Blockbuster blood thinning patent revoked
Mr Justice Meade has revoked Bristol Myers Squibb’s (BMS) European patent No. EP1427415 (EP’415) and corresponding supplementary protection certificate (SPC) that relate to the compound Apixaban (ELIQUIS) for lack of plausibility (Sandoz Limited, Teva Pharmaceuticals v Bristol-Myers Squibb Holdings  EWHC 822 (Pat). Apixaban (Eliquis) is used for thromboembolic disorders and is one of BMS biggest sellers.
The invalidity action against EP’415 for „Lactam-containing compounds and derivatives thereof as factor Xa inhibitors“ was brought by Teva and Sandoz, who were largely aligned in the attacks on the patent. BMS counterclaimed for infringement. BMS applied to amend to claims of EP’415 to include a requirement that the compound of the claim be either “a factor Xa inhibitor” (claim 7A) or “an effective factor Xa inhibitor” (claim 7B). Neither amendment cured the lack of plausibility so while Meade J held that claim 7A was formally allowable, he refused the amendment.
The Patent was published as WO 2003/026652 A1 (‘652) and summarised the invention as providing novel lactam-containing compounds that are useful as factor Xa inhibitors. The application contained a number of Markush formulae, which included a large number of compounds which were said to be useful as inhibitors of factor Xa and for the treatment or prevention of thromboembolic disorders. One section (page 170) contained a short passage stating: “Compounds tested in the [disclosed] assay are considered to be active if they exhibit a Ki of ≤10μM”. While the paragraph went on to define lower ranges of Kis as more preferred, it was accepted that these were aspirational targets and were not generated by tests done. There was no indication in the specification which or how many of the compounds were tested or with what specific results, and there was no reference to apixaban. Apixaban was given as one of 140 numbered examples.
Lack of plausibility is not itself a ground of revocation but can be alleged under the grounds of lack of inventive step or insufficiency. In this case, it was run as both Agrevo obviousness and insufficiency. Meade J reviewed the UK and EPO case law on the issue of plausibility and identified a number of key principles.
In Agrevo the Board of Appeal held that “the selection of such compounds 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…” Where the utility of the claimed compounds was not plausible [credible], the only technical contribution provided by the patentee was providing other compounds, which was not inventive. The Judge noted that in the context of an Agrevo-type objection, i.e., that there is no technical contribution at all, then the patentee ought to be able to overcome such objection by showing that there is some contribution. On the question of what it means for an invention to “work”, Meade J noted that this has to be determined from the specification where the claim is not explicit. The patentee may be able to rely on a more limited contribution than the most ambitious one claimed but this must be fact-dependent and will still have to find basis in the specification.
In Warner-Lambert the Supreme Court focused on the “patent bargain” – the extent of a patent monopoly as defined in the claims should correspond to the actual technical contribution to the art – as the foundation of modern patent law. Lord Sumption summarised a number of points about plausibility. First, that a proposition that a product is efficacious for the treatment of a given condition must be plausible. Second, it is not made plausible by a bare assertion to that effect, and the disclosure of a mere possibility that it will work is no better than a bare assertion. Third, the claimed therapeutic effect may well be rendered plausible by a specification showing that it was worth trying for a reason, e.g., reasonable scientific grounds for expecting it might work well. Fourth, although disclosure need not definitively prove the assertion that the product works for the designated purpose, there must be something that would cause the skilled person to think that there was a reasonable prospect that it would prove to be true. Fifth, such reasonable prospect must be based on a direct effect on a metabolic mechanism specifically involved in the disease, whether known from the prior art or shown in the patent. Sixth, the direct effect on a metabolic mechanism need not be by way of experimental data, it could be demonstrated by a priori reasoning. Seventh, sufficiency is a characteristic of the disclosure, and these matters must appear from the patent. This disclosure may be supplemented or explained by the common general knowledge of the skilled person. Reliance on post-filed data could in very limited circumstances be relied upon by the patentee but it cannot be a substitute for a lack of sufficient disclosure in the specification. Nor can a patentee rely on encouragement-plus-later-tests argument; something “worth trying” did not justify a patent monopoly. Meade J summarised these as underlying the principle that a contribution by the patentee that is in the specification is needed.
In Fibrogen the Court of Appeal, stated that it must be possible to make a reasonable prediction that the invention will work with substantially everything falling within the scope of the claim or, put another way, the assertion that the invention will work across the scope of the claim must be plausible or credible. The products and methods within the claim are then tied together by a unifying characteristic or a common principle. If it is possible to make such a prediction then the claim is not insufficient simply because the patentee has not demonstrated the invention works in every case. To apply the reasonable prediction principle, first one must identify what falls within the scope of the claimed class. Second one must determine what it means to say the invention works. Third, the Court must ask whether is it possible to make a reasonable prediction the invention will work with substantially everything falling within the scope of the claim. In considering this guidance from the Court of Appeal in Fibrogen, Meade J noted that the dispute in this action turned on step two, what it meant that the invention “works” and was more complex than the facts considered in Fibrogen.
The Judge noted that there was no requirement for a patentee to file data in an application in order to establish plausibility. As an example, an effect may be made credible from the structure of a compound, for example. In terms of what level of biological or therapeutic activity is required for the purposes of plausibility, the law requires a technical contribution of some, even if low, real significance.
Findings on plausibility
Meade J held that the PCT application did not make it plausible that apixaban would have factor Xa binding to any useful degree. There was no reference to apixaban that allowed the skilled person to infer it was one of the compounds for which useful results had been achieved, the fact a quantity (3g) had been synthesized did not assist the patentee and on the facts, no prediction could be made based on its structure alone. The Judge also observed that BMS’ case on prediction from structure relied entirely on CGK, which would not have represented a contribution by the patentee. While nothing in the CGK suggested apixaban would not bind effectively, there was no positive reason to consider that it might bind successfully. As the various applications for apixaban depended on factor Xa binding, the finding that there was no plausibility of any meaningful factor Xa binding meant the patent was invalid.
Meade J went on to consider the further arguments, in case he was wrong. He held that if it were the case that the PCT application had, in fact, made it plausible that apixaban had the degree of binding of 10μM, this would not make it plausible that it would be useful in therapy because it was accepted that nanomolar potencies were needed for that. The PCT application contained nothing to indicate that apixaban was selective for factor Xa as compared with other serine proteases. If the PCT Application had made plausible a level of factor Xa inhibition which could form the basis of an effective therapy, an omission to prove selectivity would not mean plausibility for therapy or overall efficacy could not be shown.
The Judge accepted that it would not have been difficult or burdensome to test apixaban for its factor Xa inhibitory activity, and that if such tests had been done a very good level of activity would have been found. In the absence of making some showing of plausibility, however, this did not help as this submission fell within the sort of encouragement-plus-ability-to-test that the Supreme Court rejected.
Although plausibility is not a term of art, it has become an increasingly important aspect of disputes about patentability over the past decade. As noted in the Judgment, the EPO Board of Appeal has referred the different strands of plausibility case law to the Enlarged Board of Appeal for guidance. This will hopefully provide important clarification, particularly around the reliance on post-filed data to support patentability during prosecution before the EPO. There is a difficult balancing act for Patentees who want to obtain protection for potentially valuable inventions at the earliest possible date but also need to ensure that the disclosure (whether by means of data or a priori reasoning) is good enough to make the scope of the invention claimed plausible. While the hurdle of plausibility is not high, it is clear that the UK Patents Court require a real contribution by the patentee that is in the specification. The role of post-filed data is strictly limited. Given the commercial pressures to file for patent protection, this is not always an easy task for patentees. The implications of not meeting the threshold of plausibility, however, can be serious in the context of the ability to recoup the substantial costs of bringing a medicinal product to market. Given the value of the patent and corresponding SPC to BMS, we would expect that they will seek permission to appeal.
 T 939/92 Agrevo/Triazoles
 §2.5.3 T 939/92 Agrevo/Triazoles
 Warner-Lambert v Generics  UKSC 56
 See para 37, Warner-Lambert v Generics  UKSC 56
 Fibrogen v Akebia  EWCA Civ 1279
 Referral is pending under G2/21 Sumitomo
This update was prepared by HGF Partner & Head of Law Rachel Fetches.