoot accepted,
"there is nowhere [in the 605 patent] where ["the use of a system
such as TKT use" namely "homologous recombination"] is excluded
specifically". Although that is a point relied on by Mr Watson, it seems
to me to be pretty weak. The essence of Amgen’s case, as I see it, is that
homologous recombination was not referred to because, at the relevant date,
nobody had achieved it, and even an unusually skilled and inventive person
would merely have hoped, indeed, probably, expected, that it would be achievable
in the future. It would therefore be surprising if it was specifically excluded,
almost as much as it would have been surprising if it had been specifically
included. However, it is fair to say that, given that the third question involves
considering the language of the patent, and particularly of the claims, the
point is not devoid of force, albeit that I think that it amounts to a shield,
rather than a sword, so far as Amgen is concerned.
- It seems to me that, unlike in Improver [1990] FSR 181 (where the concept
of a rubber rod could be said to have existed), and unlike in Catnic [1982]
RPC 183 (where the possibility of an angle other than 90o could
be said to have existed), it cannot be said that the variant existed at the
date the patent was applied for, or even when it was published. In the previous
case the variant existed but had not been thought of by the patentee. In the
present case, homologous recombination did not exist at the relevant date.
Roche and TKT cannot, therefore, argue, as could have been argued (and presumably
was argued) in the earlier two cases, that there was an apparent and presumed
intention to exclude the variant on the part of the patentee, because the
basis of the variant (namely the use of a different, albeit well known, material
in Improver, and the slight change of angle in Catnic) could have been considered
by the patentee, and therefore must have been intentionally excluded. In the
present case, homologous recombination in eukaryotic cells, the technology
employed by TKT, had not been achieved by the relevant date.
- As in Catnic, to quote Lord Diplock, "no plausible reasons have been
advanced why a rational patentee should want to place so narrow a limitation
on his invention". It is fair to say that this point may be tied up with
my conclusion on breadth of claim and Biogen insufficiency. If I am right
on that issue, then there is indeed no reason why the patentee in the present
case should have wished to limit the extent of his claims so that it would
not extend to variations and improvements in genetic engineering over the
life time of the patent. If I am wrong in that view, then TKT does have the
answer to the point: the patentee would have been concerned to ensure that
his claims were not cast so widely as to include techniques in respect of
which the patent contains no teaching, and therefore as a result of which
the patent, or at least some of its claims, might be determined to be insufficient.
- Further, various passages in the 605 patent (e.g. at page 48) indicate that
the patentee appreciated that the disclosure he had given would in due course
result in people being able to express EPO in cells other than those enabled
by the specific teaching of the patent. It is to be noted in those passages
the patentee not merely showed that he appreciated that, with inevitable advances
in the biotechnology field, expression of EPO in other cells, and presumably
with different techniques than those identified in the patent, would be achieved,
but that he envisaged that the disclosure he has given would enable, or at
least would be a necessary contribution to, the expression of EPO in other
cells.
- In Palmaz’s Patents [1999] RPC 47, Pumfrey J rejected the patentee’s contention
that the third question in that case should be answered in the negative, and
said this:
"This is not just a departure from some descriptive word or phrase
or a matter of degree: it is the omission of whole features of the claim."
- In the present case, TKT say that the use of endogenous encoding DNA, albeit
"switched on" and promoted by exogenous DNA involves a departure
from a feature of Claim 1, namely the use of exogenous encoding DNA. However,
once one has identified the essential inventive feature of the Claim, which,
as I have mentioned when considering Biogen insufficiency and breadth of claim,
is the disclosure embodied in Table VI of the 605 patent (coupled with the
fact that it can indeed be used for expression of DNA in a eukaryotic cell)
it appears to me to follow that the departure involved in TKT’s technology
is "a matter of degree". I do not think one could go so far as to
say that there were "trivial difference", to quote Mr Watson’s description,
between TKT’s technology and that described in the patent. However, it does
seem to me that, when one looks at the difference in the technology, in the
context of the nature of the disclosure and claims of the patent, the difference
is indeed one of degree. The essential nature of the disclosure of 605 is
that it enables the expression of EPO in a eukaryotic cell to be artificially
achieved by disclosure of the EPO gene sequence.
- There is a further point with which I should deal. TKT argue that the DNA
sequences used for expression is not within any of the three integers of Claim
1. I do not agree. As the targeting sequence is upstream of the DNA sequence
shown in Table VI of 605, it seems to me that the natural EPO gene - to the
extent shown in Table VI - is used for expression of EPO - i.e. integer (a)
applies. Even if it does not do so, I consider that the three Protocol questions
are satisfied. Quite apart from this, I believe TKT’s technology to be within
integer (b). Professor Wall said that TKT’s EPO gene would hybridise with
the DNA sequence in Table VI. In any event, the DNA sequence used by TKT falls
within Claim 2 of 605.
The teaching of the 605 patent and TKT’s technology
- It is clear that TKT’s technology involved drawing on the disclosure of
the 605 patent to a significant extent. Indeed, were it not for the disclosure,
the contribution to the art, of the 605 patent, TKT could not have achieved
the expression of EPO, whether in mammalian cells or otherwise. Before turning
to the specific details, it is right to deal with Mr Kitchin’s point that,
in so far as TKT did obtain relevant information, it was from a source other
than the 605 patent. It seems to me that that is not quite the point: 605
disclosed for the first time the amino acid sequence of EPO and the nucleotide
sequence of the EPO gene (save that the uppermost part of the upstream sequence
was not included) and the use of this to obtain artificial and amplified expression
of EPO in a eukaryotic cell. This enabled that which the patent described
as being highly desirable, namely production of EPO on a commercially useful
and therapeutically worthwhile scale. The facts that others (including Jacobs
and his co-workers at GI) published the same or similar information, arrived
at by a slightly different route, thereafter, and the fact that TKT derived
its information from another such source, do not alter the relevance of the
fact that it was the patent in suit in which the information was first revealed.
As Mr Waugh points out, this is not a copyright case, where the copyright
owner must establish that it is his work which has been copied (directly or
indirectly); it is a patent infringement case, and the question therefore
is whether matter disclosed in the patent (whether or not derived from the
patent) has been drawn on or used by the alleged infringer. Even if the infringer
can show that he arrived at the same result by the same route quite independently,
or even if he can show that he arrived at a better result by a cleverer route,
that, of itself, is no defence to an action for patent infringement.
- I turn, then, to what was first disclosed in the 605 patent, without which
TKT could not have developed the technology it used for the production of
EPO. First, and perhaps most importantly, to achieve the homologous recombination
which is the fundamental feature of TKT’s technology, it was necessary to
have the two targeting sequences, running to a total of some 5,000 nucleotides.
In order to insert the CMV promoter and the DHFR gene (to effect promotion
and amplification respectively) upstream from the endogenous EPO-encoding
region in the HT1080 cells, with a view to "switching on" and amplifying
that gene, it was necessary to know the sequences of approximately 5,000 nucleotides
of the EPO gene upstream of the coding region. It is true that the downstream
segment of TKT’s targeting construct ends 675 nucleotides upstream of the
EPO translation initiation codon, and that Table VI does not disclose this
sequence, since it begins at 620 nucleotides upstream of that codon. However,
TKT’s US Patent (No. 5,641,670) indicates that TKT created probes having part
of the sequence set out in Table VI in order to clone the human EPO gene from
a genomic DNA library. This enabled TKT then to carry out further sequencing
work upstream of the -620 nucleotide in Table VI, and that could not have
been achieved without the disclosure of 605.
- The evidence of Professor Proudfoot confirms this conclusion. He accepted
that one "cannot think about using the TKT approach to express EPO...
without knowing the exon arrangement", and that, in order to implement
TKT’s technology, "one needed to have information about the EPO gene
and its sequence". Further, although it so happens that TKT’s targeting
construct ends at -675, there is no reason why it could not have included
the additional downstream sequences (albeit upstream of the start codon) set
out in Table VI of the 605 patent. Indeed, TKT’s US Patent suggests that they
started their project using targeting sequences which included sequences set
out in Table VI.
- The second feature of the disclosure of the 605 patent relied on by TKT
in its technology was the nucleotide sequence for the first three and a third
amino acids from hGH. The final one-third part of the sequence is a G which
links up with the first two nucleotides of the second exon in Table VI to
give the codon GAA (which happens to code the amino acid glutamic acid). For
the TKT technology to work, the first encoding exon (which is the exogenous
hGH sequence) must be spliced to the second encoding exon of the EPO gene
in the correct phase: if it was out of phase, then the first two nucleotides
in the second exon would be translated incorrectly, and this error in phasing
would perpetuate, as a result of which virtually every single encoding codon
would be out of phase and would therefore encode for the wrong amino acid.
Accordingly, knowledge of the phasing of the second exon, which was provided
by Table VI of 605, was essential to TKT.
- This second feature is considerably less important than the first feature,
because, if everything else were known to TKT, it would only have taken relatively
little time and work of a fairly routine nature, essentially on a trial and
error basis, to arrive at the correct phasing. However, the assistance on
this aspect given by the disclosure of 605 did not merely extend to phasing:
it also enabled TKT to ensure that the one third codon of their new first
exon matched the two thirds codon on the second exon to give the correct amino
acid.
- The third feature disclosed by the 605 patent and used in TKT’s technology
arose from the disclosure of the splice donor site sequence immediately following
exon 1 in Table VI. The importance of this to TKT was, as in relation to the
second feature, to enable the final third codon of hGH being spliced into
the two thirds codon of the second exon.
- There was a dispute between Dr Brenner and Professor Proudfoot as to whether
the splice donor site consisted of ten bases or six bases. They are both highly
distinguished scientists in this field, and I do not find it easy to choose
between them. However, in TKT’s US Patent, to which I have referred, it is
clear that TKT themselves expressed the view that it consisted of ten bases,
and that TKT used the ten base pairs from the first intron. Professor Proudfoot
accepted this, while it did not cause him to change his view as to what constituted
the splice donor site. I also note that TKT clearly indicated to the FDA that
the splice donor site was the ten bases derived from Table VI of the 605 patent.
- In these circumstances, while not doubting the genuineness (or, indeed,
the reasonableness) of Professor Proudfoot’s view, I have come to the conclusion
that, in so far as it is necessary for me to conclude as a matter of general
principle what the splice donor site amounts to in the present case, it consisted
of ten base pairs, as Dr Brenner said, rather than six base pairs, as Professor
Proudfoot indicated. More centrally, it is clear that, whatever the splice
donor site may be, TKT proceeded to develop their successful technology by
reference to a splice donor site consisting of ten base pairs, and this was
first revealed by Table VI of 605.
- It is right to add that, whatever the correct view as to the extent of the
splice donor site there were publications at the relevant date which gave
pretty good guidance as to the likely splice donor site sequences in genes
generally - e.g. Lodish et al. Molecular Cell Biology (although I was only
referred to the 4th, 1999, edition, at page 416). However, the disclosure
of the 605 patent gave certainty where it did not exist previously, on this
issue as on any other issue which depended on the sequence of the EPO gene.
- I turn to the fourth feature. As Dr Brenner said, and Professor Proudfoot
accepted, the disclosure in the 605 patent that the first encoding exon encoded
entirely of amino acids which were in the leader peptide, and that the leader
peptide extended into the first part of the second exon, "was certainly
helpful to the TKT process". Without knowing that the whole of the first
encoding exon encoded part of the leader peptide (and therefore not part of
the mature EPO polypeptide) TKT was able to develop its technology, which
involved effectively splicing out that first exon. If any part whatever of
that first exon had encoded the mature polypeptide (i.e. not part of the leader
peptide) then the technology could not have worked.
- As Mr Kitchin argues, the mere fact that TKT’s technology relied on, indeed
could not have been developed, without making use of information first vouchsafed
in the 605 patent, does not of itself necessarily mean that TKT infringe.
Authority indicates that the issue as to whether the process or product claims
of a patent are infringed can only be answered by considering whether the
infringing product or process is within the literal language of the claim
or, if it is not, whether the patentee can satisfy the three Protocol questions
in respect of the allegedly infringing product or process. However, although
claim and infringement must not be confused, I do not think that, contrary
to Mr Kitchin’s submission, it is irrelevant to consider the existence and
extent of the debt, if any, of the allegedly infringing product or process
to the disclosure of the patent which it is said to infringe, at least in
this case, particularly when one is considering an alleged infringement by
reference to the Protocol questions. In my view, one should look at the contribution
to the art of the patent, the way in which its claims are phrased, the extent
to which the alleged infringer relies on the contribution and the nature of
the alleged infringement when compared with the claims.
- Although there is no suggestion to that effect in Improver [1989] FSR 183,
perhaps because it was not relevant in that case, it appears to me that, before
I conclude that there is an infringement on the basis of the Protocol questions,
I should enquire whether the alleged infringement actually draws on the disclosure
of the patent. Where, as here, the contribution to the art of a particular
patent is to a large extent a discovery, it might cause one to reconsider
a conclusion that there had been an infringement, where the alleged infringer
uses modern technology not contemplated by the patent and does not draw on
the disclosure or contribution of the patent. After all, such a conclusion
would involve the claim, in effect, extending to a technique for expressing
EPO which "owed nothing to the teaching of the patent" or "which
could... have been envisaged without the invention", even so far as the
expression of EPO is concerned. On the other hand, for the same sort of reason,
if the alleged infringement does rely on the patent’s contribution, that might
cause one to reconsider a conclusion that there was no infringement, albeit
perhaps without quite so much concern.
- It does appear to me that, in some ways, my reasoning is encapsulated in
a passage quoted in the speech of Lord Hoffmann in Biogen [1997] RPC 1, which
I have already quoted. At [1997] RPC 48 lines 17 to 21 he cited with approval
a passage from the Board’s decision T292/85 [1989] OJ EPO 275 which includes
this:
"Unless variants of components are also embraced in the claims, which
are, now or later on an equally suitable to achieve the same effect in a manner
which could not have been envisaged without the invention, the protection
provided by the patent would be ineffectual."
(Lord Hoffmann specifically adopted part of this in a passage in his speech
at [1997] RPC 53, lines 13 to 14, quoted above).
- As I have mentioned, the extent of the claim and the existence of infringement,
while conceptually distinct, appear to me to overlap to some extent when one
is having to deal with the Protocol questions: that is apparent from the way
in which the questions were formulated, and the circumstances in which they
were formulated in Improver [1990] FSR 189 itself. At least in the present
case, it does appear to me that the issue of breadth of claim and Biogen insufficiency
and the issue of whether TKT’s process and product infringe cannot be regarded
as independent. In my judgment, they both involve considering the nature and
extent of the contribution to the art as disclosed by the patent. I believe
this is supported by the way in which Lord Hoffmann dealt with the question
of sufficiency in Biogen [1997] RPC 1. In this connection, I have in mind
in particular the observations at [1997] RPC 50, where he referred to a claim
not being permitted to extend to "ways which owe nothing to the teaching
of the patent or any principle which it disclosed".
- Another way of looking at the question of whether TKT infringes is this.
The technical contribution to the art of the 605 patent is the disclosure
of the EPO gene (albeit that part of the furthest upstream sequence is not
included). It is not suggested that the subsequent aspects of the teaching
of the 605 patent are inventive. In particular, the way in which Dr Lin used
the disclosure of the EPO gene and amino acid sequence to achieve artificial
expression of EPO, namely by heterogeneous recombination, was relatively routine.
It does not seem unreasonable if a new method of achieving artificial expression
of EPO, which, as a method owed nothing to the teaching of the patent, but
which depended on the disclosure of the patent to express EPO, infringed the
patent albeit only to the extent that it involved being adopted specifically
to express EPO.
Conclusion on TKT’s infringement
- In these circumstances, I conclude that the case that TKT infringe the 605
patent is made out, but only in connection with Claim 26. If it were the case
that TKT’s technology was inventive, then it seems to me that it may very
well be that TKT could claim a patent in relation to that technology. However,
in so far as that technology is employed to express EPO I believe that it
infringes the 605 patent. Fair protection for the patentee of 605, fair protection
for the hypothetical inventor of TKT’s technology, certainty for the public,
and the desirability of not stifling research appear to me to be satisfactorily
served by that conclusion. To conclude that the hypothetical inventor of TKT’s
technology would, for instance, be entitled to a monopoly of manufacturing
EPO in accordance with that technology would appear to me to be less than
fair to the 605 patentee and, if I can put it this way, more than fair to
the hypothetical inventor of TKT’s technology.
- Although I have held that Claim 19 is invalid on grounds of insufficiency,
and, even if valid, it is incapable of being infringed, it is right to mention
that I would have held that, at least as a matter of literal construction,
TKT’s product did not infringe Claim 19. I do not consider that its product
is a "recombinant polypeptide" within the literal meaning of that
expression in Claim 19; it does not seem to me that it is "the product
of eukaryotic expression of a exogenous DNA sequence", essentially for
the reasons I have summarised for rejecting the contention that TKT infringes
Claim 1 on a literal construction, as amplified when dealing with the questions
of construction in Claim 1 and Claim 19. However, these conclusions would
probably be vitiated by applying the three Protocol questions to the issue.
- However, problems would still arise from Amgen’s infringement argument in
light of the closing part of Claim 19. Even if the last part of Claim 19,
the urinary EPO comparator for apparent molecular weight purposes, is valid
and capable of infringement, I do not consider that TKT’s product falls within
it. Although, as I have accepted, there is a real case for saying that Dr
Strickland’s 17mM Fraction might have been discarded, I consider that, bearing
in mind the teaching of Miyake, the skilled addressee seeking to discover
whether his product falls within Claim 19, and isolating a urinary EPO for
that purpose in the same way as Dr Strickland, would have followed the 17mM
Fraction as well as the 30mM Fraction. On that basis, TKT’s product would
not have infringed Claim 19, because it has the same apparent molecular weight
on SDS-PAGE as the uEPO isolated from the 17mM Fraction, even though it has
slightly higher apparent molecular weight than the uEPO isolated from the
30mM Fraction.
Q. THE 678 PATENT
The contents of the 678 Patent
- The first application made by GI (one of the Roche parties) in the United
States for the grant of a patent relating to EPO was filed on 4th December
1984. It was followed by a second application filed on 3rd January 1985 and
a third application filed on 22nd January 1985. The application for 678 itself
was filed at the European Patent Office on 3rd December 1985.
- The issues relating to 678 are within a much more limited compass than those
relating to 605. Accordingly, it is unnecessary to go into the contents of
678 to anything like the extent necessary for 605. 678 claims a priority date
of 22nd January 1985, and purports to describe a "Method for the Production
of Erythropoeitin". It appears that the applicant for 678, GI had succeeded
in cloning the EPO gene around a year after Dr Lin of Amgen had done so. The
"Field of the Invention" claimed by 678 is described on page 3 of
the Patent as being:
"Directed to cloned genes for human erythropoietin that provide surprisingly
high expression levels, to the expression of said genes and to the in vitro
production of active human erythropoietin".
- Claims 8 and 9 of 678 are in these terms:
"8. Method for producing recombinant human erythropoietin (hEPO)
by the steps of
(a) culturing, in a suitable medium, CHO cells which contain, operatively
linked to an expression control sequence, a DNA sequence encoding hEPO, and
(b) recovering and separating the recombinant hEPO produced from the cells
and the medium,
characterised in that CHO cells are used which have the capability of producing
N- and O- linked glycosylation with incorporation of fucose and N-acetylgalactosamine
and that recombinant hEPO with N- and O- linked glycosylation is recovered
and separated from the cells and the medium.
9. Method according to claim 8, wherein the recombinant hEPO has a glycosylation
pattern comprising relative molar levels of hexoses to N-acetyglucosamine
(Nacglc) of 1.4:1 specifically galactose: [GlcNAc] = 0.9:1, and mannose: [GlcNAc]
= 0.5:1."
- The Specification contained two paragraphs of relevance which were not included
in the third application for 678. Paragraph 36 (page 12, lines 37ff) refers
to purifying "recombinant EPO produced in CHO cells as in Example 11"
and thereafter analysing "the relative amounts of sugar present".
This analysis records the presence of GlcNAc, Gal, Man, NeuNAc and Fuc and
a small amount of GalNAc. This last sugar is significant, as it confirms the
presence of a degree of O-linked glycosylation (as mentioned above). That
point is expressly made in paragraph 37 (lines 54ff) which records that O-linked
glycosylation was confirmed by SDS-PAGE analysis. Paragraph 37 also draws
attention to the presence of fucose.
- Example 10 of 678 is entitled "Expression of EPO in CHO cells - Method
I". It confirms expression of EPO in DHFR- CHO cells which have been
transfected with exogenous recombinant DNA ligated with a specified plasmid
and an artificial promoter, with amplification. Example 10 states that "the
cell line of choice for EPO production" has been deposited with the ATCC
and the reference number is given. Example 11 is entitled "Expression
of EPO in CHO cells - Method II". It describes a similar exercise to
Example 10, but in DHFR - CHO cells and a different plasmid. Unlike Example
10, there was no deposit of the Example 11 cell line. However, it is stated
that the plasmid described in Example 11 had been deposited with the ATCC.
- There is nothing of relevance in the filed application for 678 which differs
from the contents of 678 for the purpose of these proceedings.
The issues
- There was no argument relating to the issue of whether Amgen infringes the
678 patent. As I understand it, Amgen conceded infringement if 678 is valid.
The only live issue is whether 678 is valid or not. The validity of 678 is
primarily challenged by Amgen on the basis of lack of novelty and/or obviousness.
In this connection Amgen’s case principally relies upon the disclosure of
the application for the grant of 605, namely 605A. The issue is complicated
by the fact that there is a dispute as to the priority date which can be claimed
for 678.
- Only Claim 8 and Claim 9 of 678 are relied on by Roche as being valid and
infringed, and Claim 9 is not intended to have validity independent of Claim
8. Accordingly, I shall limit myself to considering Claim 8. Claim 8 of 678
claims expressing recombinant human EPO in CHO cells which had been cultured,
and which contained "operatively linked to an expression control sequence,
a DNA sequence encoding" for human EPO. The centrally relevant feature
of Claim 8 for present purposes is that the CHO cells concerned "have
the capability of producing N- and O-linked glycosylation with incorporation
of fucose..." and that the recombinant EPO has "N- and O-linked
glycosylation" when "recovered and separated from the cells...".
This is the essential ingredient for the purpose of Roche’s case, because,
given that Amgen had filed the application for 605, namely 605A, before the
date on which Roche claim priority for 678, 22nd January 1985, Roche cannot
rely on 678 to claim a monopoly in respect of anything disclosed in 605A,
provided, of course, that the disclosure relied on by Amgen in 605 is enabling.
- Amgen contend that, even if Roche are right in contending that 678 is entitled
to a priority date of 22nd January 1985, Claim 8 of 678, and in particular
the essential ingredients of O-glycosylation and fucosylation, were anticipated
by the disclosure of 605A, and in particular Example 10 thereof: in other
words, Claim 8 is said to fail on the ground of want of novelty. If Amgen
are correct as to the relevant priority date for 678, namely 3rd December
1985, then Amgen’s reliance on 605A, and in particular Example 10, rests not
merely on anticipation, but also on obviousness. If Amgen are right on the
priority date issue, they also rely on the paper published by Jacobs et al
in 1985 in Nature 313:806 ("Jacobs") as supporting the case on anticipation
and obviousness in relation to Claim 8 of 678. Of course, Amgen’s reliance
on 605A, and Example 10 in particular, depends on its being properly enabling
(which I have held it to be when considering the issue of classic sufficiency
of 605).
- It is right to add that Amgen rely, albeit very much as "long stop"
arguments, on the contentions that, in any event, Claim 8 of 678 is invalid
on the ground that it is insufficient and on the ground that it constitutes
a mere discovery. I do not propose to say anything further on those two issues,
because Amgen accept that, if they succeed in fighting off Roche’s attacks
on 605 on similar grounds (as, in my view, they do) then they can scarcely
hope to be successful in their attack on 678 in so far as that attack involves
relying on similar grounds.
- I propose first to consider whether 678 is entitled to claim a priority
date of 2nd January 1985, as opposed to 3rd December 1985. I shall then deal
with the issue of whether, assuming that Roche are correct in saying that
678 is entitled to the earlier priority date, Claim 8 of 678 ("Claim
8") was nonetheless anticipated by Example 10 of 605A ("Example
10"). I shall then turn to the issue of whether, if 678 is only entitled
to a priority dated of 3rd December 1985, Claim 8 is invalid on grounds of
obviousness over Example 10, and/or over Jacobs.
- However, before doing this, I should perhaps explain briefly why 605A can
be relied on by Amgen to support the contention that 678 is obvious or anticipated
if 678’s priority date is 3rd December 1985, but can only be relied on to
support a case of anticipation, and not one of obviousness, if 678 can claim
a priority date of 22nd January 1985. The priority date which can be claimed
by a patent is governed by Section 5 of the 1977 Act. Prima facie, it is the
date of filing - Section 5(1). However, by virtue of Section 5(2), if the
invention claimed is "supported by matter disclosed in [an] earlier application"
less than twelve months before the date of filing, the priority date may be
effectively backdated to that disclosure.
- By 22nd January 1985, Amgen had filed its application for 605, i.e. it had
filed 605A. However, 605A had not yet been published. Accordingly, at least
as a matter of principle, it is open to Amgen to rely upon 605A as anticipating
678, because of Section 2(3) of the 1977 Act which provides:
"The state of the art in the case of an invention to which... a patent
relates shall be taken also to comprise matter contained in an application
for another patent which was published on or after the priority date of that
invention, if the following conditions are satisfied, that is to say -
(a) the matter was contained in the application for that other patent both
as filed and as published; and
(b) the priority date of that matter is earlier than that of the invention."
- However, if the correct priority date for 678 is indeed 22nd January 1985,
then it would not be open to Amgen to rely on an application such as 605A
to found a basis for alleging obviousness. This follows from Section 3 of
the 1977 Act which provides in the case of obviousness:
"An invention shall be taken to involve an inventive step if it is
not obvious to a person skilled in the art having regard to any matter which
forms part of the state of the art by virtue only of Section 2(2) above, and
disregarding Section 2(3) above" (emphasis added).
- The rule that a person attacking a patent can rely upon a filed patent application
to substantiate a case for anticipation, but not for the purpose of alleging
obviousness, arises because, unlike the United States (where the principle
is first to invent), the UK, and other signatories to the EPC, follow the
first to file principle. Accordingly, a problem is thrown up by documents
which, as at the date of an application for a patent, have been filed, but
have not yet been published so as to make them available. This problem is
dealt with by deeming such documents to have been published at the date of
filing for the purpose of anticipation only, thereby substantially avoiding
the problem of concurrent grants - in this connection, see the discussion
in the House of Lords in Asahi Kasei [1991] RPC 485.
- However, by 3rd December 1985, 605A had not merely been filed: it had been
published (namely on 17th July 1985). Accordingly, Section 2(3) of the 1977
Act is not needed by Amgen. The information in the filed patent application,
605A, had been in the public domain, in the sense that the application had
been published for more than four months before the priority date which, on
this hypothesis, 678 could claim. In these circumstances, there is no reason
why 605A could not be relied on by Amgen to support a case of obviousness,
as well as a case of anticipation. Equally, Amgen could rely upon any other
publication prior to 3rd December 1985, such as Jacobs, which was published
after 22nd January, but before 3rd December, 1985.
The priority date of 678
- The third application in the United States of 22nd January 1985 ("the
third application"), which is the document upon which Roche’s arguments
as to priority date depends, describes the production of EPO from CHO cells
specifically DuX-B11 cells. It discloses methods of transforming the genetic
material in such CHO cells with vectors carrying the human EPO gene, and,
as a result, effecting the expression of EPO. It is stated in the application
that that cell line has been deposited with the ATCC. Roche contend that anyone
could have obtained this cell line from the ATCC, and, having grown it in
culture, expressed EPO which, on analysis, would have been found to be O-glycosylated
(as well as N-glycosylated) and fucosylated. However, there is nothing in
the third application which teaches or discloses that the EPO thereby produced
would be O-glycosylated or fucosylated. The earliest document upon which Roche
can rely in which O-glycosylation and fucosylation of recombinant EPO is mentioned,
was in the application for the grant of 678, which, as I have said, was filed
on 3rd December 1985.
- In these circumstances, Amgen’s contention that a claim whose alleged novel
feature is the presence of O-glycosylation and fucosylation can only claim
a priority date by reference to a document in which this element is first
disclosed, has the merit of appealing to common sense and logic. It would
seem somewhat surprising if a process claim, which had a single feature which
was said to render it novel or unobvious over a specific disclosure, could
claim a priority date by reference to documents which, whatever else they
revealed, did not make reference to, let alone claim or identify, the very
feature upon which the alleged novelty or unobviousness depends. That proposition
appears to me to be supported by Article 88(4) of the EPC, which is in these
terms:
"If certain elements of the invention for which priority is claimed
do not appear among the claims formulated in a previous application, priority
may nonetheless be granted, provided that the documents of the previous application
as a whole specifically disclose such elements" (emphasis added).
- I also draw support from Beloit [1995] RPC 705 at 732, where Jacob J said
this:
"Matter disclosed in the priority document really means "information
concerning the invention disclosed in that document". So the question
is whether the claim is supported by the information disclosed in the priority
document."
- Accordingly, at any rate at first sight, Roche’s contention that the priority
date of 678 is 22nd January 1985 must be wrong: in accordance with Article
88(4) and Jacobs J’s observation I have quoted, the priority date would appear
to be the date of the filing of the application of 678, when the O-glycosylation
and fucosylation of the recombinant EPO was first referred to and explained.
- In answer to this, Roche rely, as I have mentioned, upon the deposited cell
line referred to in the third application and in Example 10, and therefore
in the filed application for 678. As a matter of principle, it appears to
me that it could be open to Roche to rely upon what the cell line deposited
with the ATCC, and referred to in the third application, would have revealed.
In my view, the reference to "documents" which "specifically"
make the relevant disclosure in Article 88(4) of the EPC must, as a matter
of ordinary language and common sense, be capable of extending to things referred
to in those documents, at least where there is an official and well established
procedure for depositing those things, as there is in relation to micro organisms
pursuant to the European Patent Office’s Notice on Deposits -see OJ EPO 1986
8 p269.
- However, I am far from persuaded that this means that it is open to Roche
in the present case to rely upon the fact that, if treated in accordance with
the teaching in the third application, the cell line referred to therein as
deposited would produce EPO which, if it was characterised or analysed, would
turn out to be O-glycosylated and fucosylated. There was nothing whatever
about this feature in the third application, no teaching to characterise it,
let alone to look for its glycosylation.
- Mr Thorley relies upon the reasoning and decision of the House of Lords
in Merrell Dow Pharmaceuticals Inc. -v- H N Norton & Co Ltd [1996] RPC 76, a case which essentially turned on the meaning of Sections 2(1) and (2)
of the 1977 Act (which reflect Article 54 of the EPC). These sub-sections
provide:
"2(1) An invention shall be taken to be new if it does not form
part of the state of the art
(2) The state of the art in the case of an invention shall be taken
to comprise all matter (whether a product, a process, information about either,
or anything else) which has at any time before the priority date of that invention
been made available to the public... by written or oral description, by use
or in any other way."
- In Merrell Dow at [1996] RPC 76 at 89, Lord Hoffmann had to consider the
argument:
"That for a substance to be known so as to be part of the state of
the art within the meaning of Section 2, it must be known (or to be readily
capable of being known) by its chemical composition. No other description
will do" (lines 1 to 5).
- He went on to say this at [1996] RPC 89 line 13 to 90 at line 38:
"I think that on this point the Patents Act 1977 is perfectly clear.
Section 2(2) does not purport to confine the state of art about products T12/81
[1979-1985] EPOR Vol. B 308, 312 to knowledge of their chemical composition.
It is the invention which must be new and which must therefore not be part
of the state of the art. It is therefore part of the state of the art if the
information which has been disclosed enables the public to know the product
under a description sufficient to work the invention.
For most of the purposes of a product claim, knowledge of its chemical composition
will be necessary to enable the public to work the invention. It is something
they will need to know in order to be able to make it. ...Other decisions...
seem to me to make it clear that, at least for some purposes, products need
not be known under their chemical description in order to be part of the state
of the art. In BAYER/Diastereoisomers Decision Twelve/81 1979-85 EPOR Vol.
B 308312... the Technical Board of Appeal [decided that] if the recipe which
inevitably produces the substance is part of the state of the art so is the
substance as made by that recipe. [In] CPC/Flavour Concentrates Decision T303/86
[1989] 2 EPOR 95 [the Board’s decision] proceeded on the basis that for the
purpose of being part of the state of the art, a process for making flavour
concentrates was sufficiently described by a recipe for cooking food which
did not expressly refer to the flavour concentrates but would inevitably have
the effect of making them."
- I am here concerned with an argument revolving around Section 5 of the 1977
Act. Mr Watson says that I should not automatically apply the reasoning which
related to a different section, namely Section 2, of the same Act, even though
the issue involved under the two sections may be similar. I am not convinced
that that is right. What I think is more important, as is clear from the passages
I have selectively quoted from the speech of Lord Hoffmann, is that there
is no absolute rule as to the extent, if any, to which the chemical composition
of a particular substance has to be disclosed before it becomes part of the
state of the art. Where an aspect of the chemical composition is effectively
the claimed inventive concept, it appears to me illogical to conclude that
that aspect does not have to be revealed in some way by the earlier application
which is relied on by the patentee to justify an earlier priority date for
his patent under Section 5(2) of the 1977 Act: I rely in particular on the
word "disclosed" in Section 5(2). I do not read Lord Hoffmann’s
observations in Merrell Dow as calling that view into question.
- As I have said, it appears to me that it is open in principle for Roche
to rely upon the deposited cell line, because it is referred to in the third
application. However, I do not believe that that is of itself enough, without
more, to enable Roche to claim that a specific feature of the product resulting
from the processing of that cell line in accordance with the teaching of the
third application can be relied on as giving novelty over a previous disclosure
(or obviousness over the prior art) to the process described in the application.
While one must be careful of relying on an intuitive or knee-jerk reaction
(as graphically illustrated by what Lord Hoffmann had to say in Merrell Dow
at [1996] RPC 83 to 87) it does appear to me that, in the absence of clear
authority, or some other good reason to the contrary, it would be surprising
if it were otherwise. Before the feature could be relied on as having been
disclosed through the medium of a cell line referred to in the claimed priority
document, it seems to me that it would be necessary for the feature to be
clearly (albeit conceivably impliedly) identified or referred to in the document.
It may also be permissible if the feature is so obvious from the cell line
that the skilled man would appreciate it even though it was not referred to
in the document, provided he is unequivocally directed to the cell line.
- Indeed, it appears to me that Mr Thorley’s submissions on behalf of Roche
go close to accepting a not very different formulation of this principle in
any event. He accepts (rightly in my judgment) that, in light of the absence
of any teaching as to O-glycosylation or fucosylation in the third application,
upon which his argument essentially relies, it is an essential element of
his case that the skilled man, following the teaching of the third application,
would characterise what he had got. However, in my view, if it be the case
that the skilled man would inevitably have sought to characterise what he
obtained, in the sense of investigating its chemical composition, that would
not on its own be enough to enable Roche to establish that the third application
enables them to claim 22nd January 1985 as the priority date for 678. They
would have to show that the purpose of the characterisation, or at least one
of the specific purposes of the characterisation, was to investigate whether
the EPO thereby produced was O-glycosylated and fucosylated. The fact that
the addressee might happen to discover that it was O-glycosylated or fucosylated
would not be enough, because that would be no part of the teaching of the
priority document: he would have no reason to know whether this was a feature
of the substance he had made, because of the precise conditions in which he
made it, or whether it was an essential ingredient of the teaching. Not only
does that appear to me to be right as a matter of general principle, it is
of particular force in connection with the instant feature: as I have mentioned,
it is clear that the nature and extent of the glycosylation is very variable
and, particularly as at 1984, unpredictable, and, so far as O-glycosylation
was concerned, relatively uncharted territory.
- In these circumstances, it is my view that the priority date which can be
claimed for 678 is 3rd December 1985, because the third application filed
on 22nd January 1985 did not contain any teaching whatever in relation to
the O-glycosylation or the fucosylation of the recombinant EPO resulting from
the process taught in that application, or even suggesting that the addressee
should characterise the nature of the glycosylation of the EPO produced in
accordance with the teaching. It is right to add that, for the reasons given
in the next section of this part of the judgment, I do not consider that a
person following the teaching of the third application would have sought to
characterise the O-glycosylation or fucosylation of the EPO he obtained. I
shall nonetheless first consider the question of whether Claim 8 of 678 was
anticipated by Example 10 of 605A, on the assumption, favourable to Roche
and which I do not believe to be correct, that the priority date which can
be claimed by 678 is 22nd January 1985; thereafter I shall turn to consider
the validity of Claim 8 of 678 if its priority date is, as I believe, 3rd
December 1985.
Anticipation by 605A
- In order to establish that a claim in a patent has been anticipated by an
earlier disclosure, it is necessary to show that the earlier disclosure unambiguously
points to what is purportedly disclosed by the patent in suit. In the course
of his judgment in General Tire & Rubber Co. -v- Firestone Tyre and Rubber
Co. Ltd [1972] RPC lines 41ff, Sachs LJ said this:
"If the prior inventor’s publication contains a clear description of,
or clear instructions to do or make, something that would infringe the patentee’s
claim if carried out after the grant of the patentee’s patent, the patentee’s
claim will have been shown to lack the necessary novelty, that is to say,
it will have been anticipated. The prior inventor... and the patentee may
have approached the same device from different starting points and may for
this reason... have so described their devices that it cannot be immediately
discerned from a reading of the language which they have respectively used
that they have discovered in truth the same device; but if carrying out the
directions contained in the prior inventor’s publication will inevitably result
in something being made or done which, if the patentee’s patent were valid,
would constitute an infringement of the patentee’s claim, this circumstance
demonstrates that the patentee’s claim has in fact been anticipated."
- At [1972] RPC 486 lines 9-10 Sachs LJ said:
"To anticipate the patentee’s claim the prior publication must contain
clear and unmistakable directions to do what the patentee claims to have invented."
- These observations were, of course, made in relation to the Patents Act
1949, but it appears clear that they represent the current law. They have
been cited with approval in a number of cases since the 1977 Act came into
force, including, for instance, by Lord Jauncey of Tullichettle in Asahi [1991]
RPC 485 at 544. Further, the approach of the Court as embodied in those observations
is consistent with Article 54(1) of the EPC with which, indeed, Section 2
of the 1977 Act is expressly drafted to correspond - see Section 130(7) of
the 1977 Act.
- Roche’s case is that Example 10 did not anticipate Claim 8 because the Claim
is novel to the extent that it discloses that the recombinant EPO produced
in accordance with its teaching will always be O-glycosylated and fucosylated,
whereas this was not the case in relation to the teaching of the Example,
and that this teaching can, as it were, be related back to the third application
and the deposited cell line referred to therein.
- A number of preliminary points are taken by Amgen. First, it is said that
there is no clear evidence that the deposited cell line referred to in the
third application was live, or that it would certainly produce EPO which was
O-glycosylated or fucosylated. I do not think that argument is a good one.
In the first place, although not worded perfectly, it seems to me that there
is an express admission by Amgen in these proceedings to the effect that the
deposited cell line would express EPO which was O-glycosylated and fucosylated.
In any event, pursuant to Rule 10.1(ii) of the Budapest Treaty Regulations,
the ATCC is obliged to test the viability of deposits at reasonable intervals,
and it is to be noted that the ATCC apparently keep deposited cell lines for
at least 30 years. The fact that Roche at one time formally proposed to carry
out an experiment which they subsequently apparently abandoned does not, count
against Roche, in this connection despite Amgen’s case to the contrary. Roche
may well have concluded, in light of the admission by Amgen, in light of the
costs, in light of advice as to where the onus of proof lay, or because there
might be some other, albeit wholly unrelated, problem for Roche if the result
of the experiment was revealed, not to proceed with it. Quite apart from this,
so far as the ability to O-glycosylate or fucosylate is concerned, it seems
to me that, in light of the evidence discussed in the next section of this
part of the judgment, it is not merely likely on the balance of probabilities,
but overwhelmingly likely, that any EPO expressed by cells in the deposited
cell line would have been O-glycosylated and fucosylated.
- Of greater weight, in my judgment, is Amgen’s contention that glycosylation
of EPO in the deposited cell line is not conclusive on this issue because
there is no direction to the reader of the third application that he should
use those cells. In his cross examination, Professor Clausen accepted that
a person skilled in the art who was following the teaching of the third application
might decide to draw on the deposited cell line, or he might not. It seems
to me that, before I go into further points, that presents a real difficulty
for Roche, because it is fundamental to Roche’s case that the teaching of
Claim 8, to the effect that the recombinant EPO will be O-glycosylated and
fucosylated, was disclosed by the third application, and that argument in
turn is dependant on the contention that the third application refers to the
deposited cell line and that this cell line will produce EPO which is O-glycosylated
and fucosylated. If the teaching of the third application may well involve
the skilled addressee using another cell line, then, as I see it, the basis
for Roche’s argument falls away. Virtually every argument upon which Roche
rely for contending that following Example 10 of 605 may produce EPO which
is not O-glycosylated or fucosylated would apply equally to following the
teaching of the third application, if one uses cells which are not part of
the deposited cell line. This argument is particularly telling as Example
10 teaches the use of the same cells, namely DuX-B11 CHO cells.
- Amgen also rely on the fact that it is fundamental to Roche’s case that
the skilled man following the teaching of the third application would characterise
the product and in particular whether it was O-glycosylated and whether it
was fucosylated. Mr Thorley relies on passages in the evidence of Professor
Clausen and Professor Cummings to support the contention that a person obtaining
the deposited cell line would not only use it to produce EPO, but would also
characterise the EPO, and in particular its polysaccharide content in order
to see whether it was O-glycosylated and/or fucosylated. I am unpersuaded
that the evidence of either witness assisted this contention. Professor Clausen’s
evidence merely amounted to saying that, once one had the EPO, one would purify
it. He did not refer to characterisation or analysis. While he referred to
characterisation, Professor Cummings only said that it would be "a routine
matter". No witness suggested that a person following the teaching of
the third application would be very likely, let alone bound, to characterise
the EPO, let alone that the characterisation would go so far as determining
whether there were any O-glycans and any fucose.
- In light of the conclusions in the preceding paragraphs, I believe it is
strictly unnecessary for me to consider Claim 8 further: taking the most favourable
priority date from Roche’s point of view, and bearing in mind that Mr Thorley
accepts that it is essential to Roche’s case on anticipation that the skilled
man would investigate the extent if any of O-glycosylation and fucosylation
of the EPO produced in accordance with the teaching of the third application,
Roche’s case fails. However, as the points have been fully argued, and as
the issues turn on evidence and as this case may well go further, it is right
to deal Roche’s arguments on anticipation, on the assumption that the cell
line referred to in the third application can be relied on as teaching that
the EPO thereby produced would be O-glycosylated and fucosylated (or that
it does not matter whether that cell line can be relied on).
- On behalf of Roche, Mr Thorley takes three points as to why Example 10,
does not anticipate Claim 8. First, he contends that Example 10 was not enabling
in any event, due to what he says would have been the undue burden of obtaining
materials with which to repeat the experiment. Secondly, he claims that, on
the evidence, Amgen has not established that Example 10 anticipated Claim
8. Thirdly, he argues that, in light of the deleted matter, which was included
in 605A, although it is not of course in 605, Example 10 did not anticipate
Claim 8.
- I do not need to deal with the first of these arguments, because it is the
same as Roche’s argument, which I have already discussed and rejected when
considering whether 605 was invalid on grounds of classic insufficiency. Mr
Thorley’s second and third arguments essentially turn on the same fundamental
issue. Claim 8 teaches that recombinant EPO is partially O-glycosylated and
contains fucose, and Mr Thorley’s second and third arguments rely on the fact
that EPO produced in accordance with Example 10 may not be O-glycosylated
and/or fucosylated.
- Mr Thorley’s second argument is that following the teaching of Example 10
will not inevitably produce O-glycosylated rEPO. On behalf of Roche, he contends
that following the teaching of Example 10 may produce rEPO which is solely
N-glycosylated. On this issue, I heard evidence of experiments, as well as
expert evidence. As Mr Thorley rightly says, the effect of the observations
of Sachs LJ in General Tire is that, in order to anticipate, the directions
in Example 10 must "inevitably" lead to something falling within
the scope of the claim being attacked, namely Claim 8. Accordingly, as I see
it, if I am satisfied on the evidence that there is a real chance that following
the teaching of Example 10 could produce rEPO which was not O-glycosylated,
this second argument for rejecting Amgen’s case on anticipation would succeed.
- On the evidence in the case, I am satisfied that carrying out the experiment
set out in Example 10 would inevitably lead to the production of rEPO which
is partly O-glycosylated. The possibility that following the teaching of Example
10 could lead to rEPO which was not O-glycosylated was floated by Professor
Clausen. Neither he nor anybody else had conducted an experiment which produced
that result, and he was only able to point to one specific example which might
give rise to such a result, namely that of recent CHO cell lines which have
been mutated to activate dormant genes. Indeed, in cross examination he accepted
that one could not deprive a cell, in which a glycoprotein was normally O-glycosylated
and N-glycosylated (as in the case of EPO in the CHO cell), of the ability
to effect N-glycosylation without also depriving it of the ability to effect
O-glycosylation. He also thought that a cell with an inability to produce
GalNAc, but which could normally do so, would not be a cell which was likely
to be able to grow.
- Professor Cummings, who gave evidence on behalf of Amgen, also referred
to the single reported instance of a specific type of CHO cell losing its
ability to O-glycosylate protein. This was a cell line which had been specifically
mutated to lose the ability to make GalNAc and was one which had been selected
for the loss of the ability to O-glycosylate proteins. However, as Professor
Cummings pointed out (and Professor Clausen accepted), in addition to the
fact that this cell line was intentionally mutated for this purpose, it was
also a cell line which could not survive without the addition of a specific
monosaccharide which, if added to the culture, would have reintroduced the
ability of the cell to O-glycosylate. It appears to me fanciful to believe
that the skilled man reading Example 10 would specifically disregard the teaching
in the Example to use the DuX-B11 cell line, and would instead choose an unstable
cell line which had been specially mutated. The possibility that a cell line
might spontaneously lose its ability to O-glycosylate was raised by Professor
Clausen, but neither he nor any other witness was able to identify an instance
of this having occurred.
- Although examples can be found in the literature of things apparently going
wrong in cells, which lead to some sort of functional inactivation, I am not
persuaded that they take matters any further. The fact that there are reported
experiments of attempts to express glycoproteins in cells which have been
transfected and/or amplified, does not mean that such generalised evidence
can be fairly invoked to suggest that there is a real, indeed any, prospect
of a specific type of glycosylation of a specific protein in a specific cell
not taking place, particularly in circumstances where the evidence suggests
that it has done so in all examples which have been reported or have been
the subject of experiments. Further, most of the evidence relied on by Roche
in this connection was of recent cell lines which had been mutated to activate
dormant genes, and it seems clear from the evidence of Professor Clausen and
Professor Cummings that gene activation was not the only possible explanation
of what was reported in those papers. In any event, the argument that things
sometimes go wrong in expression systems in CHO cells would apply equally
to the alleged disclosure of Claim 8 as it would to the disclosure in Example
10.
- Further, the evidence of Professor Clausen that a mutation might occur accidentally
during transfection or amplification, a result of which the cell might lose
its ability to O-glycosylate or fucosylate was merely speculation. However,
it was speculation which Professor Cummings attempted to quantify, and in
this connection his quantification (contained in his written evidence in chief
in reply to Professor Clausen) was not challenged. Taking Professor Cummings’s
calculations at their most favourable to Roche, his opinion was that the chance
of a relevant mutation in a cell, that is one which would deprive it of the
ability to O-glycosylate, would be around one in a million; however, as Professor
Clausen accepted, this is significantly too high a figure, because one has
to adjust it to take into account the prospect of all the transformants being
disabled: in other words, each additional clone has to retain the inability
to O-glycosylate. Mr Watson described the prospect of that occurring as "vanishingly
small" and a "minute mathematical probability". I do not think
those descriptions are exaggerated, even in relation to a chance of one in
a million, and I certainly do not consider that they enable Roche to say that
following the teaching of Example 10 would not "inevitably" lead
to EPO thereby produced being O-glycosylated and fucosylated. It is right
to mention that it was suggested on behalf of Roche that gene amplification
might result in a single clonal cell line consisting of cells none of which
could O-glycosylate and/or fucosylate. However, there was no evidence to support
this, and indeed this was not a matter within the expertise of Professor Clausen.
- Although there is obvious force, at least in terms of literal interpretation,
in the point that the use of the word "inevitably" in the observations
of Sachs LJ in General Tire indicates that even such a very low possibility
should defeat a case based on anticipation, I do not consider such an argument
to be correct. The law of patents is ultimately concerned with practicality,
although, as parts of this judgment probably demonstrate, the theoretical
and academic have an important, indeed, in many cases, an essential, part
to play. In my judgment, if an experiment reliably produces a particular result
more than 99% of the occasions on which it is conducted, then, at any rate
for the purpose of deciding whether the disclosure of that experiment can
be said to anticipate a subsequent patent, that experiment "inevitably"
leads to the result in question. I draw some support for this conclusion from
observations, albeit they were obiter, in Fomento -v- Mentmore [1956] RPC
87 at 101, Letraset Ltd -v- Rexel Ltd [1976] RPC 51 at 60-61 and Letraset
Ltd -v- Dymo Ltd [1976] RPC 65 at 92. In Fomento it was accepted that if the
required result obtained "save in exceptional circumstances (as one might
say, 99 cases out of 100)" it would not deprive the earlier disclosure
of its anticipating quality. In Letraset at [1976] RPC 61, Russell LJ suggested
that if the experiment produced a particular result 33 out of 36 times it
would be "open to question" whether that result was "inevitable",
and that "some proportion of failure could no doubt be regarded as de
minimis or due to failure to perform the test properly".
- I turn, then, to Mr Thorley’s third argument, namely that, in light of the
contents of the deleted matter is Example 10 in 605A, it would have been apparent
that the EPO thereby produced would only have been N-glycosylated and accordingly
Roche EPO, which was O-glycosylated, as well as N-glycosylated, was not thereby
anticipated. The basis for this argument is that the deleted passage refers
to an experiment which showed that there was no N-acetylgalactosamine (GalNAc)
in "the recombinant product" derived in accordance with Experiment
10, and that this would have led the appropriately skilled reader of 605A
to deduce that this product had no O-glycosylation. This is because, as I
mentioned earlier, the presence of GalNAc is indicative of O-glycosylation,
and its absence therefore demonstrates no O-glycosylation.
- Having reached my conclusion on Roche’s second point, I do not consider
that the inclusion of the deleted matter in 605A assists Roche on this third
point. First, if, as a matter of fact, the appropriately skilled person, following
the teaching of Example 10, would actually produce a product, namely rEPO,
which is O-glycosylated in part, then, once the application embodied in 605A
had been granted (including Example 10, whether with or without the deleted
matter) a person following the "clear instructions" of the Example
would have "do[ne] or ma[de] something that would infringe the patentee’s
claim" to quote from Sachs LJ in General Tire at [1972] RPC 485. To put
the point another way, again to adopt the language of Sachs LJ at [1972] RPC
486, once one has rejected Roche’s second argument on this issue, Example
10 "contain[ed] clear and unmistakable directions", and if the skilled
man followed those directions he would have produced rEPO which was in part
O-glycosylated. The fact that an experiment included in the Example might
well have led the reader of the document to think that the product would not
be O-glycosylated or fucosylated does not mean that it would not in fact be
partially O-glycosylated or fucosylated.
- Secondly, as I have already said on the issue of added matter, I do not
consider that the notionally skilled addressee of 605A would have believed
the results reported in the deleted matter. It is true that the specific aspect
of the deleted matter which would have been rejected by the notionally skilled
addressee is the hexose ratio of the recombinant EPO, which does not directly
relate to the finding of no GalNAc (and hence no O-glycosylation) and no fucose
(and hence no fucosylation) in the recombinant EPO. Accordingly, as Professor
Clausen said in his evidence, one can see an argument for saying that, while
the addressee might reject the reading for hexose in the recombinant EPO,
he would not reject the other readings, and in particular the absence of GalNAc
and fucose in the recombinant EPO. Nonetheless, I accept Professor Cummings's
evidence to the effect that he, and the notional addressee, would have been
so concerned about the 15.09 figure in relation to the hexose content of the
recombinant EPO in the deleted matter, that he would have effectively rejected
the entire analysis. Indeed, that is the way that GI, one of the Roche parties,
expressed its view in the US interference proceedings, when it described "the
[reported] carbohydrate composition disclosure" as "plainly incorrect".
Obviousness and novelty if the priority date of 678 is 3rd December 1985
- If, as I believe to be the case, the priority date which can be claimed
for 678 is 3rd December 1985, then the validity of 678 is even more difficult
indeed to maintain against 605A. Given that 605A can be relied on by Amgen
to support a case of obviousness, it can clearly be said that it was obvious
as at 3rd December 1985, in light of the disclosure of Example 10, to produce
EPO from CHO cells. If, as is quite clear from the evidence, a possible result
of carrying out such production was that the EPO so produced was O-glycosylated
and fucosylated, then Claim 8 must be invalid on grounds of obviousness.
- Once again, Roche seek to rely upon the deleted matter in Example 10, and,
for the reasons I have already given when considering whether Example 10 can
be relied on by Amgen to defeat Claim 8 on grounds of lack of novelty, I do
not consider that the deleted matter assists Roche. Indeed, Roche’s reliance
on the deleted matter is even more difficult on the issue of obviousness than
on the issue of anticipation. In addition to the arguments open to Amgen on
anticipation, they can also rely on the fact that, if the deleted matter is
to assist Roche on obviousness, then Roche have to establish three further
points. Those three points are that the deleted matter would have caused the
reader of the third application to try to make EPO which was not O-glycosylated,
that this is something which the reader could have done, and that, in the
light of what he would have done, Claim 8 does not lack inventive step. I
agree with Mr Watson’s contention that none of these three points can be made
good. Not only is there no evidence to support the suggestion that a skilled
addressee would seek to make EPO which was not O-glycosylated or fucosylated,
but I think it most unlikely that he would have been interested in the precise
make-up of the glycans in the EPO they had produced. Secondly, Professor Cummings
could not conceive how anyone could screen for CHO cells which did not O-glycosylate
(or, presumably, fucosylate) EPO, and in light of the evidence that nobody
had ever found such CHO cells, I share his scepticism. Quite apart from this,
if one goes along with Roche’s case to the extent of assuming in their favour
that an appropriately skilled person produces EPO in accordance with the teaching
of Example 10 some of which is not O-glycosylated or fucosylated, he will
have to analyse the EPO he has produced, and separate that which is O-glycosylated
and/or fucosylated from that which is neither (if any of the latter exist,
which I very much doubt). In carrying out that exercise, he will have found
EPO which has the very characteristics, namely O-glycosylation and fucosylation,
which, on Roche’s case, are meant to be unobvious.
- Before passing on from my conclusion that Claim 8 is obvious over Example
10, it is right to refer back to the four step process identified in Windsurfing
International Inc. -v- Tabur Marine (Great Britain) Ltd [1985] RPC 59 at 73
to 74. The inventive concept in Claim 8 is said to be the production of rEPO
which is O-glycosylated and fucosylated. Assuming the mantle of the appropriately
skilled person armed with common general knowledge (the second step) I pass
on to the third step, namely identifying the alleged difference between the
prior art, Example 10, and the claimed invention, Claim 8. For the various
reasons I have given, it appears to me that the analysis reported in the deleted
matter in Example 10 does not represent any significant difference. First,
it would not be believed by the skilled reader, and in any event the skilled
reader would not have set out to make EPO which was not O-glycosylated or
fucosylated, would not have been able to do so, and, in any event, in doing
so would inevitably have made the very product which is claimed by Roche to
be inventive. That conclusion renders the fourth step unnecessary, but, essentially
for the same reasons, any difference of Claim 8 over Example 10 would have
been obvious.
- As I have mentioned, quite apart from 605A, Amgen rely on Jacobs as rendering
Claim 8 obvious. In summary form, Jacobs discloses the EPO-encoding sequence
and refers to it producing recombinant EPO COS cells. Both Professor Cummings
and Professor Proudfoot explained that, at least for anything other than transient
expression, a CHO cell would either be the cell, or a cell, of choice. I also
note that Professor Clausen accepted that CHO cells were on the shortlist
of cell lines which one would expect to use. Further, Professor Wall thought
that CHO cell lines were obvious in 1984 as a choice for effecting mammalian
gene expression, and he was not challenged on this. In light of that, and
in light of the arguments I have considered in relation to Example 10 rendering
Claim 8 obvious, I think that Claim 8 is also obvious over Jacobs.
R. CONCLUSIONS
- In these circumstances, my conclusions are as follows:
(1) The attacks on the 605 patent fail, save that Claims 19 and 20 (and
the Claims dependent thereon) are invalid on the ground of insufficiency;
(2) Subject to further arguments, I am prepared to uphold the 605 patent
subject to Amgen deleting the insufficient Claims;
(3) TKT infringe Claim 26 of the 605 patent;
(4) Roche infringe Claims 26, 27, 28, 29, 30 and 31 of the 605 patent;
(5) The 678 patent is invalid on the grounds of obviousness and lack
of novelty.
- This has been a difficult case involving a great deal of detailed technical
evidence, a lot of documentary evidence (running to over 50 pretty full files)
and much legal argument. I am grateful to all eight counsel for the assistance
they gave me, orally and in writing, before, during and after the hearing.
I also appreciate the way in which the solicitors involved prepared the evidence
and organised matters during the hearing.
