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England and Wales Court of Appeal (Civil Division) Decisions
You are here: BAILII >> Databases >> England and Wales Court of Appeal (Civil Division) Decisions >> Generics [UK] Ltd (t/a Mylan) v Yeda Research and Development Co Ltd & Anor  EWCA Civ 925 (29 July 2013)
Cite as:  RPC 4,  Bus LR 1329,  WLR(D) 316,  EWCA Civ 925
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ON APPEAL FROM THE HIGH COURT OF JUSTICE
The Hon Mr Justice Arnold
Strand, London, WC2A 2LL
B e f o r e :
LORD JUSTICE KITCHIN
LORD JUSTICE FLOYD
| GENERICS [UK] LIMITED t/a MYLAN
|- and -
|YEDA RESEARCH AND DEVELOPMENT CO. LTD
TEVA PHARMACEUTICAL INDUSTRIES LTD
WordWave International Limited
A Merrill Communications Company
165 Fleet Street, London EC4A 2DY
Tel No: 020 7404 1400, Fax No: 020 7831 8838
Official Shorthand Writers to the Court)
Andrew Waugh QC, Thomas Hinchliffe and Jeremy Heald (instructed by Bird & Bird LLP) for the Respondents
Crown Copyright ©
Lord Justice Floyd:
i) Certain claims of the patent are obvious over a publication known as Johnson 1994;
ii) The patent is invalid for obviousness on the basis of a lack of a technical contribution because:a) The specification does not make it plausible that the technical problem which it describes is solved by products falling within the claims;b) Alternatively that problem is not in fact solved by products falling within the claims.
iii) Mylan's product does not infringe because the copolymer does not conform to the claimed ratio of amino acids on a proper construction of the claims.
iv) If the patent is not construed as Mylan contend then it is bad for ambiguity-type insufficiency.
"the landmark study published in the prestigious New England Journal of Medicine, which established that the efficacy of [copolymer-1] that had been noted in the earlier studies was real. … This demonstration of efficacy was important and exciting and paved the way for the confirmation of [copolymer-1's] efficacy in a larger, more definitive, clinical trial study."
"Following these three provocative human studies, there was a long delay before further clinical study could be carried out with [copolymer-1]. In part this was due to difficulty in expanding drug production from a research laboratory to an industrial phase, which was undertaken by Teva Pharmaceutical Industries Ltd. the largest pharmaceutical company in Israel. It also proved difficult to develop a highly standardised preparation of [copolymer-1] that could be employed in further clinical trials."
"… in May 1995 the clinician would have known that the results of the Phase III trial had been announced at the ANA meeting and that results were positive, in that copolymer-1 reduced relapse rate and the accumulation of disability compared to placebo among relapsing-remitting MS sufferers. I am not satisfied that he would have known any further detail than that."
"A copolymer-1 fraction, wherein said fraction contains less than 5% of species of copolymer-1 having a molecular weight over 40 kilodaltons and wherein over 75% of said fraction is within a molecular weight range from 2 kilodaltons to 20 kilodaltons."
"copolymer-1 is a mixture of polypeptides composed of alanine, glutamic acid, lysine and tyrosine in a molar ratio of approximately 6:2:5:1."
"Example 1 consists of two sections. The first describes a chromatographic method of preparing "low-toxicity" copolymer-1. The second describes molecular weight analysis. In the first section, two batches of copolymer-1 are said to have been prepared by known methods, for example as in US 550. One of these batches was subjected to chromatographic separation, and a fraction with an average molecular weight of 7-8 kDa (referred to as "Batch A") was isolated.
The molecular weight analysis section states at  that the molecular weight distribution of the two batches was determined "on a calibrated gel filtration column (Superose® 12)" using a UV detector. The specification continues:
" Copolymer-1 batch A was found to have an average molecular weight of 7-8 kDa. 2.5% of this batch had a molecular weight above 32kDa but no copolymer-1 species present in this batch had a molecular weight of over 40kDa.
 The other batch of copolymer-1 which was not subjected to chromatography, had an average molecular weight of 12 kDa. 2.5% of the batch had a molecular weight above 42 kDa and 5% of the total copolymer-1 species in this batch had a molecular weight over 40 kDa."
Example 2 is described as a "toxicity analysis". Two assays were performed: (A) in vivo in a mouse lethality test and (B) in vitro in an RBL degranulation test.
The in vivo test involved dissolving the sample in distilled water at a concentration of 2 mg/ml. Five mice were used in each experimental group. Each mouse was injected with 0.5 ml of solution into the lateral tail vein and was observed for mortality and relevant clinical signs over a 48 hour period. If all the animals were alive with no adverse signs after 48 hrs, the batch was designated "non-toxic". If one or more mice had died or had shown adverse signs, the batch was labelled "toxic".
In the in vivo test, results for three batches of copolymer-1 are reported. These had an average molecular weight of 7.3 and 8.4 kDa (less than 2.5% copolymer-1 species over 40 kDa) and 22 kDa (more than 5% copolymer-1 species over 40 kDa). Both the 7.3 and 8.4 kDa batches were found to be "non-toxic". With the 22 kDa batch, however, three out of five mice had died after 48 hrs, so the batch was designated "toxic".
The in vitro test is introduced at . This passage explains that histamine (or serotonin) release from basophil is an in vitro model for immediate hypersensitivity. The RBL-2H3 cell line is said to have been developed as a sensitive, uniform and reproducible system, citing Basumian et al, Eur. J. Immunol., 11, 317 (1981). It is then said that degranulation can be induced by non-IgE mediated stimuli, including various peptides and synthetic polymers, citing Siraganian, Trends in Pharm. Sci., October 1983, 432. The passage concludes:
"The RBL degranulation test is, therefore, used in order to screen out those batches of copolymer-1 which evoke substantial degranulation and thus might elicit undesirable local and/or systemic side effects."
The test method is explained at . RBL-2H3 cells are loaded with tritiated serotonin and incubated with 100 µg copolymer-1. Batches which induce degranulation release serotonin which is detected with a scintillation counter. Percent degranulation is calculated as the percentage of serotonin released out of the total incorporated.
Four batches of copolymer-1 with average molecular weight 6,250 – 14,500 were analysed for both the percentage of species with molecular weight over 40 kDa and the percentage of serotonin release. The results were as follows:
[Diagram or picture not reproduced in HTML version - see original .rtf file to view diagram or picture]
The specification comments at :
"As can be seen, when the % of high molecular weight species is low (< 2.5), the % release of serotonin, indicative of toxicity, is low, and vice versa."
The skilled team
"Broadly speaking, it is agreed that the skilled team would comprise the following:
(i) Someone with an interest in the treatment of MS. This person is likely to be a clinician by training, although a clinical qualification may not be essential. For convenience I will refer to this person as "the clinician".
(ii) Someone with experience in assessing the adverse effects of drugs in both in vivo tests such as the mouse lethality assay and in vitro tests such as the RBL degranulation assay. This person is likely to be a toxicologist by training, although a toxicological qualification may not be essential. For convenience I will refer to this person as "the toxicologist".
(iii) A synthetic chemist with expertise in synthesising polydisperse polymers.
(iv) An analytical chemist with expertise in amino acid analysis.
(v) An analytical chemist with expertise in SEC."
Obviousness over Johnson 1994
i) If the clinician had taken an interest in the molecular weight information in Johnson 1994, he would have been confused by it and would have wondered whether there really had been a change in the molecular weight. Professor Schellekens had given evidence to that effect, and drawn attention to the fact that it was highly unusual for a change to be made to the active substance in the course of a series of clinical trials.
ii) The skilled person would have regarded the headline results as a good basis for further action.
iii) The best evidence for efficacy pending the publication of the full results of the trial was still Bormstein 1987.
iv) The 7 kDa material was further away from MBP in molecular weight than the higher molecular weight material, which fact might adversely affect efficacy.
v) To take two materials forward for further clinical study would have been costly.
"… even on the basis that the difference in molecular weight had been pointed out to him and that he took an interest in this information, it was Dr Coles' evidence that he would not have felt sufficiently informed about the Phase III trial to recommend development of 7 kDa rather than 14-23 kDa copolymer-1. In those circumstances, I consider that the clinician would not have concluded that the headline results provided a good basis for developing 7 kDa copolymer-1. Rather, he would want to see the full report in order to see if this shed any light on the reasons for, and significance of, the difference in molecular weight between the material used in Bornstein 1987 and that used in the Phase III trial."
"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."
Lack of technical contribution: legal issues
"To assess inventive step, the boards normally apply the "problem and solution approach". This consists essentially of:
(a) identifying the "closest prior art",
(b) assessing the technical results (or effects) achieved by the claimed invention when compared with the "closest state of the art" established,
(c) defining the technical problem to be solved as the object of the invention to achieve these results, and
(d) examining whether or not a skilled person, having regard to the closest state of the art, would have suggested the claimed technical features in order to obtain the results achieved by the claimed invention."
"2.4 …During the oral proceedings the Appellant argued that the only question arising under Article 56 EPC in the present case was whether or not, in the light of the above state of the art, a skilled person would have prepared, or tried to prepare, the claimed compounds of formula I (see point IV above), wherein R3 was optionally substituted phenyl. Article 56 did not expressly require, so he submitted, that the subject matter of a patent application had to solve a technical problem, and that, accordingly, the issue of inventive step had to be decided without regard to the solution of any technical problem.
2.4.1 Whilst the Board agrees with the Appellant that the above question is the one which has to be answered under Article 56 EPC, it does not agree with his inference that the existence of a technical problem and its solution, including the problem of proposing alternatives to known activities (e.g. chemical processes) or physical entities (e.g. chemical compounds), is irrelevant to answering this question and so deciding the issue.
2.4.2. The reason for this is, that it has for long been a generally accepted legal principle that the extent of the patent monopoly should correspond to and be justified by the technical contribution to the art (see T 409/91, OJ EPO , No. 3.3. and 3.4 of the reasons, and T 435/91, OJ EPO 1995, 188, reasons No. 2.2.1 and 2.2.2). Now, whereas in both the above decisions this general legal principle was applied in relation to the extent of the patent protection that was justified by reference to the requirements of Articles 83 and 84 EPC, the same legal principle also governs the decision that is required to be made under Article 56 EPC, for everything falling within a valid claim has to be inventive. If this is not the case, the claim must be amended so as to exclude obvious subject-matter in order to justify the monopoly. Moreover, in the Board's judgment, it follows from this same legal principle that the answer to the question what a skilled person would have done in the light of the state of the art depends in large measure on the technical result he had set out to achieve. In other words, the notional "person skilled in the art" is not to be assumed to seek to perform a particular act without some concrete technical reason: he must, rather, be assumed to act not out of idle curiosity but with some specific technical purpose in mind.
2.4.3 For this reason, the Boards of Appeal consistently decide the issue of obviousness on the basis of an objective assessment of the technical results achieved by the claimed subject-matter, compared with the results obtained according to the state of the art. It is then assumed that the inventor did in fact seek to achieve these results and, therefore, these results are taken to be the basis for defining the technical problem (or, in other words, the objective) of the claimed invention (which problem may, as already stated above, be to provide a further - or alternative - process or physical entity, here a group of chemical compounds). "
"2.5.3 This argument must, however, fail, since in the Board's judgment the answer to the question as to what a person skilled in the art would have done depends on the result he wished to obtain, as explained in point 2.4.2 above. If this result is only to be seen in obtaining further chemical compounds, then all known chemical compounds are equally suitable as the starting point for structural modification, and no inventive skill needs to be exercised in selecting, for instance, the compound of formula XIV of D3 for this purpose. …
It follows from these considerations that a mere arbitrary choice from this host of possible solutions of such a "technical problem" cannot involve an inventive step (see also e.g. T 220/84 of 18 March 1986, No. 7 of the reasons). In other words, the Board holds that, in view of the underlying general legal principle set out in point 2.4.2 above, the selection of such compounds, in order to be patentable, must not be arbitrary but must be justified by a hitherto unknown technical effect which is caused by those structural features which distinguish the claimed compounds from the numerous other compounds.
2.5.4 It follows directly from these considerations that a technical effect which justifies the selection of the claimed compounds must be one which can be fairly assumed to be produced by substantially all the selected compounds."
"12. The appellant filed post-published evidence … establishing that GDF-9 was indeed a growth differentiation factor. This cannot be regarded as supportive of an evidence which would have been given in the application as filed since there was not any. The said post-published documents are indeed the first disclosures going beyond speculation. For this reason, the post-published evidence may not be considered at all. Indeed, to do otherwise would imply that the recognition of a claimed subject-matter as a solution to a particular problem could vary as time went by. Here, for example, had the issue been examined before the publication date of the earliest relevant post-published document, GDF-9 would not have been seen as a plausible solution to the problem of finding a new member of the TGF-Beta superfamily and inventive step would have had to be denied whereas, when examined thereafter, GDF-9 would have to be acknowledged as one such member. This approach would be in contradiction with the principle that inventive step, as all other criteria for patentability, must be ascertained as from the effective date of the patent. The definition of an invention as being a contribution to the art, i.e. as solving a technical problem and not merely putting forward one, requires that it is at least made plausible by the disclosure in the application that its teaching solves indeed the problem it purports to solve. Therefore, even if supplementary post-published evidence may in the proper circumstances also be taken into consideration, it may not serve as the sole basis to establish that the application solves indeed the problem it purports to solve. "
"The specification did claim that a taxol coated stent would prevent restenosis and Conor did not suggest that this claim was not plausible. That would have been inconsistent with the evidence of its experts that taxol was just the thing to try. It is therefore not surprising that implausibility was neither pleaded nor argued. The same was true of the proceedings in the Netherlands (see paragraph 4.17 of the judgment)."
"The Court of Appeal upheld the judgment of Pumfrey J on the ground that the patent contained no "disclosure" saying that taxol was specially suitable for preventing restenosis. Again, I agree that the description, though offering a theory (its anti-angiogenic properties) as to why taxol would prevent restenosis, did not offer any evidence that this would turn out to be true. If it had not turned out to be true, the patent would have been insufficient. But there is in my opinion no reason as a matter of principle why, if a specification passes the threshold test of disclosing enough to make the invention plausible, the question of obviousness should be subject to a different test according to the amount of evidence which the patentee presents to justify a conclusion that his patent will work."
"Has the patentee made a novel non-obvious technical advance and provided sufficient justification for it to be credible? This is the basis of all the reasoning - see e.g. [2.4.2] of AgrEvo. A selection which makes a real technical advance in the art is patentable."
i) Article 56 of the EPC is in part based on the underlying principle that the scope of the patent monopoly must be justified by the patentee's contribution to the art;
ii) If the alleged contribution is a technical effect which is not common to substantially everything covered by a claim, it cannot be used to formulate the question for the purposes of judging obviousness;
iii) In such circumstances the claim must either be restricted to the subject matter which makes good the technical contribution, or a different technical solution common to the whole claim must be found;
iv) A selection from the prior art which is purely arbitrary and cannot be justified by some useful technical property is likely to be held to be obvious because it does not make a real technical advance;
v) A technical effect which is not rendered plausible by the patent specification may not be taken into account in assessing inventive step;
vi) Later evidence may be adduced to support a technical effect made plausible by the specification;
vii) Provided the technical effect is made plausible, no further proof of the existence of the effect is to be demanded of the specification before judging obviousness by reference to the technical effect propounded.
"In my judgment, however, these decisions represent the limits to which post-dated evidence may properly be put. In short, post-dated evidence may be relied on to confirm that the disclosure in the patent either does or does not make it plausible that the invention solves the technical problem. Post-dated evidence may not be relied upon either to establish a technical effect which is not made plausible by the specification in order to rebut an allegation of obviousness or to contradict a technical effect which is made plausible by the specification in order to found an allegation of obviousness. In my view it would be bizarre if, as counsel for Mylan submitted, a patent which at the time it was applied for disclosed what everyone thought was a good invention could be revoked 20 years later because subsequent advances in science had revealed that in fact the invention did not solve the technical problem. "
"It is hard to see how the notion that something is worth trying or might have an effect can be described as an invention in respect of which anyone would be entitled to a monopoly"
"On the other hand, if it is not possible to make such a prediction or if it is shown the prediction is wrong and the invention does not work with substantially all the products or methods falling within the scope of the claim then the scope of the monopoly will exceed the technical contribution the patentee has made to the art and the claim will be insufficient. It may also be invalid for obviousness, there being no invention in simply providing a class of products or methods which have no technically useful properties or purpose." (emphasis supplied)
"it would be bizarre if, as counsel for Mylan submitted, a patent which at the time it was applied for disclosed what everyone thought was a good invention could be revoked 20 years later because subsequent advances in science had revealed that in fact the invention did not solve the technical problem."
"Another important matter to consider is the reaction of experts at the time of the invention, both before and after."
"I confess I view with suspicion arguments to the effect that a new combination, bringing with it new and important consequences in the shape of practical machines, is not an invention, because, when it has once been established, it is easy to show how it might have been arrived at by starting from something known, and taking a series of apparently easy steps." (emphasis supplied)
The technical contribution propounded by the patent
Was the technical contribution made plausible by the specification?
Technical contribution in fact?
"These clinical trial analyses include up to 957 patients on Cop-1 compared to up to 642 patients on placebo. I believe this is enough to assess whether there is, in fact, a clinically meaningful difference between the local and systemic adverse effect profiles of the Earlier Cop-1 and the Later Cop-1. By "clinically meaningful difference", I mean a difference which will influence clinical decision-making. I conclude that there is no such clinically meaningful difference between the adverse effects profiles of the Earlier Cop-1 and the Later Cop-1 and that a reduction in molecular weight of Cop-1 from that used in the Bornstein 1987 and 1991 studies does not lead to a reduction in the adverse effects as the Patent claims."
"… it is necessary to distinguish between claims that are difficult to construe or that have a "fuzzy boundary" (in the words of Lord Hoffmann in Kirin-Amgen Inc v Hoechst Marion Roussel Ltd  UKHL 46,  RPC 9 at ) on the one hand from claims that are truly ambiguous on the other. It is regrettably common for claims to be difficult to construe, but the court will nevertheless strive to give such claims a sensible meaning having regard to the inventor's purpose. It is also common for claims to have a fuzzy boundary, because an integer of the claim involves some question of degree or an imprecise functional limitation. It is well established that is not itself objectionable. If a claim is truly ambiguous, so that it is unclear what is the correct test to determine whether or not a product or process infringes, however, then the claim is insufficient..."
"is the ratio of amino acids in the sample in question approximately 6:2:5:1, taking into account the variation that will arise in both amino acid analysis and the synthesis of copolymer-1"?
"The skilled team would consider that the word "approximately" was intended to cater for variations in both amino acid analysis and the synthesis of copolymer-1. They would proceed on the basis that the inventors might well be intending to allow for a level of error in analysis of greater than ±5%. As for the variability in synthesis, they would not think it was appropriate to take twice the variance in the analysis as marking the limit of compositions that could properly be regarded as constituting copolymer-1. They would take into account the effect of changes in molar ratio in terms of numbers of amino acids as shown by Prof Sampson's illustrations, and as a result would be inclined to accept a greater deviation in the proportion of tyrosine than in the case of the other amino acids. Accordingly, the skilled team would conclude that the claim was one that had a fuzzy boundary. It is therefore not possible to say precisely where that boundary lies. What can be said is that in my judgment the skilled team would not regard a relative difference in tyrosine of 29.6%, as in the case of batch GMA2, as taking the batch outside the claim. Furthermore, I do not consider that the claim is ambiguous."
"Based on the Patent alone, I understand 'approximately' to allow for the variability associated with the amino acid analysis technique and for the variability associated with the synthesis of the copolymer-1. I have explained above that if experimentally determined values for the composition of two samples differed by more than twice the variance [of the reproducibility of the amino acid analysis technique], then it is highly unlikely that the two samples have the same compositions. Therefore, I would understand 'approximately 6:2:5:1' to exclude any composition in which the molar fraction of any single amino acid differed by more than ± 10% from the calculated value of its molar fraction …"
|Exactly 6:2:5:1||US550 6:2:4.5:1||Teitelbaum Batch I/
|Teitelbaum Batch II
"the skilled reader would proceed on the basis that the inventors might well be intending to allow for more than a 5% error in amino acid analysis. If the skilled reader allowed for a 10% error in analysis, Prof Kent's own logic would lead to a 20% limit; and if he allowed for a 15% error, that would lead to a 30% limit.", and
"the skilled reader would appreciate from the Patent and his common general knowledge that copolymer-1 did not consist of a single species, but rather a random mixture of different species, and would note from Teitelbaum 1971 that two batches synthesised in an identical manner had appreciably different molar ratios."
Lord Justice Kitchin
Lord Justice Moses