The Board of Appeal decision in T 0816/22 considered whether post-published phase III clinical trial data showing lack of efficacy can invalidate a second medical use patent that appeared plausible based on the data in the application as filed. The patent related to the use of a C1-esterase inhibitor for treating antibody-mediated rejection in kidney transplant patients. The Board of Appeal found that whilst early phase II data in the application as filed made the therapeutic effect credible (a.k.a. plausible), the later phase III trial results raised serious and substantiated doubts about whether the claimed treatment actually worked. The Board of Appeal concluded that the post-published data outweighed the early results in the application as filed and rendered the claims insufficient.
Legal Background: Sufficiency of disclosure for second medical use claims
Under established EPO practice, the assessment of sufficiency under Article 83 EPC requires that a skilled person be able to reproduce the claimed invention using the teaching of the patent application as filed and common general knowledge. For medical use claims, the application must make it plausible that the claimed therapeutic effect can be achieved. However, importantly, clinical trials are not necessarily required to establish plausibility. The disclosure requirement for medical use inventions may be satisfied by preclinical or early clinical data that makes the therapeutic effect credible, or even just a mechanistic explanation linking the observed effects to treatment of the disease . In a memorable case from last year, for example, a Board of Appeal upheld a patent for the therapeutic effect of “fish juice”, despite rather sketchy evidence for its efficacy .
However, even if the application makes the claimed therapeutic effect plausible at filing, previous decisions have indicated that post-published evidence may be used to demonstrate the insufficiency of the original disclosure. T 609/02, for example, found that whilst clinical trials are not required to support sufficiency, post-published evidence showing lack of efficacy may raise serious doubts about whether the invention can be performed. Critically, once such serious doubts are raised through post-published evidence, the burden shifts to the patent proprietor to dispel those doubts. Nonetheless, according to the same case law, the key date on which the sufficiency standard should be met is the date of filing. As indicated in T 609/02, post-published evidence may be taken into account, but only to back-up the findings in the application (Case Law of the Boards of Appeal, II-C-7.2.1).
Phase II promise vs phase III reality
The case in T 0816/22 concerned Takeda’s European patent EP3071219. The granted patent claimed methods of treating antibody-mediated rejection (AMR) in organ transplant patients using C1-esterase inhibitor (C1-INH). Specifically, the claims specified administering C1-INH at a dose of 5,000-20,000 units given in divided doses over 10-20 days for treating AMR in kidney transplant patients. The patent was opposed by CSL Innovation inter alia for lack of sufficient disclosure underArticle 83 EPC. While the Opposition Division initially upheld the patent in amended form, both parties appealed the decision.
The application as filed disclosed phase II data relating to Takeda’s C1 Esterase Inhibitor Cinryze, showing reduced chronic glomerulopathy (CG) in C1-INH treated patients compared to placebo. This evidence was however subsequently undermined by post-published phase III trial results for Cinryze showing no difference in transplant glomerulopathy between C1-INH and placebo groups after 6 months of treatment in a larger cohort of patients. The questions thus became whether the sufficiency of the claim should be judged in view of the evidence available at the filing or priority date, or whether the later evidence could undermine the plausibility of the claimed invention.
From plausible to insufficient
At Opposition, the OD found that the phase II data and mechanistic explanation provided in the application as filed made the claimed therapeutic effect plausible at the time of filing. However, on appeal this initial finding of plausibility was not enough to maintain the patent in the face of the clear evidence from a larger phase III trial showing no efficacy (NCT02547220). As summarised by the Board of Appeal, the post-published evidence showed “the complete absence of any therapeutic effect with the claimed dosage regimen. For the very parameter that was considered ‘a clinical marker of AMR in a transplant patient’ in the patent…[the post-published evidence] found no effect for a larger patient cohort” (r. 16).
The Patentee argued that beneficial effects might have emerged with a longer patient follow-up, but the Board of Appeal rejected this speculation. In its decision the Board of Appeal emphasised it was “not sufficient for the patent proprietor to refer to potential beneficial effects that might arise when following up with patients for a longer period of time”. The Board of Appeal concluded that “a phase III clinical trial with the same setup as the examples in the patent and using the dosage regimen which is an embodiment of the claim could not reproduce the claimed subject-matter…as it did not exhibit any efficacy after 36 months” (r. 16). For the Board of Appeal, this raised serious doubts about sufficiency that the patentee had failed to counteract. The Board of Appeal therefore revoked the patent in its entirety.
Final Thoughts
The Board of Appeal in this case arguably shifted the goal posts with respect to the sufficiency standard. The established case law is clear that sufficiency and plausibility should be considered in the context of application as filed and the common general knowledge of the skilled person at the filing date. However, it is difficult to unsee later evidence that an invention does or does not work. Provided with post-published evidence, a Board of Appeal will thus inevitably view the original disclosure with some benefit of hindsight. However, the reality is that most drugs will fail a phase III. Given the expected high failure rate of clinical trials in general, it is unclear why failure at phase III trial should therefore have the effect of undermining the plausibility of a claimed therapeutic effect assessed before the trial read-out.
The decision in T 0816/22 thus highlights a tension in EPO practice regarding second medical use patents. In contrast to regulatory approval, it is possible to obtain a patent for a new therapeutic based on preliminary data from pivotal clinical trials. However, the decision in T 0816/22 indicatesthat even a patent based on phase II data may be vulnerable to invalidation if subsequent clinical trials fail to support the claimed use. On the flip-side, if a patent application is not filed until pivotal clinical trial results become available, the outcome of early clinical trials may be cited as prior art against the patent.
Of course, one might point out that a patent for a treatment that doesn’t work at phase III is unlikely to have much value. From this perspective, filing your application early based on initial trial results, would seem to be the judicious course of action. If a claimed treatment effect is subsequently shown to work in pivotal trials, the application may be further supported by these data. If the drug in question is not proved to be efficacious in pivotal trials, a patent is of little value anyway. In the present case, the drug product to which the present case is approved for use for another indication and Takeda does not appear to be pursuing its use in kidney transplant patients. The failure of the phase III trial was known even before the opposition division decision. We can only speculate that Takeda continued to defend the case in order to keep their options open, perhaps hoping for some evidence of efficacy in long-term follow-up data.
The decision in T 0816/22 once again raises the question of whether we have the correct sufficiency/enablement standard for therapeutic use inventions and the prior art that may be cited against them. An obvious alternative to the unashamedly post-hoc approach to sufficiency taken by the Board of Appeal in T 0816/22 would be to apply the same sufficiency/enablement standard to therapeutic inventions and prior art disclosures as is required for regulatory approval.
This post is based on a previous article on IPKat.
