7.2.3 Evidence of therapeutic effect
Overview
7.2.3 Evidence of therapeutic effect
In G 2/21 (OJ 2023, A85) the Enlarged Board summarises the applicable principles in relation to therapeutic effects, mostly with reference to earlier case law, as follows.
The scope of reliance on post published evidence is much narrower under sufficiency of disclosure (Art. 83 EPC) compared to the situation under inventive step (Art. 56 EPC). In order to meet the requirement that the disclosure of the invention be sufficiently clear and complete for it to be carried out by the person skilled in the art, the proof of a claimed therapeutic effect has to be provided in the application as filed, in particular if, in the absence of experimental data in the application as filed, it would not be credible to the skilled person that the therapeutic effect is achieved. A lack in this respect cannot be remedied by post-published evidence." (G 2/21, point 77 des motifs).
The board in T 294/20 discussed the findings of G 2/21, notably in relation to the issue of proof and to which extent G 2/21 confirmed the existing case law. The board, adressing how the suitability may be derived from the patent or application, recalled a relevant passage from the leading decision T 609/02: "It is required that ... the claimed compound has a direct effect on a metabolic mechanism specifically involved in the disease ...". The appellants relied on decision T 950/13 to argue that such information may be in the form of a "plausible technical concept". However, the board considered that a "plausible technical concept" might not be stretched to include a mere hypothesis which had not to be supported by any evidence. Instead, the board confirmed the principles developed in decision T 609/02 that, "it is not always necessary that results of applying the claimed composition in clinical trials, or at least to animals are reported. Yet, this does not mean that a simple verbal statement [...] is enough to ensure sufficiency of disclosure [...]. It is required that the patent provides some information in the form of, for example, experimental tests, to the avail that the claimed compound has a direct effect on a metabolic mechanism specifically involved in the disease, this mechanism being either known from the prior art or demonstrated in the patent per se." (T 609/02, point 9 of the Reasons). The board stated that the burden to show the suitability was on the applicant (T 294/20 quoting G 1/03, OJ 2004, 413, point 2.5.3 of the Reasons). The board stated that this burden could not be discharged or shifted to the EPO or the public by merely alleging that a claimed therapeutic effect had to be regarded as having been demonstrated as long as it had not been disproven.
In T 979/23, as well as early parent case T 1779/21, the board noted that G 2/21 endorsed the conclusions in decisions T 609/02, T 754/11 and T 887/14. The expression "proof of a claimed therapeutic effect" in G 2/21, point 77 of the Reasons could not therefore be interpreted as a deviation from the established case law in the context of second medical uses; it does not apply a stricter requirement than the established case law prior to decision G 2/21. Rather, by referring in the same sentence to a particular situation in which "in the absence of experimental data in the application as filed, it would not be credible to the skilled person that the therapeutic effect is achieved", the Enlarged Board confirmed that means other than experimental data in the application as filed could establish proof of a claimed therapeutic effect. What was required, however, in the absence of experimental evidence, was for the patent or the application as filed to provide some information demonstrating that the claimed compound had a direct effect on a metabolic mechanism specifically involved in the disease, this mechanism being either known from the prior art or demonstrated in the patent itself (see T 609/02, points 5 to 9 of the Reasons). The board in T 1779/21 concluded that a contribution to the state of the art which enables the skilled person to carry out the invention had to be present in the application as filed.
The Enlarged Board construes the term "plausibility" differently compared with the earlier case law (see in particular points 72 and 92 of the Reasons). The Enlarged Board departed from the concept of "plausibility". It held that the term "plausibility" did not amount to a distinctive legal concept or a specific patent law requirement under the EPC, in particular under Art. 56 and 83 EPC.
The question is whether or not the skilled person, having regard to the disclosure of the patent and the common general knowledge at the relevant date of the application, would have considered that the compounds referred to in the claim are suitable to achieve the therapeutical effect (see T 609/02, point 9 of the Reasons). Or, in other words, whether it was plausible (or, in yet other words, whether it was credible) that the therapeutic effect could be achieved by the claimed composition (as recapitulated in T 966/18).
Either the application must provide suitable evidence for the claimed therapeutic effect or it must be derivable from the prior art or common general knowledge. The disclosure of experimental results in the application is not always required to establish sufficiency, in particular if the application discloses a plausible technical concept and there are no substantiated doubts that the claimed concept can be put into practice (T 950/13 citing ex parte case T 578/06 which related to proof that the technical problem had been properly solved to justify its wording as part of the assessment of inventive step; T 578/06, which summarises the notions of plausibility and post-published documents, is cited in G 2/21 (OJ 2023, A85), point 60 of the Reasons. The board in T 294/20 had to deal with the appellants' (patent proprietors') argument, relying on T 950/13, that such information might be in the form of a "plausible technical concept"; in this context the board (see present section supra) relied on and confirmed principles developed in T 609/02, and discussed the "plausible technical concept" in T 950/13.
Decision T 950/13 was cited by the respondent (proprietor) in T 25/20 in which the invention concerned methods and compositions for treating symptoms associated with Post-Traumatic Stress Disorder (PTSD) using Cyclobenzaprine. Claims 1 and 6 related to second medical uses of a composition comprising cyclobenzaprine. According to the respondent, the situation was analogous to that underlying T 950/13. In both cases, the application as filed did not contain experimental evidence. Nevertheless, in each case the mode of action of the drug was disclosed. Hence credibility of the technical concept should also be acknowledged in the present case. However, in the board's view the purported mode of action of cyclobenzaprine in the present case was not a mechanism at the molecular level which was of generally recognised importance for the disease or the symptom to be treated. Instead, the application as filed offered as support for the purported mode of action merely the known suitability of cyclobenzaprine for treating sleep disturbances associated with various conditions other than PTSD. This suitability alone was not sufficient to establish credibility in the present case because there were substantiated doubts about the purported mode of action and the technical concept based on it. This was different from T 950/13, in which the board did not identify such doubts.
A claimed therapeutic application may be proven by any kind of evidence as long as it reflects the therapeutic effect on which the therapeutic application relies (T 814/12, referring to T 609/02 in particular).
G 2/21, which ruled in particular on taking post-published documents into account for inventive step, states on the basis of the principle of free evaluation of evidence that evidence submitted by a patent applicant or proprietor to prove a purported technical effect relied upon for acknowledgement of inventive step of the claimed subject-matter may not be disregarded solely on the ground that such evidence, on which the effect rests, had not been public before the filing date of the patent in suit and was filed after that date (see points 90-91 of the Reasons).
In T 1210/20 the board found that the appellant's contention that according to the point 77 of the Reasons of G 2/21, proof of a technical effect was unconditionally required in the application as filed, was not correct. Rather, this paragraph refered to the requirement for proof in the application as filed in particular if it would not be credible to the skilled person that the claimed therapeutic effect was achieved on the basis of the application as filed. The corollary was that if a therapeutic effect was rendered credible by the application as filed, then such proof – in terms of concrete experimental data – might not be necessary. The board further explained that point 74 of the Reasons in G 2/21 was consistent with point 77 in that it does not state that proof in the application as filed is a requirement for sufficiency of disclosure to be acknowledged. In order to fulfill the requirements of sufficiency of disclosure, it was enough that the application as filed rendered the claimed therapeutic application credible.
Interpretation of G 2/21 -– in relation to Art. 83 EPC – as to whether proof such as experimental data is required in the application, can be found in T 1210/20 already mentioned and can also be found in the following decisions for example : T 1779/21, T 25/20, T 116/18 of 28 July 2023 date: 2023-07-28 (referring board's decision, points 11.12.3 and 11.12.3 of the Reasons), T 853/22; T 294/20 (also discusses the level of proof).
Regarding the limits of the applicability of G 2/21, see T 2037/22 (point 3.3 of the Reasons) in relation to a non-therapeutic effect. Indeed, the board in T 2037/22 (PBAT resin composition), addressed the issue of proof of a claimed technical effect which was not a therapeutic effect and stated that the (opponent) appellant's argument relying on G 2/21 was based on a generalisation of analysis made by the Enlarged Board which exclusively concerned the case law relating to claimed therapeutic effects; the Enlarged Board in G 2/21, however, did not make such a generalisation.
- T 0867/23
In T 0867/23 the board decided on the basis of the patent as granted (main request). Claim 1 was worded as a purpose-limited product claim in accordance with Art. 54(5) EPC. The treatment of "primary negative symptoms of schizophrenia" was a functional feature of claim 1.
The parties were in dispute regarding whether the application as filed made the claimed therapeutic effect plausible, and whether post-published evidence could be taken into account. The question was whether, on the basis of the evidence contained in the application as filed, cariprazine was demonstrated to have the claimed therapeutic effect on primary negative symptoms of schizophrenia.
In support of its reasoning, the board cited G 2/21 (point 77 of the Reasons), in which the Enlarged Board had explained that, in order to meet the requirement of sufficiency of disclosure, "[…] the proof of a claimed therapeutic effect has to be provided in the application as filed, in particular if, in the absence of experimental data in the application as filed, it would not be credible to the skilled person that the therapeutic effect is achieved. A lack in this respect cannot be remedied by post-published evidence..
In the board's view, this statement of the Enlarged Board did not set a new standard for reliance on post-published evidence in the context of sufficiency of disclosure, i.e. a standard which would depart from the previously cited case law summarised in G 2/21 (as noted in T 979/23). Following G 2/21, a reliance on post-published evidence was not ruled out generally in the context of sufficiency of disclosure for second medical use claims. The reliance on post-published evidence could also not be limited to situations in which it served no useful purpose, i.e. cases in which the effect was already convincingly proven in the application to such an extent that the use of post-published evidence, as a superfluous confirmation of the already proven effect, would be of no relevance. The board explained that, in other words, the scope of reliance on post-published evidence was not zero.
In the case in hand, the board considered that the application as filed contained experimental data reflecting an effect on primary negative symptoms of schizophrenia, and thus disclosed the suitability of cariprazine for the claimed therapeutic indication (see T 609/02). Under these circumstances, the board established that post-published evidence D13 could be taken into account to back up the findings in the application as filed.
The board found that D13 confirmed the findings of the patent, and showed improvements in negative symptoms while excluding indirect effects related to positive, depressive, or EPS (extrapyramidal) symptoms as causal factor. Accordingly, D13 supported the conclusion that cariprazine was effective on primary negative symptoms and refuted the appellants' objection that the improvement could relate to secondary negative symptoms. Therefore, the criteria of sufficiency of disclosure were satisfied.
- T 0816/22
In case T 816/22, the patent contained data from a randomised, double-blind, placebo-controlled pilot study to evaluate the safety and efficacy of Cinryze (C1 esterase inhibitor [human]) for the treatment of acute antibody-mediated rejection (AMR) in recipients of donor-sensitised kidney transplants.
The patent proprietor had alleged inter alia that for medical use claims, the patent had to disclose the suitability of the product to be manufactured for the claimed therapeutic application. Clinical trials were not required to establish such suitability.
According to the opponent, D54 (clinical trial results) represented the best available evidence concerning the efficacy of the claimed treatment and it demonstrated a complete failure to provide any therapeutic effect. The opponent alleged also that it could not be expected that an opponent had to conduct even more comprehensive clinical studies than a phase III trial in order to discharge its burden of proof of insufficiency. The disclosure of a patent was insufficient if the invention could not be reproduced across the whole breadth of the claims. Even a plausible disclosure of a therapeutic effect (which was missing in the present case) still had to be subject to refutation by evidence that the therapeutic effect was not in fact attained (which was provided by documents D15, D16 and D54), the standard of proof being "serious doubts, substantiated by verifiable facts".
In view of the small number of patients (clinical trial), the opponent considered that a treatment effect had not been demonstrated. The board, however, did not deem it necessary to establish this and instead started from the assumption that the opposition division was correct in finding that the experimental data provided in the patent, together with the mechanistic explanation provided, made it plausible (or credible) to the skilled person at the time of filing that a therapeutic effect on AMR could be achieved; however, this in itself was not enough to demonstrate that the invention was sufficiently disclosed if the opponent provided evidence which raised serious doubts that the therapeutic effect could indeed be achieved.
Post-published documents D15, D16 and D54 related to the phase III clinical trial. Due to the termination of the trial after 36 months, data was not collected, analysed and reported for any of the secondary endpoints related to efficacy (see D54). The patent proprietor argued that the termination of the trial was a commercial decision which did not mean that there was no therapeutic effect of any kind.
To the board, what was crucial was whether the skilled person, with the teaching of the patent in hand and applying common general knowledge, was able to reproduce the invention, i.e. to achieve a therapeutic effect on kidney transplant AMR when administering C1-INH intravenously using the dosage regimen indicated in the claim and identified in the presently discussed embodiment. The board agreed with the patent proprietor that therapy was not limited to completely curing a disease or condition, but also included alleviating, removing or lessening the symptoms of any disorder or malfunction of the human or animal body.
D54 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, D54 found no effect for a larger patient cohort. The board considered this sufficient to raise serious doubts based on verifiable facts that the claimed treatment achieved a therapeutic effect. In view of this evidence, 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.
In conclusion, a phase III clinical trial with the same setup as the examples in the patent and using the dosage regimen which was an embodiment of the claim could not reproduce the claimed subject-matter as exemplified in the embodiment under discussion as it did not exhibit any efficacy after 36 months. The patent proprietor had not dispelled the serious doubts regarding the presence of a treatment effect in view of these data. Therefore, the invention as claimed was not reproducible.