Thursday, October 15, 2020 T 421/14 - Sufficiency for a composition with non-responders

No response for a subpopulation

How credible should evidence for a composition be? In this case, the opponent argued that the initial analysis of therapeutic efficacy lacked statistical significance. Only a post hoc analysis revealed a  significantly better response for a treatment group compared to a placebo group. Moreover, the effect only occurred in a subpopulation of responders, not for the general population. Is one allowed to claim a composition for a general group even if the majority are non-responders, or should one disclaim the non-responders?  

Another issue, was the public availability of two documents C30 and C31.  C30 was poster and C31 a slide show, both allegedly displayed at a public conference by the proprietor. Both were also included in the IDS statement for a corresponding US patent. Who should prove the public availability in this situation, and what is the appropriate standard?

A related case T 799/16 sharing some of its reasons with the present decision has also been decided. 

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Reasons for the Decision

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2. Sufficiency of disclosure - main request

2.1 The patent in suit seeks to provide a sustained-release oral dosage form of an aminopyridine, most preferably 4-aminopyridine (also called dalfampridine or fampridine), which can be used in the treatment of patients suffering from multiple sclerosis (see paragraphs [0001] and [0009] of the patent in suit and paragraphs [0002] and [0010] of the application as filed).

2.2 The independent claims of the main request specify a dosage regime involving twice-daily treatment with 10 mg of sustained-release aminopyridine, for increasing walking speed. The board considers that the wording of claim 11 does not introduce any limitation not already provided by the term "stable dose treatment" and by the specified dosage of 10 mg bid.

2.3 These claims all relate to a further medical use. According to the established case law of the Boards of Appeal, attaining the claimed therapeutic effect is regarded as a functional technical feature of such claims. In order to meet the requirement of sufficiency of disclosure of Article 83 EPC, the therapeutic efficacy of the composition and dosage regime for the claimed therapeutic indication must therefore be credible.

2.4 It was not in dispute that the person skilled in the art is capable of preparing sustained-release dosage forms of aminopyridines. All objections raised by the appellants with regard to sufficiency concerned the credibility of the alleged therapeutic efficacy. The respondent relied, in this respect, on the data and analysis of a clinical trial (the "MS-F202" trial), as presented in Example 5 of the application as filed.

2.5 Example 5 (see the application as filed, paragraphs [0101] to [0133], and the associated figures) relates to a phase 2, 20-week, double-blind, placebo-controlled treatment study in 206 subjects diagnosed with multiple sclerosis (MS), designed to investigate the safety and efficacy of three dose levels of sustained-release 4-aminopyridine. The dosages administered in this study during a 12-week stable-dose treatment period were 10 mg bid, 15 mg bid and 20 mg bid. The primary efficacy endpoint was an increase, relative to baseline, in walking speed on the "Timed 25 Foot Walk".

Non-responders

2.6 As acknowledged in the application as filed (see paragraph [0079]), it was known that only a proportion of patients, estimated to be about one third, responded to treatment with 4-aminopyridine. The existence of a population of non-responders was also confirmed by the inventors' own results reported in Example 5.

Aminopyridines are potassium channel blockers whose proposed mechanism of action is the restoration of conduction in demyelinated axons. Given the highly variable pathology of MS, only a proportion of MS patients would be expected to possess axons of appropriate functional relevance susceptible to this mechanism of action, which would explain the occurrence of non-responders (see the application as filed, paragraphs [0005] and [0079]).

Contrary to the appellants' view, the existence of non-responders is not a reason to deny sufficiency of disclosure, and the treatment of non-responders does not have to be excluded or disclaimed.

The existence of a substantial proportion of patients who are non-responders is a common phenomenon which is observed with drugs in many treatment areas, such as diabetes, migraine or cancer treatment. It is common practice to treat patients with a drug and change their medication should it turn out that they do not respond to the treatment.

If it can be shown that a relevant proportion of patients benefits from a treatment and that it has acceptable safety, the criterion of sufficiency of disclosure is met since the person skilled in the art has the necessary technical information to perform the treatment.

Therapeutic utility of 10 mg bid 4-aminopyridine ("fampridine")

2.7 As explained in the respondent's reply to the statements setting out the grounds of appeal (section 4) and in document C32 (figures), multiple sclerosis (MS) is a disease that is characterised by unusual variability in the occurrence of symptoms, with frequent episodes of relapse and remission being common. Progression of disability may occur, at variable rates, from onset or from a later stage, with or without plateau or remission phases. As a result of the fluctuating nature of MS symptoms, recognising the clinical benefit of therapies is particularly difficult. This is acknowledged in the application as filed (paragraph [0081]), which states:

"Given the often large variations in function experienced by people with MS, it is difficult for the subject or a trained observer to separate a treatment-related improvement from a disease-related improvement without the element of consistency over time. Consistency of benefit might therefore be expected to be a more selective measure of true treatment effect than magnitude of change".

2.8 According to the respondent, presumably due to these fluctuations, the pre-planned first analysis of the data obtained in the clinical trial of Example 5 for the primary efficacy endpoint (percent change in average walking speed during the 12-week stable-dose period relative to baseline) did not show statistically significant differences between any of the 4-aminopyridine groups and the placebo group (see paragraphs [0103], [0114] and Figure 3 of the application).

That was also the case for a second approach (the "protocol-specified responder analysis"), which identified successful response for each subject as improvement in walking speed (percent change from baseline) of at least 20% (see paragraphs [0104], [0115] and Figure 4 of the application).

2.9 To overcome this difficulty, and following the rationale explained in point 2.7 above, the inventors introduced an adapted evaluation method which focused on the consistency of response rather than the intensity of response to the drug (the post-hoc responder analysis).

This post-hoc analysis identified likely responders as subjects exhibiting a faster walking speed for at least three of five assessment visits during the double-blind stable-dose treatment period as compared with the maximum value observed among a set of five non-treatment visits - four before treatment and one after discontinuation of treatment (paragraph [0105] of the application). Furthermore, the proportions of subjects meeting this criterion in the pooled fampridine groups and in the placebo group were compared.

2.10 This analysis revealed the existence of a subset of subjects who responded to the drug with clinical meaningfulness (paragraph [0120] of the application). The number of subjects who met the post-hoc responder criterion in the pooled fampridine-treated group was 58 (36.7%) versus 4 (8.5%) apparent "responders" in the placebo-treated group, and this difference was statistically significant (p<0.001) (paragraph [0122] and Figure 8). The post-hoc responder rates based on consistency of improved walking speed were significantly higher in all three active-dose groups (35%, 36% and 39%) compared to placebo (9%; p<0006 for each dose group, adjusting for multiple comparisons) (see paragraph [0121] and Figure 7). The mean improvement in walking speed for the fampridine responders was more than 24% (paragraph [0107] and Figure 10). No notable differences in efficacy were found between 15 mg bid and 10 mg bid among responders (see paragraph 0132]). It was also reported that serious adverse effects did not occur in the 10 mg bid group (paragraph [0133]).

2.11 While the appellants, referring to the results summarised in point 2.8 above, disputed that therapeutic efficacy had been demonstrated, the board considers that the explanation for the initial finding of lacking statistical significance, the rationale given for the post-hoc methodology and the respective results presented in Example 5 of the application (see points 2.9 and 2.10 above) are convincing and are also sufficient to have rendered the alleged therapeutic efficacy and safety of 4-aminopyridine at 10 mg bid credible on the effective date of the patent.

Therapeutic efficacy across the scope claimed

2.12 The data presented in the application as filed and the corresponding passages of the patent in suit only relate to 4-aminopyridine, but not to other aminopyridines. Without experimental data it is indeed not possible to ascertain whether the specific dosage of 10 mg bid would be acceptably effective and safe in the case of other aminopyridines. The appellants' already plausible objection in this regard was further substantiated by the findings of document C16, which provides a direct comparison between 4-aminopyridine and 3,4-aminopyridine.

The authors of C16 reported that 4-aminopyridine had a more favourable toxicity profile and was also more effective than 3,4-aminopyridine, including for ambulation (see C16: page 1136, "Results" and "Conclusion"; and page 1139, column 2, lines 1 to 19). While the capsules used according to C16 were immediate-release rather than sustained-release formulations, this does not render the comparison meaningless for the present purpose, since both drugs were administered in immediate-release form and a considerable difference in efficacy was observed. In the studies described in C16, the daily doses of 3,4-aminopyridine were twice as high as the doses of 4-aminopyridine (see C16: second page, "Patients and Methods", last sentence, indicating that identical capsules containing either 5 mg 4-aminopyridine or 10 mg 3,4-aminopyridine were used). The mean daily doses of 4-aminopyridine and 3,4-aminopyridine were 23 mg (range 10 to 35 mg) and 46 mg (range 20 to 70 mg), respectively (see C16: page 1138, column 1, first paragraph).

These are valid reasons why the dosage regime of 10 mg bid cannot simply be extrapolated to further aminopyridines.

Conclusion

2.13 For the reasons set out in point 2.12, the subject-matter of the independent claims of the main request is insufficiently disclosed within the meaning of Article 83 EPC, as far as the scope covering aminopyridines other than 4-aminopyridine is concerned.

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5. Admission of documents C30 and C31

5.1 Documents C30 and C31 were filed, for the first time, by appellant-opponent 1 with its statement setting out the grounds of appeal, in conformity with Article 12(1) and (2) RPBA. Pursuant to Article 12(4), second clause, RPBA, these documents are thus, as a rule, to be taken into account in the appeal proceedings.

5.2 Pursuant to Article 12(4), first clause, RPBA, the board has the discretionary power to hold evidence to be inadmissible which could (and should) have been presented in the proceedings at first instance.

5.3 However, the argument that C30 and C31 had been available to the appellants at an earlier time did not constitute a compelling reason for the board to hold these documents inadmissible pursuant to Article 12(4) EPC.

6. Admission of document C27

6.1 The opposition division did not admit late-filed document C27 into the proceedings, since its prior-art status was in dispute and no evidence regarding this issue had been presented by the opponents (see the decision under appeal, point 5 of the Reasons).

6.2 The document was re-submitted by appellant-opponent 1 with its statement setting out the grounds of appeal, in conformity with Article 12(1) and (2) RPBA, together with evidence regarding its publication. In these appeal proceedings, the respondent did not dispute the public availability of C27 on the effective date of the patent and did not maintain the objection against its admission. Hence, the board saw no reason for holding C27 inadmissible pursuant to Article 12(4) RPBA.

7. Public availability of documents C30 and C31

7.1 Relying on documents C30A and C38 (see P308 on pages 25 and 48) inter alia, the appellants contended that the poster C30 and the slide presentation C31 (both undated) had been presented to the public at the 7th Annual Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis and 18th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS) which took place in Baltimore, Maryland (USA) on 18-21 September 2002, i.e. before the effective date of the patent in suit.

7.2 C30 and C31 are identical to references CC15 and CC16 listed in document C30A ("List of References cited by Applicant"), which mentions that these were presented at the ACTRIMS/ECTRIMS conference in September 2002. The respondent itself filed both documents at the US Patent and Trademark Office (USPTO) in 2012 (see C30B and the reply to the statements setting out the grounds of appeal, footnote on page 13), together with the document list C30A, as part of an Information Disclosure Statement (IDS) for the case file of US application number 11/102,559 (see the respondent's letter dated 30 September 2016, point 1.4). The documents were downloaded by appellant-opponent 1 from the USPTO's online register (PAIR).

7.3 The respondent disputed, however, that the content of C30 and C31 was indeed identical to what was presented at the ACTRIMS/ECTRIMS conference.

According to the respondent, these documents had been filed at the USPTO years after the conference in question. At that point in time, it was not known beyond reasonable doubt to the US attorney who wrote C30B (the accompanying letter submitted to the USPTO together with C30A, C30 and C31) whether C30 and C31 really had been presented at the conference of 2002.

As explicitly stated in document C30B, identification of the references in C30A was not meant to be construed as an admission that they were prior art.

Furthermore, C30B included the following statement:

"On information and belief, after reasonable inquiry, the poster and slide presentation listed as References CC15 and CC16, respectively, in the attached List of References Cited, were presented at the ACTRIMS 7th Annual Conference and ECTRIMS 18th Congress on September 18-21, 2002. Applicants reserve the right to correct this information should further information show such correction is warranted."

The respondent also argued that, while there was no evidence from the appellants to show that C30 and C31 were an accurate description of what was disclosed at the ACTRIMS/ECTRIMS conference, the appearance and inaccurate content of C30 and C31 suggested that they were not the visual aids actually used at the conference.

Furthermore, the respondent contended that the presentation of slides or of a poster in both cases also involved an aural element. It could not be established what an audience would have understood in each case in the light of the oral discussion with the presenter.

7.4 It was a disputed subject among the parties what standard of proof was required regarding the public availability of documents C30 and C31.

7.5 According to the case law of the Boards of Appeal, the usual standard of proof is the overall balance of probabilities.

7.6 The stricter standard of proof "beyond all reasonable doubt" has been used, exceptionally, in cases of public prior use where all the supporting evidence lay within the power and knowledge of the opponent. (The issue of public prior presentation of posters or slides has, as a rule, been assessed in line with the requirements for public prior use).

In these appeal proceedings, that condition is not fulfilled since C30 and C31 alleged to be public prior disclosures are the patent proprietor's (respondent's) own documents.

7.7 The respondent also argued that both C30 and C31 involved "ephemeral" oral presentations and that, therefore, the standard of proof for ascertaining the content of the oral disclosure must be higher (see decision T 1212/97, point 2 of the Reasons).

The board considers that, at least in the case of the poster C30, this argument is not convincing, since the disclosure relied on by the appellants is the printed and therefore "fixed" content of the poster displayed, whereas T 1212/97 cited by the respondent deals with the alleged information content of an orally delivered lecture (without a written complement in the form of a script, handout or later publication).

7.8 The question of whether citing a reference in an IDS is, as a matter of principle, an acknowledgement that it is prior art is irrelevant to the issue under discussion. What is more relevant is that the respondent explicitly stated in C30B that to the respondent's best knowledge ("on information and belief and after reasonable inquiry"), C30 and C31 (designated "CC15" and "CC16" in C30A) were presented at the ACTRIMS/ECTRIMS conference of 2002.

7.9 In the case of the poster C30, the respondent's own statement in C30B leaves little room for doubt that this poster was indeed displayed, whereby the entirety of the information printed on the poster was disclosed to the public. In this situation, it was for the respondent to show that this was not the case.

7.9.1 The respondent did not provide first-hand evidence from witnesses, in particular the presenters themselves, regarding the actual printed content of the poster presented at the ACTRIMS/ECTRIMS conference. Instead, the respondent's argument is based on circumstantial evidence. Pointing out certain errors in the technical content of document C30 as well as typographical and formatting errors, the respondent contended that such errors were not expected to occur in a presentation by professional scientists and that the poster therefore could not have been presented in the version shown in C30. C30, retrieved at a later point in time, might simply have been a draft.

7.9.2 This argument is speculative and not persuasive, even less so since it is the respondent itself which should know the exact circumstances. The board also notes that the respondent never retracted its statement in C30B. As a consequence, on the overall balance of probabilities, the poster C30 is considered to form part of the prior art.

7.10 The situation is different in the case of C31, due to C31 being a slide presentation. Slides are typically used as the basis of an oral presentation. No evidence is on file from which it may be inferred that the slides of C31 were handed out in printed form at the conference, or that all of the slides were shown to an audience. There is no evidence regarding the manner or speed of the oral presentation. The printed content of the slides alone is insufficient for establishing what precisely the members of the audience would have understood, and retained, from an oral presentation at the ACTRIMS/ECTRIMS conference during which all or some of the slides of C31 may have been shown. Hence, and irrespective of the standard of proof applied, the content of C31 cannot be considered to be prior art.

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This decision T 0421/14 (pdf) has European Case Law Identifier:  ECLI:EP:BA:2019:T042114.20190903. The file wrapper can be found here. Photo obtained  via PixaBay under the Pixabay license (no changes made).