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England and Wales Court of Appeal (Civil Division) Decisions |
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You are here: BAILII >> Databases >> England and Wales Court of Appeal (Civil Division) Decisions >> Gedeon Richter Plc v Bayer Pharma AG [2012] EWCA Civ 235 (07 March 2012) URL: http://www.bailii.org/ew/cases/EWCA/Civ/2012/235.html Cite as: [2012] WLR(D) 66, [2012] EWCA Civ 235, [2013] Bus LR D17 |
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ON APPEAL FROM THE HIGH COURT OF JUSTICE
CHANCERY DIVISION (PATENTS COURT)
The Hon Mr Justice Floyd
Strand, London, WC2A 2LL |
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B e f o r e :
THE RT HON LORD JUSTICE KITCHIN
and
SIR ROBIN JACOB
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Gedeon Richter plc (a company incorporated under the laws of Hungary) |
Appellant |
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- and - |
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Bayer Pharma AG (a company incorporated under the laws of Germany) |
Respondent |
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for the Appellant
Andrew Waugh QC and Thomas Hinchliffe (instructed by Simmons & Simmons LLP)
for the Respondent
Hearing dates: 7/8 February 2012
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Crown Copyright ©
Lord Justice Kitchin and Sir Robin Jacob:
Introduction
(a) Claims 1 and 19 of 069 were invalid for obviousness over two items of prior art. However, he permitted Schering to amend the patent to delete claims 1-5 and make claim 19 dependent on claim 6.(b) Claim 6 of 069 was not invalid for obviousness. This claim is now amended claim 1.
(c) Claim 1 of 301 (as amended) was not invalid for obviousness.
(d) 301 (as amended) and 069 were not invalid for added matter.
Technical background and common general knowledge
"25. Low solubility APIs present particular difficulties for the formulator. Such APIs run the risk of incomplete absorption. Steps can be taken to improve the dissolution properties of poorly soluble APIs. Those of particular relevance to this case are (a) reducing particle size by micronisation, i.e. fine milling of the drug to produce a higher surface area (for example, icing sugar as against granulated) and (b) applying the API onto the surface of inert carrier particles. These are, however, only examples of the techniques which the skilled formulator would have in his armoury for dealing with poorly soluble drugs as part of his common general knowledge.
26. A skilled person would be aware that, in the case of a drug which is sensitive to stomach acid, taking steps to increase solubility would be likely to increase the rate at which the drug degraded. This was particularly notable in the case of the antibiotics penicillin G and erythromycin which are highly unstable in the gastric environment, but it is a factor which the formulator would have in mind for any acid labile drug."
"31. If studies show that a drug has a tendency to degrade in acid conditions, it is possible to protect the drug from the acid environment in the stomach by means of an enteric coating. The coating is designed to be insoluble in acid conditions. The formulation is therefore discharged without dissolution from the stomach by the stomach emptying process into the more alkaline environment of the small intestine. The coating is designed to dissolve in those conditions, and the drug is then released for absorption at that stage.
32. Enteric coatings are also used to protect the stomach lining from the action of a drug, but that application is not directly relevant here. As at 1996 there were 261 drugs on the market with enteric coats, about one third of which were so formulated to protect the drug from acid.
33. A consequence of the mode of action of the enterically coated drug is that there is a delay in the onset of action while the formulation is discharged from the stomach.
34. Whilst there is no doubt that enteric coatings overcame the problem of acid degradation in the stomach, they undoubtedly had some problems of their own. The first is the delayed onset of action which I have already mentioned. This is a particular problem in a drug for which there is an urgent need for immediate onset.
35. A second and related problem with the enteric coating is that the period of delay will be the subject of inter- and intra-patient variability because of the differences in gastric emptying times to which I have referred. One reference suggests that the residence time for a delayed dosage form is between 30 minutes and 4.5 hours. Examples were found of drugs which were delayed even longer, one by up to 12 hours.
36. By the priority date, however, these problems had been met to a large degree by providing enterically coated granules. Their small size enabled them to pass through into the intestine at a faster and less variable rate. The notion of providing enterically coated granules in a hard gelatine two-part capsule was well established by the priority date. Compressing the granules into a tablet was a slightly different matter. Professor Buckton did not accept that these tablet formulations were part of the common general knowledge, and I conclude that it was not."
Added matter
"98. We can deal with this quite shortly. The added subject-matter is said to be contained in Claim 6. Mr Silverleaf put it this way:
'We say that if that claim covers water soluble spheronising agents, it must also disclose the possibility of using them or it does not actually read on to them at all; because otherwise the teaching of the document is to use water soluble ones. We say if in fact the claim is wide enough to cover water soluble spheronising agents, there must be added matter.'
99. The trouble with that submission is that claim 6 does not mention – so cannot possibly teach – water soluble spheronising agents. It just specifies 'a spheronising agent.' The fallacy in the argument is to equate disclosure of subject matter with scope of claim, a fallacy struck down as long ago as 1991 in AC Edwards v Acme Signs & Displays [1992] RPC 131 (see e.g. per Fox LJ at p.143)."
The parent application – disclosure
"Drospirenone, which may be prepared substantially as described in, e.g., US 4,129,564 or WO 98/06738, is a sparingly soluble substance in water and aqueous buffers at various pH values. Furthermore, drospirenone is rearranged to an inactive isomer under acid conditions and hydrolysed under alkaline conditions. To ensure good bioavailability of the compound, it is therefore advantageously provided in a form that promotes rapid dissolution thereof."
"It has surprisingly been found that when drospirenone is provided in micronized form (so that particles of the active substance have a surface area of more than 10,000cm2/g, and the following particle size distribution as determined under the microscope: not more than 2 particles in a given batch with a diameter of more than 30µm, and preferably = 20 particles with a diameter of = 10 µm and = 30 µm) in a pharmaceutical composition, rapid dissolution of the active compound from the composition occurs in vitro ("rapid dissolution is defined as the dissolution of at least 70% over about 30 minutes, in particular at least 80% over about 20 minutes, of drospirenone from a tablet preparation containing 3 mg of drospirenone in 900 ml of water at 37°C determined by the USP XXIII Paddle Method using a USP dissolution test apparatus 2 at 50 rpm). Instead of providing the drospirenone in micronized form, it is possible to dissolve it in a suitable solvent, e.g. methanol or ethyl acetate, and spray it onto the surface of inert carrier particles followed by incorporation of the particles containing drospirenone on their surface in the composition."
"Without wishing to be limited to any particular theory, it appears that the in vitro dissolution rate of drospirenone is connected to the dissolution rate in vivo resulting in rapid absorption of drospirenone in vivo on oral administration of the compound. This is an advantage because isomerization of the compound in the gastric environment and/or hydrolysis in the intestine is substantially reduced, leading to a high bioavailability of the compound."
"To obtain a more rapid rate of dissolution, it is preferred to include carriers or excipients which act to promote dissolution of both active substances. Examples of such carriers and excipients include substances that are readily soluble in water such as cellulose derivatives, carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, gelled starch, gelatin or polyvinylpyrrolidone. In particular, it appears as though polyvinylpyrrolidone might be particularly helpful to promote dissolution."
"The composition of the invention may be formulated in any manner known in the pharmaceutical art. In particular, as indicated above, the composition may be formulated by a method comprising providing drospirenone and, if desired, ethinylestradiol in micronized form in said unit dosage form, or sprayed from a solution onto particles of an inert carrier in admixture with one or more pharmaceutically acceptable excipients that promote dissolution of the drospirenone and ethinylestradiol so as to promote rapid dissolution of drospirenone and preferably ethinylestradiol on oral administration."
"1. A pharmaceutical composition comprising, as a first active agent ….. (drospirenone) in an amount corresponding to a daily dosage, on administration of the composition, of from about 2 mg to about 4 mg, and, as a second active agent ….. (ethinylestradiol) in an amount corresponding to a daily dosage of from about 0.01 mg to about 0.05 mg, together with one or more pharmaceutically acceptable carriers or excipients.
2. A composition according to claim 1 wherein the drospirenone is in micronized form or sprayed from a solution onto particles of an inert carrier.
….
7. A composition according to any of the preceding claims wherein the pharmaceutically acceptable carrier or excipient is selected so as to promote rapid dissolution of the first and second active agents.
8. A composition according to any of the preceding claims wherein at least 70% of the first and second active substances are released within 30 minutes of administration thereof.
9. A composition according to claim 8, wherein at least 80% of the first and second active agents are released within 20 minutes of administration thereof."
"The section then goes on to describe a first aspect of the invention as relating to a combination formulation of DSP at a dose of 2 to 4 mg and EE at a dose of 0.01 to 0.05mg. This is the invention which is reflected in Claim 1 of the Parent Application. I shall call this "the dosage range invention".
"46. Thus far the skilled person would understand that it was advantageous to provide DSP in a form that promotes rapid dissolution because that in turn would promote rapid absorption and thus give less opportunity for degradation in the stomach or the intestine. This leads to "good" or "high" bioavailability. Two particular ways of achieving this are described, namely micronisation and spraying onto inert carrier particles."
"Insofar as this point relies on the 900 ml of water used in the dissolution test, it is met by the unconditional amendments, and falls away. The 3 mg point remains live (although it would be met by the conditional amendment application). Professor Buckton's evidence was, as one would expect, that the choice of a 3 mg tablet would yield a different dissolution rate to the choice of a 2 mg or 4 mg tablet. By deleting the reference to the loading of the tablet in the granted patent, Schering have changed the technical disclosure of the paragraph which became [17] in the granted patent. The original paragraph only contained a test for a 3 mg tablet. The test in the granted patent is not specific to any tablet, and suggests for the first time that any tablet loading which passes the test will do. That is additional matter relevant to the invention. The relevant conditional amendment will have to be made."
The 301 patent – disclosure
"A tablet comprising, as a first active agent drospirenone in an amount corresponding to a daily dosage, on administration of the tablet, of 3 mg, and as a second active agent, ethinylestradiol in an amount corresponding to a daily dosage of from about 0.015 mg to 0.03 mg, together with one or more pharmaceutically acceptable carriers or excipients, wherein at least 70% of said drospirenone is dissolved from said tablet preparation containing 3 mg drospirenone within 30 minutes, as determined by USP XXIII Paddle Method II using 900 ml water at 37°C as the dissolution media and 50 rpm as the stirring rate."
The 069 patent – disclosure
"A pharmaceutical composition comprising, ethinylestradiol and inert carrier particles containing drospirenone on their surface, wherein drospirenone is present in the composition in an amount corresponding to a daily dosage of from about 2 mg to about 4 mg; and ethinylestradiol is present in the composition in an amount corresponding to a daily dosage of from about 0.01 mg to about 0.05 mg, wherein at least 70% said drospirenone is dissolved from said composition within 30 minutes, as determined by USP XXIII Paddle Method II using water at 37°C as the dissolution media and 50 rpm as the stirring rate."
The added matter objection against the 301 patent
"The composition of the invention may be formulated in any manner known in the pharmaceutical art."
"When one turns to 301 as granted, references to "the invention" must now be taken as limited to a rapid dissolution form. Thus it is fair to note that [38], whilst unchanged from the text of the Parent Application, is now making a different statement from that which it made in the context of the Parent Application. It now says that the composition of the invention (i.e. rapid dissolution forms) may be formulated in any manner known in the art. When the invention related simply to dosage ranges, this did not imply anything about rapid dissolution or high bioavailability. It now says that rapid dissolution form may be formulated by any known method which achieves rapid dissolution. But that, in my judgment, was the clear disclosure of the Parent Application. In both cases the skilled person would understand the specification as teaching that any known way of achieving rapid dissolution would do. No matter is added in the granted text of 301 in this respect."
The added matter objection against the 069 patent
"The skilled person reading the Parent Application would understand that what was important was the finished composition. Once the DSP had been applied to the surface it does not matter how it got there. He would see spraying as an example of a process for getting it there, but not as an essential part of the invention of the product. [38] in the granted 069 is therefore merely making explicit that which was implicit in the Parent, namely that other methods of achieving application of DSP onto the surface, if they are known to the person skilled in the art, will do just as well. Accordingly, in my judgment, this objection is not made out."
Added matter – conclusion
Obviousness
Oelkers
[84] Oelkers was published in 1995. Oelkers was a scientist in the Endocrinology Department of the Freie Universität, Berlin. Other clinicians came from the Catholic University of Liege, Belgium. The final author, Heithecker, was from Schering's Department of Fertility Control and is one of the named inventors of the patents in suit.
[85] Oelkers describes a study in which three groups of 20 women received either: (A) 30µg/3mg, (B) 20µg/3mg, or (C) 15µg/3mg of EE / DSP and as a control (D) 30µg EE and 150µg levonorgestrel (Microgynon). The 3 mg/day dose of DSP used in each of the three groups was chosen to provide a safety margin over the threshold dose of 2mg. Body weight and blood pressure fell in the three test groups, but rose for the control group.
[86] The authors thought this to be the first report on a combined oral contraceptive that leads to a small decrease in body weight and blood pressure. They conclude by saying that:
"…it is conceivable that a combination [oral contraceptive] of this new type of progestogen may be of special benefit to women susceptible to weight gain and a rise in blood pressure."
[87] These findings were of significance because prolonged use of hormonal oral contraceptives can lead to small mean increases in body weight and blood pressure.
[88] Oelkers reveals that DSP was formerly called dihydrospirorenone. There is, however, no information about how to formulate it. The volunteers, it is to be inferred, were given the API in pill form.
Krause I
[89] Krause I was published in 1982, some thirteen years before Oelkers. It was published in the Journal of Chromatography, which, because of its essentially analytical content, is not a journal regularly read by formulators as part of their work. Krause and his co-worker Jakobs, a laboratory technician, were scientists working at the Department of Pharmacokinetics at Schering in Berlin. Krause I is not about contraception at all. In terms of the drug studied, its principal focus is spirorenone ("SP") which is an aldosterone antagonist (a type of drug for treating high blood pressure). It works as a diuretic, that is to say by eliminating excess water from the body.
[90] Here it is worth noting some chemistry which, though not part of the common general knowledge, could be readily discovered by a reader of Krause. SP and DSP are complex polycyclic molecules which differ only by the presence of an additional C-C double bond in SP in one of its constituent ring structures. The inactive isomer in each case is caused by the rearrangement of a ring at the opposite end of the molecule. There was no dispute that DSP and SP would be regarded as analogous compounds. Equally one cannot make any assumptions about the behaviour of a molecule merely because it has a similar structure.
[91] Krause reports that SP was currently under investigation in man using subjects with constant oral water loading. During the studies, plasma samples were withdrawn from the two male test subjects for analysis of the SP levels. SP was known from in vitro studies to isomerise in the stomach to a re-arranged compound which was inactive. Krause observed that if substantial amounts of this compound were found in blood, a formulation resistant to gastric juice would have to be developed. The aim was therefore to establish an assay procedure capable of detecting low plasma concentrations and which was able to separate the active and inactive isomers of SP.
[92] DSP (which Oelkers had pointed out was dihydro-SP) is a metabolite of SP. Krause detected the metabolite in his plasma samples.
[93] So far as the in vitro experiments are concerned, Krause reports that both SP and DSP undergo the isomerisation reaction in vitro. His graph shows that about half the SP is converted to inactive isomer in about 150 minutes and about half the DSP is converted in about 90 minutes.
[94] Krause does not expressly say whether these in vitro results are obtained at room temperature, although there is an indication that the chromatographic system was operated at that temperature. Professor Davies would have assumed that it was so operated in the absence of any other explanation. Professor Buckton did not really dispute this.
[95] In relation to these in vitro results he states that:
"…the process of re-arrangement was relatively slow compared to possible absorption rates in the stomach…"
[96] The analysis of the plasma samples from the two test subjects showed that inactive isomerisation product of SP:
"…was not detectable in the plasma, suggesting that the absorption process was much faster than the acid catalysed isomerisation of the drug."
[97] There are no express conclusions about the isomerisation product of DSP in plasma, although it is not visible in the relevant trace. For reasons which Professor Davies explained (see below), one would not expect it to be.
Krause III
[98] Krause III was published in 1982. Krause's co-authors on this occasion include clinicians from the Department of Internal Medicine at Schering. Krause III was published in the European Journal of Clinical Pharmacology. This is, again, not a journal which would be read regularly by formulators as part of their work.
[99] The aim of this further work was, firstly, to evaluate the pharmacokinetics of the drug (again as an aldosterone antagonist) in male test subjects who were not given the heavy oral water load. Secondly, the inactivation of SP by isomerisation was to be investigated in a larger number of volunteer males (thirteen instead of two). Thirdly, they were to follow the appearance of the active metabolite (believed to be DSP) after single and repeated doses.
[100] Krause concludes, once again, that the isomerisation product of SP could not be detected in the plasma in either 1 or 14 doses. He also observed that there was a distinct lag time of absorption, and that there was a problem with absorption at higher doses.
[101] There is no detail of the pharmaceutical formulation administered to the subjects, except that it is to be inferred that a macrocrystalline form was used. An express suggestion to use a micronised material in future is therefore made. Professor Davies infers, and I accept, that the use of macrocrystalline material would have restricted the scope for acid catalysed isomerisation to take place in the stomach.
(1) The skilled team (which would, it is common ground, include a skilled formulator and a skilled medicinal chemist) would read Oelkers. It discloses a combined oral contraceptive which would be of interest to the team because it may be of special benefit to women susceptible to weight gain and a rise in blood pressure. Oelckers had actually formulated pills of different doses and tried them with three groups of twenty women against a reference sample.(2) The team would decide that Oelkers was worth following up. Since Oelkers says nothing about formulation, the follow up would consist of the standard step of in vitro tests to see how soluble and stable the compounds were. The tests would be in what one can call "stomach conditions" i.e. at 370C and stomach acidity. The experts were agreed that they would do the tests themselves rather than see what the literature said about the matter.
(3) The experiments would show that within 45 minutes (within the mean residence time of a drug in the stomach) half the DSP would have isomerised (and thus rendered inactive).
(4) The team would then consider what to do about this. Only two routes were open: one would be to try an enteric coating (the usual method for protecting a drug from destruction by stomach acid so that it could reach the small intestine where it would be absorbed) or to disregard the apparent problem of an uncoated pill at this stage.
(5) The skilled team would also have done a literature search on DSP. This would produce only 11 papers, including those by Krause, concerned with spirorenone (SP).
(6) The skilled team would read Krause and learn that the observed in vitro isomerisation of SP was not replicated in vivo.
(7) So the skilled team would say to itself: "We wonder whether what happens with SP in vivo (admittedly with a macro-crystalline form of the drug and other differences) would also happen with DSP which is structurally very similar to SP. If it also survived in the stomach notwithstanding fast dissolution, then enteric coating (which might have its own problems) would not be necessary. It might work, so let's try."
(8) And that would lead them to the inventions of both patents.
[42] In the Court of Appeal, Jacob LJ dealt comprehensively with the question of when an invention could be considered obvious on the ground that it was obvious to try. He correctly summarised the authorities, starting with the judgment of Diplock LJ in Johns-Manville Corporation's Patent [1967] RPC 479, by saying that the notion of something being obvious to try was useful only in a case in which there was a fair expectation of success. How much of an expectation would be needed depended upon the particular facts of the case. As Kitchin J said in Generics (UK) Ltd v H Lundbeck A/S [2007] RPC 32, para 72:
"The question of obviousness must be considered on the facts of each case. The court must consider the weight to be attached to any particular factor in the light of all the relevant circumstances. These may include such matters as the motive to find a solution to the problem the patent addresses, the number and extent of the possible avenues of research, the effort involved in pursuing them and the expectation of success."
[150] The evidence in this case is unusual for another reason. It is common in a patent case, with all the benefits that hindsight brings, to have a clear explanation of how the invention works. Yet none of the witnesses proffered an explanation of why it was that DSP does not degrade in vivo when it does so rapidly in vitro. Mr Thorley proffered the suggestion that the in vitro result at pH 1 is at the extreme acid end of the pH observed in the stomach, and that actual conditions are milder. I do not think that this explanation would satisfy the skilled formulator working to the objectives that oral contraceptives require. It is certainly not one which was advanced with confidence by any witness. I think one has to be particularly aware of the dangers of hindsight in such a case.
Lord Justice Mummery: