T 0209/22 - Post-published data for sufficiency of second medical use claims

Key points

• "Appellant-opponent 2 contended that the clinical study described in document D21, which took place before the priority date of the patent in suit, constituted public prior use that anticipated the combination therapy according to claim 1 as granted. In a second approach, the appellant also argued that D21 itself (a written disclosure of the study protocol) anticipated the claimed subject-matter."
• The Board: "These objections must fail already because the study of D21 was a phase I study performed on healthy volunteers (i.e., not on patients suffering from COPD or asthma). The claim feature that requires attaining the claimed therapeutic effect in the treatment of COPD or asthma [] could not have been anticipated in such a context, simply because the study subjects did not suffer from COPD or asthma. Accordingly, neither D21 itself nor the alleged prior use based on D21 provide a basis for denying novelty. "
• Note that the Board's above remark seems to apply more broadly than the disclosure of study protocols at hand: even the results of the phase I study can not anticipate the therapeutic effect because they are results on healthy subjects in a phase I study. I will come back to this at the end of the post. 
• Turning from novelty to sufficiency: "For the requirement of sufficiency to be met, the claimed efficacy has to be credible at the effective date of the patent, i.e. on the basis of the information provided in the patent application together with the common general knowledge then available to the skilled person."
• The claim is a second medical use claim directed to the combination of two compounds, umeclidinium and vilanterol, for the treatment of COPD and/or asthma. 
• " A further study, in which a combination of umeclidinium bromide and vilanterol triacetate was administered to healthy volunteers, resulted in the finding that the combination was well tolerated and effective in providing bronchodilation, and in particular that it showed the largest difference relative to placebo (see the application as filed, pages 25 to 26). While no quantitative data or assessment of statistical significance in relation to the observed improvement ("largest difference") is reported, it may be concluded from this comparative statement that the combination was at least as efficacious as the monotherapies in providing bronchodilation, in a four-way crossover study with sixteen subjects."
• " Based on the information provided in the application as filed, there is thus a strong presumption that dual therapy with umeclidinium/vilanterol would be effective in the treatment of asthma or COPD, and that a dosage regimen of once-daily administration would be feasible. Both aspects would have been regarded as credible at the effective date."
• "The functional effect of bronchodilation is required in the treatment of both COPD and asthma. The claimed efficacy against asthma is, therefore, credible. The appellants have not established serious doubt in relation to the dual therapy's efficacy in relieving asthma."
• "The experimental set-up of the combination study on healthy volunteers described in the application as filed corresponds to the study set-up described in D21 [...]. The appellants [opponents]  submitted that, if D21 and the corresponding study, in the board's opinion, did not take away the novelty of the claimed subject-matter, then it followed that the combination study as described in the application as filed could not be regarded as enabling in support of the claimed therapeutic use."
• Note that D21 does not contain the results of the study; the application does, but only with healthy subjects.
• The Board: "different standards indeed apply. To be novelty-destroying, a prior-art disclosure must meet the standard of direct and unambiguous disclosure of the claimed subject-matter. This criterion was not met by D21 and the corresponding clinical study with regard to attaining the claimed therapeutic effect, because the study was performed with healthy subjects (see section 4 above). The study with healthy subjects as described on pages 25 to 26 of the application as filed likewise does not disclose attaining a therapeutic effect in the treatment of COPD or asthma patients."
• As a comment, it may be useful to distinguish in the context of novelty between "direct and unambiguous disclosure" (which is always met by a verbatim disclosure) and the additional requirement that the disclosure in the prior art must be enabling. This could also help to maintain a clear difference between Art.83 and Art. 123(2). In the alternative approach of the present decision, the phrase "direct and ambiguous disclosure" involves an aspect of enablement. 
• If we distinguish between disclosure and enablement, the proposed difference in standards is in the enablement factor. However, T 206/83, r.2, already emphasized that there should be a uniform concept of enablement in the EPC (I discussed this in my amicus brief in pending referral G 1/23). (Note a further component of novelty is the ''falling within the scope of the claim" rule; see my article in epi Information 4/2020).
• Because there is a difference between D21 and the application (only the application contains the results of the clinical trial, I understand), the Board seems to provide the remark about different standards as an obiter remark.
• "In the case in hand, the information presented in the application as filed is regarded as adequate for establishing sufficiency of disclosure, for the reasons given above. This conclusion is not exclusively based on the results observed in the study performed on healthy volunteers but on a combination of this with further data discussed in the application as filed [including document D3 that is discussed in the application, D3 is about monotherapy with one of the compounds, namely vilanterol] It is furthermore corroborated by post-published data"
• "Further corroboration is provided by post-published document D8, which shows that a combination product conforming to claim 1 ("ANORO") was indeed authorised in May 2014 for the treatment of COPD by once-daily administration (see D8: page 2, points 2 to 4.2 and page 15, point 9). D8 (see pages 9 to 11) also reports the supporting results of phase III clinical studies"
• Note G2/21 r.77: "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."
• "Starting from the disclosure of document D3, the objective technical problem may thus be formulated as providing a combination product comprising vilanterol and a specific anticholinergic agent for use in the treatment of COPD or asthma and which also facilitates patient compliance."
• The Board considers the solution to be not obvious: "At the relevant date, both vilanterol and umeclidinium were still in early stages of their pharmaceutical development. While the basis for proceeding with the pharmaceutical development of a compound is favourable preclinical data, this does not necessarily give rise to a well-founded expectation of success, even less in the case of a combination product when neither combination partner has, as yet, progressed to the clinical stage of development."
• "D3 does not disclose the practical implementation of monotherapy [with vilanterol] or combination therapy with vilanterol [and a further substance], which also means that efficacy and safety of the compound in actual patients had not yet been confirmed. On pages 99 to 100, preclinical results are summarised. "
• "While the authors in D3 assert that the proposed compounds are long-acting and "may be suitable for once-daily administration", there is no data in D3 to back up this claim, apart from the in vitro data discussed above. Thus, it cannot be verified that this assessment is more than speculation."
• As a comment, it seems that the Board would have found a second medical use claim directed to vilanterol monotherapy to be non-obvious over D3 (assuming that the claim also complies with Art. 83).
• As a comment, I understand there were no clinical results on the efficacy of vilanterol before the filing date. Yet, the second medical use claim is held to be sufficiently disclosed in this case, i.e., the therapeutic effect is credible, relying inter alia on the discussion of D3 in the application. D3 is the same document that the Board criticizes under inventive step (not verifiably more than speculation). It seems to me that the only results of Phase III clinical trials (i.e., with patients) for vilanterol were in the post-published document D8. 
• However, the present application added the results of the Phase I study in healthy subjects over the cited documents (D21 is only the protocol, and D3 contains only in vitro results). Yet, the Board also appears to indicate that even these results can not "anticipate" the second medical use claim (assuming, for the moment,  not even in combination with a verbatim disclosure of the claim).
• Hence, there appear to be two options to interpret the decision: (i) the results of the phase I study in the application as filed on healthy subjects were the critical difference of the technical teaching of the application and the prior art, or (ii), the term "credible" used in G2/21, r.74 and r.77 in connection with second medical use claims is not the same standard as "well-founded expectation of success" applied by this Board for obviousness of such a claim. Whether option (ii) is fine or problematic under the EPC is beyond the scope of this blog post. 
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EPO 

The link to the decision and an extract of it can be found after the jump.

https://www.epo.org/en/boards-of-appeal/decisions/t220209eu1

5.4 The board arrived at different conclusions, for the following reasons:

5.4.1 Vilanterol and umeclidinium are disclosed in documents D3 and D4, respectively, as potential agents for the treatment of respiratory diseases such as, in particular, COPD and asthma.

Both documents are referenced in the application as filed (see page 2, lines 19 to 27 and page 3, lines 1 to 5). The agents according to D3, including vilanterol, are identified in D3 as beta2-adrenoreceptor agonists having an advantageous profile of action with long duration (see D3: page 1, third paragraph; page 13, line 23 to page 15, line 1; supported by in vitro data on page 99), while the agents according to D4, including umeclidinium, are identified in D4 as muscarinic acetylcholine receptor antagonists (see D4: title; page 2, lines 17 to 26; claims 6 to 10).

5.4.2 On pages 23 to 25, the application as filed summarises the results of clinical studies that were performed in relation to umeclidinium or vilanterol monotherapy. In particular, it is mentioned that both compounds had been found to provide 24h duration of bronchodilatory action in COPD patients (see page 24, second paragraph, and page 25, first paragraph).

5.4.3 A further study, in which a combination of umeclidinium bromide and vilanterol triacetate was administered to healthy volunteers, resulted in the finding that the combination was well tolerated and effective in providing bronchodilation, and in particular that it showed the largest difference relative to placebo (see the application as filed, pages 25 to 26). While no quantitative data or assessment of statistical significance in relation to the observed improvement ("largest difference") is reported, it may be concluded from this comparative statement that the combination was at least as efficacious as the monotherapies in providing bronchodilation, in a four-way crossover study with sixteen subjects.

5.4.4 The studies described in the application as filed used the FEV1 parameter as relevant outcome measure. While the FEV1 parameter may not reflect improvements in all aspects of COPD (as argued by appellant- opponent 2), it was nevertheless accepted in the art and by regulatory authorities as indicative of relieving a patient's symptoms caused by bronchoconstriction (see D55: page 417, first paragraph and page 440, last paragraph stating that FEV1 is "[t]he universally used measure of lung function in clinical studies of COPD"). The fact that there may be a justified general interest in considering additional symptoms and complementary parameters (as also discussed in D55) is not sufficient to raise serious substantiated doubt about the suitability of FEV1 as an outcome measure for assessing the therapeutic efficacy of the claimed combination.

5.4.5 Based on the information provided in the application as filed, there is thus a strong presumption that dual therapy with umeclidinium/vilanterol would be effective in the treatment of asthma or COPD, and that a dosage regimen of once-daily administration would be feasible. Both aspects would have been regarded as credible at the effective date.

5.4.6 Further corroboration is provided by post-published document D8, which shows that a combination product conforming to claim 1 ("ANORO") was indeed authorised in May 2014 for the treatment of COPD by once-daily administration (see D8: page 2, points 2 to 4.2 and page 15, point 9). D8 (see pages 9 to 11) also reports the supporting results of phase III clinical studies, not only with regard to the FEV1 parameter, but also including favourable symptomatic and other outcomes.

5.4.7 The functional effect of bronchodilation is required in the treatment of both COPD and asthma. The claimed efficacy against asthma is, therefore, credible. The appellants have not established serious doubt in relation to the dual therapy's efficacy in relieving asthma.

5.5 The experimental set-up of the combination study on healthy volunteers described in the application as filed corresponds to the study set-up described in D21 (see points 5.4.3, 4.1 and 4.2 above). The appellants submitted that, if D21 and the corresponding study, in the board's opinion, did not take away the novelty of the claimed subject-matter, then it followed that the combination study as described in the application as filed could not be regarded as enabling in support of the claimed therapeutic use.

5.6 The board does not agree with this conclusion since the description of the combination study in the application as filed is not the sole evidence on which the board's conclusion on sufficiency of disclosure is based. Furthermore, different standards indeed apply.

5.6.1 To be novelty-destroying, a prior-art disclosure must meet the standard of direct and unambiguous disclosure of the claimed subject-matter. This criterion was not met by D21 and the corresponding clinical study with regard to attaining the claimed therapeutic effect, because the study was performed with healthy subjects (see section 4 above).

5.6.2 The study with healthy subjects as described on pages 25 to 26 of the application as filed likewise does not disclose attaining a therapeutic effect in the treatment of COPD or asthma patients.

5.6.3 However, it is the subject-matter of claim 1 that is to be assessed for sufficiency of disclosure. According to the terms of claim 1, the therapeutic effect is attained. The question to be considered under the issue of sufficiency is whether this was credible at the effective date. The required support is by no means restricted to the description of the combination study on pages 25 to 26 of the application as filed, but can be based on any pertinent content in the application as filed, in view of common general knowledge at the effective date.

5.6.4 For the requirement of sufficiency of disclosure to be met, it is not always necessary that attaining the technical effect in question should be disclosed directly and unambiguously in the application as filed (e.g., in the form of results of a clinical phase III trial demonstrating efficacy in the claimed therapeutic use). Rather, as stated in point 5.2 above, the applicable standard is that attaining the technical effect in question has to be credible. This has to be assessed according to the circumstances of each individual case.

5.6.5 In the case in hand, the information presented in the application as filed is regarded as adequate for establishing sufficiency of disclosure, for the reasons given above. This conclusion is not exclusively based on the results observed in the study performed on healthy volunteers but on a combination of this with further data discussed in the application as filed (see points 5.4.1 to 5.4.5 and 5.4.7 above). It is furthermore corroborated by post-published data (see point 5.4.6 above).

5.6.6 Hence, the appellants' argument according to point 5.5 above cannot succeed.

5.7 For these reasons, the ground of opposition under Article 100(b) EPC does not prejudice the maintenance of the patent as granted.