The patent

"1. A pharmaceutical composition which contains a pharmaceutically suitable solid carrier and the compound having the structure (7ά, 17ά) - 17 - hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one, characterized in that the compound is crystalline pure, which purity is greater than 90%.

2. The pharmaceutical composition of claim 1, characterized in that the crystalline purity is greater than 95%.

3. The pharmaceutical composition according to claim 1, characterized in that the crystalline pure compound has the monoclinic P2₁ form.

4. The pharmaceutical composition according to claim 1, characterized in that the crystalline pure compound has the triclinic P1 form.

5. A method for the preparation of a crystalline pure compound for use in a pharmaceutical composition accordingly to claim 3, characterized in that the polymorphous compound is crystallized from mixtures of water and acetone or ethanol, or from ethyl acetate, acetonitrile, or acetone-hexane mixtures.

6. A method for the preparation of a crystalline pure compound for use in a pharmaceutical composition according to claim 4, characterized in that the polymorphous compound is crystallized from an apolar solvent."

"Surprisingly, it has now been found that the compound having the formula [in question] prepared in accordance with the method described in the above-mentioned patents, is polymorphous and consists of two crystalline pure forms.

It may be expected of polymorphous compounds that their biological activity is comparable or identical to the biological activities of the crystalline pure forms of which the polymorphous compound consists. Nevertheless, if the polymorphous compound is used as a medicament great drawbacks are associated therewith compared with its crystalline pure components. The differences in crystal structure can lead to a difference in physico-chemical parameters such as stability, rate of dissolution, melting point, analytical data and the like, which frequently are strongly influenced by the crystal forms in the polymorphous compound. This is all the more obvious since in practice it is virtually impossible to make each batch of a polymorphous compound exactly identical in respect of composition. As a consequence of these differences, it is frequently regarded as undesirable to incorporate polymorphous compounds in medicaments and it is sometimes demanded that only one of the crystalline pure components of the polymorphous compound is used.

The aim of the present invention is, therefore, to obtain a pharmaceutical composition which contains a crystalline pure form according to the formula [in question], which is completely or virtually completely free from the other crystalline form.

The term 'crystalline pure form which is virtually completely free from the other crystalline form' denotes a form which contains less than 10% and preferably less than 5% of the other crystalline form.

It has now been found that by using specific crystallization techniques two crystalline pure forms, which here are designated form I and II respectively, can be obtained from the polymorphous compound [in question].

It has moreover been found that form I is chemically appreciably more stable than the already known polymorphous compound [in question]. This improvement in stability yields great advantages in respect of the shelf-life of the pharmaceutical product in which form I is incorporated.

The invention therefore relates to a pharmaceutical composition which contains a pharmaceutically suitable carrier and the compound having the structure [in question], characterized in that the said compound is a crystalline pure or virtually pure form which is completely or virtually completely free from the other crystalline form.

A pharmaceutical composition of this type has the advantage that the reproducibility is appreciably increased and that the physical data, within acceptable limits, are always identical.

The pure crystalline compounds, and in particular the compound with form I, are suitable for treating menopausal complaints or for modulating the immune system, and also for combating osteoporosis.

Form I is obtained by crystallizing the polymorphous compound [in question] from mixtures of water and acetone or ethanol. A suitable method is to dissolve the polymorphous compound in acetone or ethanol, after which the solution is added to water. Conversely, water can also be added to a solution of the polymorphous compound in acetone or ethanol. Other suitable solvents are, for example, ethyl acetate, acetonitrile and acetone/hexane mixtures. Mixtures of methanol and water, from which only mixtures of the two crystalline forms always crystallize, are unsuitable.

Form II can be obtained by crystallizing the polymorphous compound from a selection of apolar solvents. Toluene is very suitable, as is also hexane to which a little ethyl acetate has been added. Another suitable solvent is trichloroethylene.

The rate of crystallization, which is influenced most strongly by the crystallization temperature, can also play a role in obtaining crystalline pure forms. Thus, in general good results are obtained from anhydrous acetone only when the crystallization is carried out at a relatively low temperature."

The patentee then explains that forms I and II can readily be differentiated from one another - in particular by three methods, which are then described.

"Each of the crystalline pure forms is mixed with a suitable pharmaceutical carrier and administered parenterally or orally, for example as a solid pharmaceutical administration form, such as a tablet, pill, capsule or suppository.

The dosage schemes are the same as described in the abovementioned patents. An oral daily dose of 1-5 mg is particularly suitable for administration to humans.

A pharmaceutical composition in which form I is incorporated is preferred. A composition of this type has the additional advantage that a much better stability is obtained, so that the shelf-life, even under changing storage conditions, is notably improved."

"Example 1

4.0 g of the polymorphous compound [in question] were recrystallized under nitrogen from 20ml of acetone to which a trace of pyridine had been added. During this operation the temperature was slowly brought from room temperature to - 10 ºC. The crystals were filtered off and washed with acetone at -20 ºC and dried under vacuum at 40-45 ºC. Yield 3.0g of form I (purity according to DRIFT 94%, calculated from [a certain relationship]) ... .

Example 2

1 kg of the polymorphous compound [in question] was dissolved at 20-25 ºC in a mixture of 23 l of acetone and 6 ml of pyridine. The solution was filtered dust-free and the filter was washed twice with 1 l of acetone. At a temperature of 15-20 ºC the filtrate was poured as rapidly as possible, under nitrogen, into 25 l of dust-free distilled water, to which seed crystals of form I had been added. The suspension was cooled to 0-5 ºC and stirred for one hour at this temperature. The crystals were filtered off, washed with dust-free distilled water and dried under vacuum at 40 ºC. Yield 0.95 kg of form I (purity according to DRIFT 97.2%).

Example 3

In a manner comparable to that described in Example 2, four batches of form I were obtained with a purity of, respectively, 100%, 95.2%, 93.3% and 99.2% (all determined by means of DRIFT).

Example 4

2.3 kg of the polymorphous compound [in question] were dissolved in a mixture of 63 l of 96% ethanol and 114 ml of pyridine. This mixture was then poured as rapidly as possible, while stirring well, into a dust-free mixture of 53.5 l of water and 268 ml of pyridine at 18-20 ºC, to which seed crystals of form I had been added. Rinsing was carried out with 3 l of ethanol and the mixture was stirred for 15 min at 18-20 ºC. The crystals were filtered off, washed twice with a mixture of 10 l of dust-free distilled water and 2 ml of pyridine and then washed three times with 18 l of dust-free distilled water at 50 ºC. The crystals were dried under vacuum at 40 ºC. Yield 2.1 kg of form I (purity according to DRIFT 94.7%).

Example 5

5.0 g of the polymorphous compound [in question] were dissolved in 50 ml of ethyl acetate, to which a trace of pyridine had been added, at 40 ºC. 300 ml of hexane at about 35 ºC were added while stirring vigorously, after which the mixture was cooled to 0 ºC and stirred for a further 30 min. The crystals were filtered off and washed with hexane at 0 ºC. Yield 4.25 g of form II (purity according to DRIFT 100%).

Example 6

A tablet having the following composition was prepared:

Base granules were prepared by mixing the lactose with a portion of the starch. The remainder of the starch was mixed to a slurry with water and added to the mixture. The whole was granulated and dried. These base granules were mixed with ascorbyl palmitate and form I, sieved, finely mixed with magnesium stearate and then tabletted.

Example 7

A tablet having the same composition as in Example 6 was prepared by first mixing form I with 10% of the lactose and the ascorbyl palmitate and then mixing this mixture with the lactose, starch and starch slurry. The mixture was dried, finely mixed with magnesium stearate and tabletted.

Example 8

A capsule having the following composition was prepared:

The components were mixed with one another in the manner described in Example 6, granulated and filled into gelatin capsules."

The statutory provisions

"1(1) A patent may be granted only for an invention in respect of which the following conditions are satisfied, that is to say -

(a) the invention is new;

(b) it involves an inventive step;

...

and references in this Act to a patentable invention shall be construed accordingly.

...

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 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 (whether in the United Kingdom or elsewhere) by written or oral description, by use or in any other way.

...

3 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 ...

...

72 Subject to the following provisions of this Act, the court ... may by order revoke a patent for an invention on the application of any person (including the proprietor of the patent) on (but only on) any of the following grounds, that is to say -

(a) the invention is not a patentable invention;

...

125(1) For the purposes of this Act an invention for a patent ... for which a patent has been granted shall, unless the context otherwise requires, be taken to be that specified in a claim of the specification of the ... patent ... as interpreted by the description and any drawings contained in that specification, and the extent of the protection conferred by a patent ... shall be determined accordingly.

...

(3) The Protocol on the Interpretation of Article 69 of the European Patent Convention (which Article contains a provision corresponding to subsection (1) above) shall, as for the time being in force, apply for the purposes of subsection (1) above as it applies for the purposes of that Article."

The power in this court to revoke a patent for an invention which is not a patentable invention extends to a European Patent (see section 77).

The Convention and the Protocol on its Interpretation

"(1) The extent of the protection conferred by a European Patent ... shall be determined by the terms of the claims. Nevertheless, the description and drawings shall be used to interpret the claims.

... ".

The Protocol on the Interpretation of Article 69 of the Convention provides:

"Article 69 should not be interpreted in the sense that the extent of the protection conferred by a European Patent is to be understood as that defined by the strict, literal meaning of the wording used in the claims, the description and drawings being employed only for the purpose of resolving an ambiguity found in the claims. Neither should it be interpreted in the sense that the claims serve only as a guideline and that the actual protection conferred may extend to what, from a consideration of the description and drawings by a person skilled in the art, the patentee has contemplated. On the contrary, it is to be interpreted as defining a position between these extremes which combines a fair protection for the patentee with a reasonable degree of certainty for third parties."

The challenges

The prior art

"Conformational analysis of 3-oxo 5(10)-unsaturated steroids.

Single-crystal X-ray structure analysis of

17-hydroxy-7ά-methyl-19-nor-17ά-pregn-5(10)-en-20-yn-3-one (Org OD 14)".

Its authors were J.-P. Declercq and M. Van Meerssche, apparently academic scientists at the University of Louvain, and a third person, F.J. Zeelen, described in the heading as of "Organon Scientific Development Group, 5340 BH Oss, The Netherlands". A note advises that Mr. Zeelen is the author to whom correspondence should be addressed. The abstract of the article narrates:

"Two crystallographically independent molecules with differing half-chair conformations of ring A were found in the analysis of Org OD 14. These results are compared with published X-ray structure analyses and Westheimer-type calculations of related steroids. It is concluded that the energy differences between the half-chair and envelope conformations of ring A of 3-oxo 5(10)-unsaturated steroids are small."

Org OD 14 would appear to denote a compound by then identified by Organon as of interest for the purposes of pharmaceutical development. The authors introduce their article and continue:

"We now report a single-crystal X-ray analysis of another representative of [the steroid class in question]: 17-hydroxy-7ά-methyl-19-nor-17ά-pregn-5(10)-en-20-yn-3-one (Org OD 14)."

A footnote to this sentence is in the following terms:

"Org OD 14 is a compound of interest for the treatment of menopausal complaints."

Certain references are then given. Under the heading 'Experimental" the authors give the experimental parameters within which the analysed single crystal was obtained. These include the following:

It is not disputed that the "system" described in these parameters as "monoclinic" is the monoclinic P2₁ form referred to in claim 3 of the patent.

"Two independent molecules were found and their coordinates are given in Table II. The two structures found show many of the features often observed in steroids such as the 13β-envelope conformations of the D-ring and the chair conformations of the C-ring. The B-rings in both conformations are half-chair with the 7ά-methyl group in an axial position."

The coordinates in Table II are (subject to errors of calculation) consistent with that described in the patent.

The expert testimony and matters agreed therein

"Dr. Newton has recently retired as resident medicinal chemist in the chemistry department of the University of Cambridge, a position he held since 1996, and he is visiting professor at the University of Sussex. He holds a number of posts with various scientific companies and, possibly most relevant to the present proceedings, was employed by Glaxo from 1971 to 1996, originally as a senior research chemist and subsequently as director of various research projects. Professor Bernstein is and has been since 1971 professor of chemistry at Ben-Gurion University of the Negev, Beersheva, Israel. He teaches courses in general chemistry, crystallography and organic state chemistry, including polymorphism and crystallisation. He has specialised and built an international reputation in the field of crystallography and has participated in a large number of conferences on the subject. Indeed, Dr. Newton was willing to defer to Professor Bernstein on matters of pure crystallography."

The issues before the Lord Ordinary and his disposal of them

Accordingly, the Lord Ordinary held that all the claims in issue had been anticipated and on that basis revoked the patent in its entirety.

Submissions by junior counsel for Akzo

Submissions by junior counsel for Arrow

Response by senior counsel for Akzo

Submissions by senior counsel on behalf of Arrow

Discussion

The role of an appellate court

"The question of whether an invention was obvious had been called 'a kind of jury question' ... and should be treated with appropriate respect by an appellate court ... Where the application of a legal standard such as negligence or obviousness involves no question of principle but is simply a matter of degree, an appellate court should be very cautious in differing from the judge's evaluation."

"I do not think the question of novelty involves the application of a 'not altogether precise legal standard'. It involves a precise standard. Nor is it applied to a 'combination of features of varying importance'. On the contrary one must look for every claim element to see whether it is fully disclosed in the prior art. It may be that in some cases, Biogen-type principles may come into the question at an earlier stage. I have in mind, for instance, where the court has to evaluate evidence as to what a particular prior use actually was and whether it was enabling or where there is an evaluation of what is exactly disclosed by something like a photograph ... , or even, perhaps, the meaning of a technical term or phrase where experts have disagreed. But in a case such as this, where the issue is simply what does the prior art describe and does it fall within the claim, the Biogen principle does not apply."

Mummery and Pill L.Js agreed.

"These I restated in Technip France SA's Patent ... at paras. [71] - [74]. In brief, the Biogen appeal principle ... applies to obviousness but not to novelty, save in special cases, for instance where there is a conflict of expert testimony on the meaning of a technical term or as to what exactly is disclosed by the prior art. The Biogen appeal principle itself is, in short, that an appellate court must exercise caution in differing from the trial judge's evaluation of the facts unless he has erred in principle."

Novelty

"It is often said, on the basis of the words 'a position between these extremes', that the Protocol represents a compromise between two different approaches to the interpretation of claims. But that is not quite accurate. It is a protocol on the interpretation of art. 69, not a protocol on the interpretation of claims. The first sentence does deal with interpretation of the claims and, to understand it, one needs to know something about the rules which English courts used to apply, or impose on themselves, when construing not merely patents but documents in general. The second sentence does not deal with the interpretation of claims. Instead, it makes it clear that one cannot go beyond the claims to what, on the basis of the specification as a whole, it appears that 'the patentee has contemplated'. But the last sentence indicates that, in determining the extent of protection according to the content of the claims but avoiding literalism, the courts of the Contracting States should combine 'a fair protection for the patentee with a reasonable degree of certainty for third parties'."

Lord Hoffmann then explained the principles upon which, at common law, the English courts had traditionally approached the issue of construction. He continued:

"32. Construction, whether of a patent or any other document, is of course not directly concerned with what the author meant to say. There is no window into the mind of the patentee or the author of any other document. Construction is objective in the sense that it is concerned with what a reasonable person to whom the utterance was addressed would have understood the author to be using the words to mean. Notice, however, that it is not, as is sometimes said, 'the meaning of the words the author used', but rather what the notional addressee would have understood the author to mean by using those words. The meaning of words is a matter of convention, governed by rules, which can be found in dictionaries and grammars. What the author would have been understood to mean by using those words is not simply a matter of rules. It is highly sensitive to the context of, and background to, the particular utterance. It depends not only upon the words the author has chosen but also upon the identity of the audience he is taken to have been addressing and the knowledge and assumptions which one attributes to that audience ...

33. In the case of a patent specification, the notional addressee is the person skilled in the art. He (or, I say once and for all, she) comes to a reading of the specification with common general knowledge of the art. And he reads the specification on the assumption that its purpose is both to describe and to demarcate an invention - a practical idea which the patentee has had for a new product or process - and not to be a textbook in mathematics or chemistry or a shopping list of chemicals or hardware. It is this insight which lies at the heart of 'purposive construction'. ...

34. 'Purposive construction' does not mean that one is extending or going beyond the definition of the technical matter for which the patentee seeks protection in the claims. The question is always what the person skilled in the art would have understood the patentee to be using the language of the claim to mean. And for this purpose, the language he has chosen is usually of critical importance. The conventions of word meaning and syntax enable us to express our meanings with great accuracy and subtlety and the skilled man will ordinarily assume that the patentee has chosen his language accordingly. As a number of judges have pointed out, the specification is a unilateral document in words of the patentee's own choosing. Furthermore, the words will usually have been chosen upon skilled advice. A specification is not a document inter rusticos for which broad allowances must be made. On the other hand, it must be recognised that the patentee is trying to describe something which, at any rate in his opinion, is new; which has not existed before and of which there may be no generally accepted definition. There will be occasions upon which it will be obvious to the skilled man that the patentee must in some respects have departed from conventional use of language or included in his description of the invention some element which he did not mean to be essential, but one would not expect that to happen very often."

At paragraph 47 Lord Hoffmann added:

"The Protocol, as I have said, is a Protocol for the construction of art. 69 and does not expressly lay down any principle for the construction of claims. It does say what principles should not be followed, namely the old English literalism, but otherwise it says only that one should not go outside the claims. It does however say that the object is to combine a fair protection for the patentee with a reasonable degree of certainty for third parties. How is this to be achieved? The claims must be construed in a way which attempts, so far as is possible in an imperfect world, not to disappoint the reasonable expectations of either side. What principle of interpretation would give fair protection to the patentee? Surely, a principle which would give him the full extent of the monopoly which the person skilled in the art would think he was intending to claim. And what principle would provide a reasonable degree of protection for third parties? Surely again a principle which would not give the patentee more than the full extent of the monopoly which the person skilled in their art would think that he was intending to claim. Indeed, any other principle would also be unfair to the patentee, because it would unreasonably expose the patent to claims of invalidity on grounds of anticipation or insufficiency."

The other members of the Appellate Committee agreed with Lord Hoffmann.

"The well known principle that patent claims are given a purposive construction does not mean that an integer can be treated as struck out if it does not appear to make any difference to the inventive concept. It may have some other purpose buried in the prior art and even if this is not discernible, the patentee may have had some reason of his own for introducing it. In my judgment therefore the claim requires that something which can fairly be described as a conduit must extend upwards within the cylinder and its outer surface must, together with the walls of the cylinder, define the pump chamber."

"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. If the reader skilled in the art would have understood that the patentee intended that the claim should have a particular ambit, then to construe it as not confined to that ambit, by either strict or liberal construction, would be unfair to the patentee. It is the patentee that chooses the words and to widen the ambit contrary to his intention would invalidate the patent and to restrict the ambit could allow use of the invention without payment."

" ... claim 3 is a claim to a particular product, namely tibolone of a particular crystalline structure".

That statement was challenged by Akzo on the ground that it posited that the claim was to a compound of a particular crystalline structure without regard to the integer(s) "A pharmaceutical composition which contains a pharmaceutically suitable solid carrier and ... ". Reference to construction of claims 1-3 is made by the Lord Ordinary also at para. [24] where he says:

"Akzo's second argument was that the fact that Declercq revealed a single crystal of Form I, which was by definition 100% pure, was irrelevant on a proper construction of claims 1-3. The claims in the patent were to a 'pharmaceutical composition' containing the compound, i.e. tibolone. That must involve a recognition that a crystal is not sufficient; a pharmaceutical compound clearly cannot be made of a single crystal."

That reference, however, is made only in the context of the "single crystal" argument (to which I shall return), not in the context of construing the whole integers of the claim. In para. [28] the Lord Ordinary records an argument that

" ... any challenge to claims 1-3 on grounds of lack of novelty would have to demonstrate not just that the form and purity of the crystal were anticipated but also that the incorporation of the tibolone of the requisite form and purity into the pharmaceutical composition similarly lacked novelty".

The argument, as recorded, then continued:

"The incorporation of the tibolone into a pharmaceutical composition was not anticipated in Declercq. A challenge to the whole of claims 1-3, properly construed, would, [counsel] submitted, involve Arrow in 'mosaicing', i.e. building a case on anticipation by putting together a mosaic of different sources of prior disclosure".

In response to this argument the Lord Ordinary at para. [29] said:

"It cannot be, and was not, suggested that there is anything novel about the making of pharmaceutical composition incorporating tibolone." (emphasis added).

That sentence may in terms be accurate, though as I shall explain the de quo is not whether there was anything novel about the making of a pharmaceutical composition incorporating tibolone but whether there was anything novel in making a pharmaceutical composition which contained (a pharmaceutically suitable solid carrier and) tibolone with a certain minimum crystalline purity. The Lord Ordinary added towards the end of that paragraph:

"I consider that the addressee of the patent would not understand the incorporation of the compound into the pharmaceutical composition to be part of the invention claimed by the patent. Nor is this a realistic interpretation of the claims read in context, even if construed by the Court without looking through the eyes of the notional addressee."

These propositions were not supported by Arrow in seeking to maintain the Lord Ordinary's conclusion on anticipation. They are plainly, as a matter of construction, wrong.

"it would have been open to Akzo to limit claims 1-4 by reference to some quantitive criteria but, for whatever reason, they have not done so. It was not suggested that, even adopting a purposive construction, those claims should be read as incorporating some such criteria capable of being expressed with sufficient precision."

"a pharmaceutical composition which contains a pharmaceutically suitable solid carrier and the compound having the structure [specified], characterised in that the compound is crystalline pure, which purity is greater than [90 or 95%]",

such that it could be said to have anticipated claims 1 or 2, or such a composition where the crystalline pure compound has the monoclinic form, such that it could be said to have anticipated claim 3. Taking account of the whole integers, that imports, in my view, a combination of a pharmaceutically suitable solid carrier with tibolone in a crystalline purity of more than the stated percentages and, so far as claim 3 is concerned, of a particular crystalline form. The issue is whether that combination was anticipated by Declercq.

"a pharmaceutical composition which contains ... the compound [tibolone] characterised in that the compound is crystalline pure, which purity is greater than [90 or 95% or, as regards claim 3, in the monoclinic form]".

I leave out of account for present purposes the integer of "a pharmaceutically suitable solid carrier" because, if I had been persuaded that Declercq did disclose the use of tibolone of the requisite crystalline purity for pharmaceutical purposes, the possibility of its combination with a suitable solid carrier would not to the skilled man, in my view, have been novel.

" ... [The effect of the cited cases as a whole is to show that] the hypothetical addressee is not a person of exceptional skill and knowledge, that 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."

"amount of water and the temperature and rate of the crystallisation may impact upon the result and the serendipitous nature of the discovery of different polomorphic forms means that one can, in any event, never have absolute certainty in this field".

If the Lord Ordinary's findings are read in context, his conclusion was, in my view, to the effect that, using acetone, that is, following the procedure envisaged in the prior art, the skilled person would ordinarily obtain crystals, some at least of which were monoclinic. That conclusion is consistent with the experimental examples given in the patent which envisage polar solvents (including acetone and water) producing a high percentage of the monoclinic form.

Claim 5

"A suitable method is to dissolve the polymorphous compound in acetone or ethanol, after which the solution is added to water. Conversely, water can also be added to a solution of the polymorphous compound in acetone or ethanol."

It is not clear to me what is the difference between these methods - we were not enlightened on this - but each appears to envisage a step whereby the compound dissolved in acetone is added to water (or vice versa). This would be consistent with evidence from Professor Bernstein (at para. 75 of his report, which was accepted by Dr. Newton at page 389) that water so added acts as an anti-solvent giving rise to precipitation of the crystals. Examples 2 and 4 appear to envisage a similar procedure.

Obviousness

"Where the application of a legal standard such as negligence or obviousness involves no question of principle but is simply a matter of degree, an appellate court should be very cautious in differing from the judge's evaluation."

The corollary of that proposition is that, where the judge of first instance has erred upon a matter of principle, his decision is open to review by an appellate court.

"(i) the inventive concept in the patent is the identification of a crystalline pure form of tibolone and a method of producing it; (ii) the skilled addressee would have known of tibolone and would have knowledge that steroids are likely, though not certain, to be polymorphous; (iii) the difference is the discovery of polymorphism in tibolone and the identification of the method of producing one of the two different polymorphic forms. Stage (iv) requires one to ask whether the steps required to achieve this would have been obvious to the skilled man."

He answered the question posed in the last stage with a clear "No".

"It is the inventive concept of the claim in question which must be considered, not some generalised concept to be derived from the specification as a whole. Different claims can, and generally will, have different inventive concepts. The first stage of identification of the concept is likely to be a question of construction: what does the claim mean? It might be thought there is no second stage - the concept is what the claim covers and that is that. But that is too wooden and not what courts, applying Windsurfing stage one, have done. It is too wooden because if one merely construes the claim one does not distinguish between portions which matter and portions which, although limitations on the ambit of the claim, do not. One is trying to identify the essence of the claim in this exercise."

That passage was cited with approval by Jacob L.J. in Pozzoli SPA v BDMSO SA at paras. 17-18; in the latter paragraph he added:

"So what one is seeking to do is to strip out unnecessary verbiage, to do what Mummery L.J. described as make a précis."

Mummery and Keene LJs agreed. Neither of these cases appears to have been cited to the Lord Ordinary - the latter was, of course, issued after his decision. The import of them appears to be that it will, at least commonly, be important in seeking to identify any inventive concept to have regard to the claims discretely. The Lord Ordinary did not undertake such an exercise. His failure to do so might be regarded as an error in principle, though in the circumstances of this case, where claims 2 and 3 are so closely related to claim 1, I doubt whether, as regards these claims, the absence of a discrete treatment was a fundamental flaw. It may be otherwise as regards claim 5, which is a process rather than a product claim.

"This is not a real person. He is a legal creation. He is supposed to offer an objective test of whether a particular development can be protected by a patent. He is deemed to have looked at and read publicly available documents and to know of public uses in the prior art. He understands all languages and dialects. He never misses the obvious nor stumbles on the inventive. He has no private idiosyncratic preferences or dislikes. He never thinks laterally. He differs from all real people in one or more of these characteristics."

No quarrel was taken with that description and I am content to adopt it.

"7.6 A skilled man wishing to develop Tibolone as a pharmaceutical product would need to identify a robust and repeatable process for making a well defined stable form of the drug.

7.7 The synthetic route to the compound is described in the 279 [patent]. ... The skilled man would be well aware of the fact that most steroids exhibit polymorphism (see references to common general knowledge at paragraph 5.1.9). Since he would have known that different steroidal polymorphs may have different melting points, densities, spectroscopic properties, bioavailabilities and stabilities ... he would want to define a single polymorph having suitable physical and bioavailability profiles.

7.8 The skilled man would have been aware of the prior art and of the 1984 [Declercq] Paper. The latter would have been a very important document since it teaches how to make a pure polymorph and defines it analytically. Thus, by following the teaching of the 279 to make the compound and then recrystallising it from acetone as taught by the 1984 [Declercq] Paper the skilled man would have a method of preparing pure Form I polymorph.

7.9 For these reasons I think that claims 1 and 2 of the Patent are obvious since the 1984 [Declercq] Paper already described Form I Tibolone. Claim 3 is likewise obvious since the 1984 [Declercq] Paper precisely describes the crystal structure referred to in the Patent as monoclinic P2₁ form ...

7.10 In my opinion it would have been obvious at the priority date of the Patent to obtain and use the polymorph claimed at claims 1-3 in its pure crystalline form ... ".

"Despite Professor Bernstein's undoubted eminence in his field, I prefer the evidence of Dr. Newton to the effect that by the late 1980s polymorphism as a phenomenon would have been well-known to a process research chemist working in the pharmaceutical industry; and they would have known that it was widespread in pharmaceuticals, particularly steroids."

That is a finding of fact by the Lord Ordinary. Neither side before us sought to challenge it. At paragraph [43] the Lord Ordinary continued:

"But there is a difference between, on the one hand, knowing of polymorphism as a phenomenon, or even knowing that it is likely to be found in steroids; and, on the other hand, being able to use or apply that knowledge. The point Professor Bernstein was making, for example in para. 12 of his Report, was that polymorphism in any particular compound was usually discovered by serendipity rather than by systematic research. The important conclusion from this was that set out at para. 56 of that Report, that: ' ... even the skilled person could not know in advance that any steroid might be polymorphic. He certainly would not know in advance how to obtain it, or what its properties might be.' Despite the existence of polymorphic screening - which was less common in the 1980s than it is today - I did not understand Dr. Newton to disagree strongly with this opinion; and, in any event, I accept it as correct."

Again, that is a finding of fact, in this instance accepting as well-founded the quoted passage. Again, neither side before us sought to challenge it, though there was some discussion about the first sentence - its import it was suggested, was that "even the skilled person could not know in advance that any [particular] steroid [was] polymorphic".

"The relevant issue is not so much whether there was an awareness of polymorphism amongst the relevant people at the relevant time, but whether that knowledge pointed the way to a discovery of polymorphism in any particular case."

I shall return to that sentence in due course.

"The obviousness attack on the claims in the patent has to be considered against this background. Let it be assumed that the skilled but unimaginative addressee of the patent knows of tibolone, and knows that there is a likelihood that tibolone, being a steroid, is polymorphous. Without the benefit of hindsight, I do not see why he would want to look for a pure polymorphic form of tibolone. After all, tibolone had been known from the 1960s, and there was no evidence of any concerted effort to find out if it was polymorphous. Nor do I see how he would go about finding a new polymorphic form. He might know of the Declercq paper, which would tell him about what is now called Form I, and about the use of acetone, but not about tibolone being polymorphic. If he carried out a crystallisation using acetone, he would probably have produced what we now know as Form I tibolone. But that would support Arrow's argument on anticipation rather than obviousness (see para. 34 above). It seems to me that the 'obviousness' line of attack, as distinct from that based on anticipation, assumes that the skilled but unimaginative addressee of the patent would be looking to develop a pure polymorphic form of tibolone and would have had the knowledge of how to achieve it. Without the benefit of knowing (with hindsight) that such a form had been found, I do not consider that he would have had either the motivation or the means."

"In particular, it is likely to be very difficult to establish that such matters of principle are involved in decision made by the judge in assessing technical evidence and its bearing on the issues that he has to decide."

Act: Currie, Q.C., Higgins; Maclay Murray & Spens (Petitioners and Respondents)

Alt: McNeill, Q.C., Delibegović-Broome; McClure Naismith (Respondents and Reclaimer)

20 May 2008

Act: Currie, Q.C., Higgins; Maclay Murray & Spens (Petitioners and Respondents)

Alt: McNeill, Q.C., Delibegović-Broome; McClure Naismith (Respondents and Reclaimer)

20 May 2008

Construction of the Patent

"The claims in the patent were to a 'pharmaceutical composition' containing the compound, i.e. tibolone. That must involve a recognition that a single crystal is not sufficient: a pharmaceutical compound clearly cannot be made of a single crystal" (my emphasis).

The Lord Ordinary's response to that argument, in part, is recorded at para. [27] of his Opinion where he states:

" ... it would have been open to Akzo to attempt to limit claims 1-4 by reference to some quantitative criteria. But, for whatever reason, they have not done so. It was not suggested that, even adopting a purposive construction, those claims should be read as incorporating some such criteria capable of being expressed with sufficient precision. Even if it had been so argued, I would have felt unable to construe the relevant claims as being restricted to pure Form 1 tibolone in some quantity greater than a single crystal. On that basis, the prior disclosure in Declercq of a single crystal of what we now know to be Form 1 tibolone and which, being a single crystal, is by definition 100% pure, is sufficient to invalidate claims 1-3".

As your Lordship in the chair has observed, this court has not been invited to make any new findings-in-fact. Whether or not claims 1-3 are capable of embracing a single crystal in a pill, capsule or tablet is left, therefore, to be determined by construing the words of the patent itself, without the assistance of any findings-in-fact based on the evidence of any skilled person or persons as to this issue.

"The invention therefore relates to a pharmaceutical composition which contains a pharmaceutically suitable carrier and the compound having the structure (7ά, 17ά) - 17 hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one, characterized in that the said compound is a crystalline pure or virtually pure form which is completely or virtually completely free from the other crystalline form".

That statement does not exclude the possibility of such a composition comprising a single crystal of tibolone which would, ex hypothesi, be 100% pure. I have to remind myself that the notional addressee of this patent is the person skilled in the art and that I am not such a person. While a person skilled in the art may have said that a pharmaceutical composition consisting of a single crystal of tibolone would be regarded by someone like himself as either a nonsense or, alternatively, at least that it would be inherently improbable that it would be viable as an effective drug, no evidence to that effect was provided to the court below, and the position remains the same before this court. It would therefore be, in my view, quite illegitimate, in that state of affairs, for this court to speculate on such questions, far less to reach any conclusion by acting as if it were the skilled addressee. The court's task is one of construction of the words employed by the patentee. A purposive approach to the construction of those words does not, it seems to me, render it legitimate either to cut down or extend the clear meaning of the language of a claim, in the absence of relevant evidence pointing in that direction. Put another way, construction of the language must not lead to the court crossing into the forbidden territory of re-wording or amending the claim in the guise of construing it.

Novelty

"To determine whether a patentees' claim has been anticipated by an earlier publication it is necessary to compare the earlier publication with the patentee's claim. The earlier publication must, for this purpose, be interpreted as at the date of its publication, having regard to the surrounding circumstances which then existed, and without regard to subsequent events. ... If the earlier publication, so construed, discloses the same device as the device which the patentee by his claim, so construed, asserts that he has invented, the patentee's claim has been anticipated, but not otherwise".

On the basis of what Declercq itself said, and the particular context in which he had said it, I consider that it did not disclose what the patentee asserts he has invented in claims 1-3 and 5. I do not read any of the evidence in this case as justifying the opposite conclusion. For these reasons I consider that Arrow's attack on the novelty of claims 1-3 and 5 fail.

Obviousness

"The notion of crystalline form may require some explanation. The same substance may exist in different solid forms, depending upon the arrangement of its molecules. In crystalline form the molecules arrange themselves in an organised pattern called a lattice which gives the crystal a distinctive shape. On the other hand, in an amorphous form or an oil, the molecules are randomly distributed in a substance that has no particular shape. Some substances have only one crystalline form. They are called monomorphic. But others have a variety of patterns into which the molecules may arrange themselves. They are polymorphic. Different crystalline forms can be distinguished by a number of conventional tests. Infra-red ration ('IR') will result in a spectrum of readings of absorbance which are characteristic of their particular crystal. X-ray diffraction ('XRD') will likewise give a characteristic series of readings. The IR and XRD readings are the crystal fingerprints. Some compounds form one or more types of crystals which include, as part of their crystalline structure, molecules of the solvent from which the crystal has been precipitated. They are called solvates or, if the solvent is water, hydrates".

The evidence of both Dr. Newton and Professor Bernstein, in the present case, was if you crystallised from acetone you would expect to get some Form 1 tibolone (see the Lord Ordinary at paragraph [37] of his Opinion). The conclusion therefore had to be, it was submitted on behalf of Arrow, that it was not inventive to use monoclinic tibolone as an ingredient in a pharmaceutical concept. Knowing, as he would, that the tibolone might be polymorphic the skilled man would be interested in having it in a pure form. If you are crystallising from acetone and you are obtaining some Form 1 tibolone then, for the purposes of the present discussion, it was said, it did not matter that in the course of that you might also come across some Form 2 tibolone. The basic point was that the placing of pure form tibolone (which ex hypothesi would include a single crystal) in a pharmaceutical composition could not be said to be inventive.

"Often the nature of the enquiry is helped by the well-known Windsurfing steps, (1984) RPC 59 at page 74. I summarise:

a) identify the inventive concept of the claim;

b) identify the common general knowledge of the skilled man;

c) identify the difference(s) between the prior art under consideration and

that in the inventive concept of the claim;

d) ask whether the difference(s) would have been obvious or require

invention".

His Lordship went on to say

"No one suggests that this is always the appropriate test. In the end the enquiry is simply that posed by the statute, as for instance, Sir Donald Nicholls VC pointed out in Mólnyke v P & G (1994) RPC 49 at pp. 112-3. He went on to say, at p. 113:

'In applying the statutory criterion (i.e. as to whether an alleged inventive step was obvious) and making these findings (i.e. as to obviousness) the court will almost invariably require the assistance of expert evidence. The primary evidence will be that of properly qualified expert witnesses who will say whether or not in their opinions the relevant step would have been obvious to a skilled man having regard to the state of the art.'"

" ... by following the teaching of the 279 to make the compound and then re-crystallising from acetone as taught by the 1984 (Declercq) Paper the skilled man would have a method of preparing pure form 1 polymorph".

Dr. Newton then continued at para. 7.9:

"For these reasons I think that claims 1 and 2 of the Patent are obvious since the 1984 (Declercq) Paper already described Form 1 Tibolone. Claim 3 is likewise obvious since the 1984 (Declercq) Paper precisely describes the crystal structure referred to in the Patent as monoclinic P2₁ form".

I repeat that the knowledge, or otherwise, of the discovery of the polymorphous character of tibolone seems to me to have bedevilled the discussion of this question and certainly led, in my view, the Lord Ordinary to misdirect himself when dealing with the matter. On this branch of the case, it seems to me that the question is, can it be said to be inventive to place a single crystal of monoclinic form 1 tibolone in a pill, tablet or capsule? Judging matters from the viewpoint of the skilled man who was aware of only Form 1 monoclinic tibolone as at the priority date, I agree with Arrow that, on the evidence, it cannot.