The Court of Appeal has rejected Mylan’s appeal against Arnold J’s first instance finding that Yeda’s European Patent (UK) No. 0 762 888 (the Patent) - which relates to a material known as copolymer-1 – was valid and would be infringed by Mylan's proposed generic product. Copolymer-1 is the active in a product which Teva (Yeda's exclusive licensee) sells under the brand Copaxone and, which is prescribed for the treatment of relapsing-remitting multiple sclerosis (“MS”). The decision is particularly interesting because, whilst the Court of Appeal reached the same conclusion as Arnold J, it disagreed with his approach to the issue of post-dated evidence in relation to obviousness.
We discussed Arnold J’s decision in our September 2012 bulletin.
Copolymer-1 is a synthetic polypeptide developed in the late 1960s by the Weizmann Institute of Science. It is a random copolymer made from four amino acids: alanine, glutamic acid, lysine and tyrosine. It is a mixture of different polypeptides of different lengths and different amino acid sequences.
The Patent relates to an “improved composition of copolymer-1” and claims the compositions themselves, their use in the treatment of MS and a method for making copolymer-1. Claim 1 is to “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".
The Patent explains that “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”.
Copolymer-1 had been the subject of a 1971 trial in relation to suppression of experimental allergic encephalitis (EAE) in animals where it had a molecular weight in the region of 23 kiloDaltons (kDa). It was subsequently the subject of a 1987 pilot clinical trial in relapsing-remitting MS which had led to an announcement, made with some degree of caution, that it might be beneficial in patients with such a condition. The material tested in that trial was of a molecular weight of 14-23 kDa. A further trial went ahead which led to a paper (Johnson 1994) and results that were announced at the annual meeting of the American Neurological Association. The Johnson paper recorded that co-polymer 1 had a molecular weight of approximately 7 kDa, i.e. much lower than that recorded in the earlier trials.
Mylan argued that, in the light of Johnson 1994 and the announcement at the ANA meeting (the latter being part of the general common knowledge), it would have been obvious for the skilled clinician to recommend development of copolymer-1 with a molecular weight as disclosed by Johnson 1994 (compared to the higher molecular weight disclosed in earlier works).
Arnold J had concluded that, even if a clinician had taken an interest in the molecular weight information in Johnson 1994, he (the skilled clinician) would have found it confusing and would have wondered whether there had in fact been a change in the molecular weight (Teva's expert had given evidence that it was highly unusual for a change to be made to the active substance in the course of a series of clinical trials). This factor, taken together with all the relevant circumstances, led Arnold J to conclude that the results reported in Johnson 1994 and at the ANA meeting would not have provided a sound basis for developing the 7 kDa copolymer-1. Floyd LJ, giving the judgment of the Court of Appeal, affirmed Arnold J’s finding, holding that there was “ample evidence” to support the finding that the 7kDA material was not an obvious candidate for further testing.
The Court’s upholding of Arnold J’s findings on obviousness is a reminder of the challenges faced by a party seeking to overturn a trial judge’s obviousness finding. As Floyd LJ observed (quoting the oft cited dicta of Lord Hoffmann in Biogen v. Medeva (1996)) “an appellant faces a significant hurdle in showing that a judge’s conclusion on the issue of obviousness should be disturbed on appeal where he has not gone wrong in principle.”
Lack of technical contribution
In addition to its conventional obviousness attack, Mylan argued that the Patent was obvious for want of a technical contribution. Such an obviousness attack has its roots in the EPO decision in AgrEvo (1996), a decision which has been endorsed subsequently by the UK Courts. The principle in AgrEvo was usefully summarised by Jacob LJ in Dr Reddy’s v. Eli Lilly (2010) (emphasis added): “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.” By parity of reasoning, a technical effect which is not rendered plausible by the specification may not be taken into account in assessing inventive step.
At first instance, Arnold J held that the technical contribution claimed in the patent lay in “the proposition that copolymer-1 as claimed caused (not might cause) less irritation at the injection site and/or a reduced incidence of systemic side effects.”
The Court of Appeal first considered whether the claimed technical contribution was made plausible by the specification and concluded that it was, holding that “The general trend disclosed by the results made it plausible that as a general proposition the claimed copolymer-1 was superior to copolymer-1 falling outside the claim…. The judge was entitled to reach the conclusion that it was made plausible that there was a connection between lower molecular weight and reduced toxicity and reaction.”
The thornier question for consideration was whether the invention had in fact made a technical contribution i.e. whether the lower molecular weight product of the claims was superior to the prior art copolymer-1. At first instance, Arnold J held that the evidence was inconclusive and that it was not possible to determine whether lower or higher molecular weight copolymer-1 caused fewer side effects or neither. In doing so, Arnold J had rejected the evidence of Mylan’s expert (Dr Coles) that the clinical trials demonstrated not merely that there was no evidence of a difference but that there was evidence of no difference. On appeal, Floyd LJ concurred with the trial judge that the clinical trial data was inconclusive and did not support a finding that there was evidence of no difference between the prior art formulation and the product claimed in the Patent.
At first instance Mylan contended that it was legitimate for the Court to take into account clinical data which post-dated the priority date of the Patent in assessing the question of technical contribution. Arnold J considered that such evidence was not admissible to contradict a technical effect made plausible by the specification (on the basis of “the fundamental principle … that whether a claimed invention is obvious or not should be judged as at the priority or application date”). However, he did go on to consider the post-dated evidence (perhaps recognising the likelihood of an appeal), albeit he held that such evidence did not support Mylan’s claim that the lower molecular weight copolymer-1 was no different to the prior art copolymer-1.
On appeal, Floyd LJ considered whether Arnold J was right to hold that the Court could not admit post-dated evidence. Floyd LJ did not dispute the “fundamental principle” enunciated by Arnold J observing that: “The evidence which is relied on to show that the invention was an obvious step for the skilled person to take must, plainly, be evidence which would have been available to the skilled person at the time. But in order to determine whether an invention is obvious at the priority date one needs to decide an anterior, and purely factual question: what is the invention?”
In considering whether post-dated evidence was therefore admissible, Floyd LJ made a preliminary observation that that there was no general principle that all the evidence on the issue of obviousness had to be evidence available at the priority date. For example, the Court could take into account “secondary evidence“ (e.g., the reaction of those skilled in the art to the invention) and evidence of subsequent commercial success.
Accordingly, Floyd LJ could not “see any principled objection” to evidence as to the true nature of the advance made by the invention being admitted observing that: “The problem and solution approach to obviousness requires the court or tribunal to judge inventiveness by reference to what it is that the invention brings with it: its technical effect or advance. Like any other fact relevant to an issue, however, it must be open to being refuted. In doing so one is not judging the obviousness of the claimed invention by reference to later evidence: one is simply defining by evidence what it is that the invention is or brings with it.”
In reaching the conclusion that such post-dated evidence was properly admissible Floyd LJ factored in the following:
- The problem and solution approach, by its very name, suggested it had to be shown that the patentee had in fact provided a solution to a problem.
- The underlying principle of the problem and solution approach was that the patentee’s monopoly had to be justified by his contribution to the art – this had to be one which existed in fact.
- If all the patentee had contributed was a plausible but untrue prediction, this would be the “very antithesis of a contribution”.
- In general, the greater the claimed technical contribution, the more difficult it will be for the party attacking the patent to show that the invention was obvious. Accordingly, it would be wrong in principle not to allow a challenge on the facts to the existence of the technical effect.
- There was support for this approach in the Court of Appeal’s decisions in Dr Reddy’s and Regeneron v Genentech.
Having set out at some length his views on the role of post-dated evidence it is curious that there was no explicit reference to such evidence in the Court of Appeal’s judgment. Rather, as noted, the Court held that the trial judge was right to find that there was no evidence to support Mylan’s claim that there was no difference between the “old” and the “new” copolymer-1. The reader can only assume that the Court of Appeal took into account the post-dated evidence relied upon by Mylan in reaching this conclusion.
The Court of Appeal went on to uphold the finding of infringement.
Arnold J had said that it would be “bizarre if … 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”. He also expressed concern that allowing a party to challenge a patent by post-dated evidence would place the burden of proof on the patentee to show affirmatively that the invention did solve the technical problem. Following the Court of Appeal’s decision, greater emphasis may now be put on post-dated evidence (such as the results of clinical trials), both in relation to arguments of insufficiency ( as discussed in our case note on Arnold J's decision in Lilly v Janssen) but also importantly in relation to whether the patent is invalid for lack of technical contribution.