T 1433/14 - Plausibility strikes again (Influenza vaccine)

Key points

•  "[If] it becomes apparent that a purported technical effect is not achieved by all of the claimed subject-matter, for instance because it is not plausible that the claimed subject-matter actually achieves the purported effect [...], then the problem cannot be considered as having been solved (see point 10. above). In such a case the technical problem is reformulated in a less ambitious way and the obviousness of the claimed solution to that reformulated problem in the light of the cited prior art is assessed" 
•  "the patent itself contains no evidence of any kind, in the form of results from either in vivo or in vitro experiments or otherwise to show that any "Replikin" peptide, and in particular a peptide of SEQ ID NO: 141, is capable of acting as a vaccine against H1N1 influenza virus." 
• "The fact that the so-called malignin peptide of the sequence "YKAGVAFLHKKNDIDE", derived from a brain cancer protein, is able to elicit antibodies in rabbit and that these are cytotoxic to cancer cells in vitro [..] would not be considered generalisable to the present case by the skilled person, since this evidence relates to a different disease (cancer) and a different immunogen" 
•  " the board concludes that at the relevant date of the patent, the skilled person would not have considered it credible that the peptide of SEQ ID NO: 141 could be used as a vaccine against any influenza virus" 
• " In view of the conclusion [] above, the evidence in post-published documents D11, D16, D17, D18, D23, D23a, D29, D30, D47, D55 and D56, all submitted to show that the claimed subject-matter indeed has the technical effect ascribed to it in the patent, cannot be taken into account in the assessment of inventive step." 
• The medical use claims (first medical use claims) are insufficiently disclosed for the same reason.

EPO T 1433/14 - link

Reasons for the Decision

1. The appeal complies with Articles 106 to 108 and Rule 99 EPC and is therefore admissible.

Admission of documents D44 to D57 and D60 to D65 into the proceedings - Article 13(1) RPBA

2. None of the above mentioned documents were relied on by the board in reaching its decision and they were not referred to by the parties in their relevant submissions. Consequently, the board did not decide on the admission of these documents.

Admission of auxiliary requests I to III into the proceedings - Article 12(4) RPBA

3. The board has the power to hold inadmissible facts, evidence or requests which could have been presented or were not admitted in the first instance proceedings (Article 12(4) RPBA). Auxiliary requests I to III were all filed with the statement of grounds of appeal. The board is persuaded by the appellant's arguments that they could not have filed them in the first instance proceedings because they were not prepared for the focus on plausibility in the context of the discussion of inventive step, in view of the fact that this topic was not mentioned in the summons to oral proceedings. The board therefore decided to admit these requests.

[...]

Main request and auxiliary requests I to III - claim 1

5. Claim 1 of auxiliary request III is for a peptide which "has" the amino acid sequence of SEQ ID NO: 141 ([...]).
The claim further states that the peptide is an "isolated or synthesized H1N1 influenza virus Replikin peptide from a hemagglutinin protein wherein said peptide consists of 7 to 50 amino acids comprising (1) at least one lysine residue located six to ten residues from a second lysine residue; (2) at least one histidine residue; and (3) at least 6% lysine residues".

[...]

7. The following considerations concern a peptide consisting of SEQ ID NO: 141 and affect all claims encompassing this peptide, either as the sole subject-matter or as an embodiment.

Inventive step - Article 56 EPC

8. In assessing whether or not a claimed invention meets the requirements of Article 56 EPC, the boards of appeal apply the "problem and solution" approach.

9. This approach involves (a) identifying the "closest prior art" by taking into account the general purpose of the invention, (b) assessing the difference between the closest prior art and the claimed invention and determining the technical effects of that difference, (c) defining the technical problem as one which aims at achieving these effects and, finally, (d) determining whether or not the skilled person would have considered the claimed subject-matter as an obvious solution to this technical problem, having regard to the state of the art within the meaning of Article 54(2) EPC.

10. Thus, one step of the "problem and solution" approach is the determination of the technical effect of the invention in relation to the closest prior art. This effect is then taken into account when formulating the objective technical problem. It is determined on the basis of the disclosure in the patent application or patent and takes into account whether or not the effect is achieved by substantially all embodiments of the claimed subject-matter, to ensure that claimed subject-matter can be considered as representing a solution to this problem as being solved by the claimed subject-matter (see decision T 939/92, reasons 2.6).

11. It is also established practice of the boards to begin the assessment of inventive step with the technical effect/technical problem ascribed to the claimed subject-matter in the patent application or the patent. However, if it becomes apparent that a purported technical effect is not achieved by all of the claimed subject-matter, for instance because it is not plausible that the claimed subject-matter actually achieves the purported effect (see Case Law of the Boards of Appeal of the European Patent Office, 8th edition, I.D.4.2), then the problem cannot be considered as having been solved (see point 10. above). In such a case the technical problem is reformulated in a less ambitious way and the obviousness of the claimed solution to that reformulated problem in the light of the cited prior art is assessed (Id., I.D.4.4.1).

12. In the present case, the appellants argued that the peptide of claim 1 has the technical effect that it could be used as a vaccine against H1N1 influenza virus infection, as supported by the disclosure in the application in the following ways:

i) a sequence motif consisting of 7 to 50 amino acids comprising (1) at least one lysine residue located six to ten residues from a second lysine residue; (2) at least one histidine residue; and (3) at least 6% lysine residues which was termed a "Replikin" was identified (see paragraph [0005] of the patent).
ii) the "Replikin" count in H1 hemagglutinin proteins was correlated to the occurrence of influenza epidemics and pandemics and thus an indicator of these epidemics and pandemics (see paragraph [0032] of the patent). Table 4 listed the H1N1 virus-derived hemagglutinin "Replikin" sequences in order of frequency of occurrence, i.e. those found in viruses in more years were higher in the table.
iii) the peptide "SEQ ID NO: 141" was in the seventh position in Table 4, which showed that it was very likely to be useful as a protective vaccine.
iv) the general usefulness of peptides comprising a "Replikin" sequence for vaccination was demonstrated by the brain cancer cell-derived peptide malignin, having the sequence "YKAGVAFLHKKNDIDE" (see paragraph [0020] of the patent).
v) the fundamental structure-function relationship of a "Replikin" sequence of an H1N1 virus-derived hemagglutinin protein was such that each and every hemagglutinin Replikin" sequence which was H1N1 virus-derived could be used for vaccination (see paragraph [0074] of the patent).

13. The board is not persuaded that the skilled person, when reading these disclosures in the light of the common general knowledge in the art, would consider it plausible that the peptide of claim 1 can be used as a vaccine at all and in particular, as a vaccine against H1N1 influenza virus infection.

13.1 In fact, at paragraph [0030], the patent discloses that the "Replikin" amino acid sequence count or concentration in the hemagglutinin protein may be correlated to influenza epidemics and pandemics and thus act as an indicator of these and pandemics. This is also true for the peptide of SEQ ID NO: 141, since Table 4 lists individual peptides according to the frequency of their occurrence in influenza epidemic years.

14. However, there is no evidence either in the patent or in the state of the art that there is a link between the above mentioned disclosure and the ability of any "Replikin" peptide to act as a vaccine against influenza virus infection. The disclosure in Table 4 of the high number of epidemic years in which SEQ ID NO: 141 occurs in the virus hemagglutinin protein is of no relevance to the assessment of whether or not it can elicit a protective immune response to influenza virus, i.e. be useful as a vaccine, as there is no evidence, either in the patent or in the state of art, linking the two.

15. Indeed, the patent itself contains no evidence of any kind, in the form of results from either in vivo or in vitro experiments or otherwise to show that any "Replikin" peptide, and in particular a peptide of SEQ ID NO: 141, is capable of acting as a vaccine against H1N1 influenza virus.

16. The fact that the so-called malignin peptide of the sequence "YKAGVAFLHKKNDIDE", derived from a brain cancer protein, is able to elicit antibodies in rabbit and that these are cytotoxic to cancer cells in vitro (see paragraph [0020] of the patent) would not be considered generalisable to the present case by the skilled person, since this evidence relates to a different disease (cancer) and a different immunogen (i.e. the peptide differs from SEQ ID NO: 141).

17. The board has also seen no evidence that would allow it to conclude that the skilled person at the relevant date of the patent would have known on the basis of his common general knowledge that "Replikin" peptides in general could elicit protective immunity against any pathogen at all.

18. Finally, the assertion that the structure-function relationship between "Replikin" sequences in the H1N1 hemagglutinin protein means that each and every H1N1 "Replikin" sequence present in an H1N1 hemagglutinin can be used for vaccination is unsupported by evidence.

19. In view of the above considerations, the board concludes that at the relevant date of the patent, the skilled person would not have considered it credible that the peptide of SEQ ID NO: 141 could be used as a vaccine against any influenza virus and H1N1 influenza virus in particular.

20. In accordance with the established jurisprudence of the boards of appeal, the assessment of inventive step is to be made at the effective date of the patent on the basis of the information in the patent together with the common general knowledge then available to the skilled person. That is to say that "post-published evidence to support that the claimed subject-matter solves the problem to be solved is taken into account if it is already credible from the disclosure in the patent that the problem is indeed solved" (see Case Law of the Boards of Appeal of the European Patent Office, 8th edition, I.D.4.6).

21. In view of the conclusion in paragraph 19. above, the evidence in post-published documents D11, D16, D17, D18, D23, D23a, D29, D30, D47, D55 and D56, all submitted to show that the claimed subject-matter indeed has the technical effect ascribed to it in the patent, cannot be taken into account in the assessment of inventive step.

22. As a consequence, the technical problem must be reformulated in a less ambitious way taking into account a technical effect that is achieved by the claimed subject-matter (see point 11. above).

23. In the board's view a properly formulated problem is arrived at by applying the problem and solution approach (see point 9. above) in the following way.

24. As concerns the closest prior art, the skilled person would have known of peptides derived from the hemagglutinin protein of a type H3 influenza A virus for instance from document D4 (see abstract). This document discloses a series of 16-mer peptides spanning the entire sequence of an influenza hemagglutinin protein derived from a combination of two H3N2 strains, A/Beijing/32/92 and A/Hong Kong/90, and made for the purpose of identifying epitopes recognised by T cells, and finally for the development of cross reactive T-cell vaccines for influenza virus infection. A number of the peptides disclosed also comprise the "Replikin" sequence motif.

25. In view of this, the peptides disclosed in document D4 can be taken as representing the closest prior art for the claimed peptide.

26. Given that SEQ ID NO: 141 derives from the H1 hemagglutinin protein, the difference between the mentioned general knowledge of the above skilled person representing the closest prior art and the peptide claimed lies in its primary structure, i.e. its particular sequence, which is dictated by the sequence of the H1 type hemagglutinin and its length, i.e. it has 33 amino acids, compared to 16 amino acids. The board has seen no evidence that these structural differences manifest themselves in any technical effect other then the peptide being immunogenic.

27. In view of this difference and the associated technical effect, the problem to be solved by the claimed subject-matter is formulated as the provision of a further immunogenic peptide from a influenza A virus hemagglutinin protein.

28. The board has the following considerations about the obviousness of the claimed 33 amino acid long peptide represented by SEQ ID No. 141. It was generally known in the art that immunogenicity is a property shared by peptides in general, including those derived from the influenza A virus hemagglutinin proteins. Indeed, it was commonly known that very short peptides are less likely to be immunogenic than longer ones, which is reflected in document D4, where 16-mer peptides were chosen to map the T-cell epitopes of hemagglutinin from an H3N2 strain of influenza virus. As to choosing a peptide derived from a H1 hemagglutinin protein instead of one from an H3 hemagglutinin protein, the skilled person knew that the four prevalent strains of influenza virus contained H1 type hemagglutinin (see e.g. the patent at paragraph [30] and document D2 at column 1). This alone would have provided an incentive to seek immunogenic peptides from this protein. Thus, concentrating on a hemagglutinin type H1 was obvious to the skilled person.

29. The person skilled in the art, seeking to identify immunogenic peptides derived from a haemagglutination type H1 protein would, on the basis of the knowledge that peptides in general and those derived from haemagglutination in particular are immunogenic (see document D4, page 7501, right-hand column, final paragraph and document D8, abstract), would have considered that any peptide derived from that protein, and especially those of 16 or more amino acids in length, including the peptide consisting of SEQ ID NO: 141, would have provided equally suited solutions to the formulated technical problem.

30. It is established case law that in such a situation, arbitrarily selecting one these equally suitable solutions is considered as obvious (see Case law of the Boards of Appeal of the European Patent Office, 8th edition, I.D.9.18.7). The board sees no reason to deviate from this case law.

31. Hence, the board comes to the conclusion that the claimed subject-matter does not meet the requirements of Article 56 EPC.

32. The above finding of obviousness applies equally to the subject-matter of claim 1 of all higher ranking requests (i.e. the main and auxiliary requests I and II) because the subject-matter of claim 1 of auxiliary request III is an embodiment of claim 1 of each of these requests.

Disclosure of the invention - Article 83 EPC

Auxiliary requests IV to VI - claim 1

33. The subject-matter of claim 1 of each of auxiliary requests IV and VI is an antibody for use in therapy of the human or animal body and is thus, a "use-limited" product, as provided for by Article 54(4) EPC.

34. The requirements of Article 83 EPC are complied with if the patent discloses the claimed invention in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art. In the present case this means that the skilled person at the relevant date of the application should be able to make the claimed antibody and in the light of case law, the patent must disclose its suitability for a therapeutic application, i.e. for a medical use (see Case Law of the Boards of Appeal of the European Patent Office, 8th edition, II.C.6.2).

35. As to the suitability of the claimed antibodies for the therapeutic application, the only therapeutic application of the claimed antibodies mentioned in the patent is the prevention or treatment of patients influenza virus infection (see paragraph [0083]). The board decided in point 19. above, that at the relevant date of the patent, the skilled person, reading the application and taking into account the general knowledge in the art, would not have considered it credible that the peptide of SEQ ID NO: 141 could be used as a vaccine against H1N1 influenza. This conclusion must apply equally to the antibodies of claim 1 of auxiliary requests IV to VI since these are the antibodies that are elicited by the peptide having SEQ ID NO: 141. Hence, the patent does not disclose the suitability of antibodies raised against the peptide of SEQ ID NO: 141 for the claimed therapeutic application.

36. It follows that claim 1 of each of the above requests does not meet the requirements of Article 83 EPC.

37. No claim request is allowable.

Order

For these reasons it is decided that:

The appeal is dismissed.