T 1074/09 (Vaccine/ SANOFI PASTEUR LIMITED) 28-11-2013

Main request

Amendments (Articles 100(c) and 123(2) EPC) - claims 4 to 10,

13 and 14

1. In the decision under appeal the opposition division considered that this request fulfilled the requirements of Article 123(2) EPC. The appellant contested this decision.

2. Claim 9, when read as referring back to claim 2, relates to a multi-valent immunogenic composition in which two antigens, the high molecular weight (HMW) protein of a non-typeable strain of Haemophilus influenzae (H. influenzae) and the outer membrane protein of Moraxella catarrhalis (M. catarrhalis) having an apparent molecular mass of 200 kDa, are specified in an otherwise generically defined multi-valent immunogenic composition.

3. It is undisputed that this combination of antigens is not explicitly disclosed in the application as filed. The relevant question to be answered is thus whether or not this combination of antigens is clearly and unambiguously derivable from the application as filed.

4. The application as filed discloses on page 7, lines 14 to 20 a generic composition as follows "In accordance with one aspect of the present invention, there is provided a multi-valent immunogenic composition for conferring protection in a host against disease caused by infection with Haemophilus influenzae and Moraxella catarrhalis, which comprises at least four different antigens, comprising at least one antigen from Haemophilus influenzae and at least one antigen from Moraxella catarrhalis, at least three of which antigens are adhesins and at least one of which adhesins is from Moraxella catarrhalis." In the following paragraphs on page 7, line 21 to page 8, line 3, and page 8, line 18 to page 9, line 4 these various antigens of H. influenzae and M. catarrhalis are more closely defined. Thus, according to e.g. page 7, lines 21 to 24: "One of the antigens which is an adhesin may be a high molecular weight protein (HMW) of a non-typeable strain of Haemophilus, particularly an HMW1 or HMW2 protein of the non-typeable strain, which may be produced recombinantly." Or according to page 8, lines 1 to 3: "One of the antigens which is an adhesin may be an outer membrane protein of Moraxella catarrhalis having an apparent molecular mass of about 200 kDa, as determined by SDS-PAGE, and may be produced recombinantly."

5. The subject-matter of claim 9, when read as referring back to claim 2, results from the combination of the generic definition provided on page 7, lines 14 to 20 with the selection of the HMW protein provided on page 7, lines 21 to 24 and the selection of the 200 kDa protein provided on page 8, lines 1 to 3. In other words, it results from a combined selection from the list of possible antigens disclosed in the application as filed.

6. As to whether or not the particular combination of claim 9 contravenes Article 123(2) EPC, established case law of the Boards of Appeal (see decision T 686/99 of 22 January 2003, reasons, point 4.3.3) stipulates that: "The content of the application as filed must not be considered to be a reservoir from which individual features pertaining to separate sections can be combined in order artificially to create a particular combination. In the absence of any pointer to that particular combination, this combined selection of features does not, for the person skilled in the art, emerge clearly and unambiguously from the content of the application as filed (cf. T 727/00 of 22 June 2001, point 1.1.4 of the reasons)." (Emphasis added by the board).(See also Case law of Boards of Appeal of the European Patent Office, 7th edition 2013, sections II.E.1.1.4 and II.E.1.7.1).

7. The application as filed lists the various antigens that can be used without any pointer regarding the possible combination of these antigens other than a composition comprising four defined antigens or a generic composition comprising only one of the disclosed specific antigens (see page 7, line 21 to page 9, line 2). The skilled person reading pages

7 to 9 would understand clearly and unambiguously that one of the antigens could be a HMW protein or a Hia protein or an analog of the Hin47 protein or the 200 kDa protein but not that the HMW and the 200 kDa should be combined in an otherwise generically defined composition. This combination has not been individualised in the application as filed. Also the claims as filed cover only combinations where a single antigen or all four antigens are defined.

8. It follows, that the combination of page 7, lines 14 to 20, page 7, lines 21 to 24 and page 8, lines 1 to 3 results in the skilled person being presented with a new combination of features and thus new technical information which he or she would not derive clearly and unambiguously, using common general knowledge, from the application as filed. The same argumentation applies mutatis mutandis to the subject-matter of claims 4 to 8 and 10.

9. The respondent submitted that the skilled person understood that the passages on page 7, line 14 to page 8, line 3 could be combined. The board is not persuaded by this argument because the relevant question is not whether the passages "could be combined" but rather whether the application as filed provides a pointer to a particular combination. In the present case, the application lists the various antigens in an undifferentiated manner without any pointer to any particular combination thereof other than the combination of each individual antigen with the generic composition and a combination of 4 defined antigens, see page 8, lines 4 to 13.

10. Claim 13 specifies the amount of the various antigens being present in claims 11 or 12 as "25 to 100 myg". The appellant submitted that there was no basis in the application as filed for the specific range "25 to 100 myg".

11. The application as filed discloses in claim 25 and in the corresponding passage on page 9, lines 14 to 21 the amount as being "about 25 to about 100 myg". The board agrees with the opposition division (see decision under appeal, reasons, point 1.3.1) that the skilled person understands that the term "about" merely reflects the experimental accuracy with which values are determined and that deletion of the term neither creates a new value nor a new range and hence no new technical information. Accordingly, claim 13 is allowable under Article 123(2) EPC.

12. Claim 14 relates to the immunogenic compositions claimed in any one of claims 1 to 13 further comprising an adjuvant. The appellant submitted that claim 14 lacked a basis because page 9, lines 3 to 4 disclosed the use of an adjuvant only in the context of the preferred embodiment.

13. Page 9, lines 3 to 4 discloses that "The immunogenic composition of the invention may be further formulated with an adjuvant." In the board's judgement, the immunogenic composition of the invention is not only the preferred embodiment (with all 4 antigens being specified) but any immunogenic composition disclosed in the application as filed as being part of the invention. Accordingly, claim 14 is allowable under Article 123(2) EPC.

14. For the reasons set out above (see points 1 to 9), the subject-matter of claims 4 to 10 extends beyond the content of the application as filed and the main request is accordingly not allowable (Article 123(2) EPC).

Auxiliary request 1

Amendments (Articles 100(c) and 123(2) EPC) - claim 1

15. The claims of this request differ from the claims of the main request only in that the component nature of the vaccine has been specified in independent claims 1, 16 and 18 (see section VII above).

16. The respondent provided no further arguments for this request and conceded that the objections set out above for the main request also applied to this request.

17. Auxiliary request 1 is not allowable under Article 123(2) EPC for the same reasons as set out above for the main request, see points 1 to 9.

Auxiliary request 2

Admissibility

18. This request was filed during the oral proceedings before the board and thus at a late stage in the proceedings. The independent claims of this request have been limited to an immunogenic composition in which all 4 antigens are defined (see section XVII above for the complete wording of independent claims 1, 5 and 6). The appellant has not contested the admissibility of this request. The board is satisfied that the amendments made in this request are straightforward, that they do not raise new issues, do not lead to any surprising turn of events or to subject-matter which diverges from the subject-matter of the higher ranking requests and accordingly, do not lead to a delay of the proceedings. Under these circumstances the board decides to admit this request into the appeal proceedings in the exercise of its discretion under Article 13(1) RPBA.

Amendments (Article 123(2) EPC)

19. The appellant did not raise any objections under Article 123(2) EPC. The board is satisfied that claim 1 finds a basis in claim 8 as filed, while claims 2 to 6 find a basis in claims 25, 26, 27 as filed and on page 9, line 12 to 13 of the application as filed. Therefore auxiliary request 2 complies with the requirements of Article 123(2) EPC.

Article 123(3) EPC

20. The appellant did not raise any objections under Article 123(3) EPC. The board is satisfied that claim 1 as amended corresponds to claim 11 as granted, while claims 2 to 6 correspond to claims 13, 14, 15, 17 and 19 as granted. Therefore the claims as amended do not extend the scope of protection vis-à-vis the claims as granted, such that the requirements of

Article 123(3) EPC are satisfied.

Sufficiency of disclosure (Articles 100(b) and 83 EPC)

21. Claim 1 concerns a multi-valent immunogenic composition for conferring protection in a host against disease caused by both H. influenzae and M. catarrhalis, and comprising at least four defined antigens (see section XVII for the complete wording of claim 1). The mention of the grant of the present patent was published in the European Patent Bulletin on 7 February 2007. The version of the European Patent Convention revising that of the year 1973 (EPC 1973) entered into force on 13 December 2007. Hence, Article 54(5) EPC 2000 (for which no corresponding provision exists in the EPC 1973) does not apply, in accordance with Article 3 of the decision of the Administrative Council of 28 June 2001 on the transitional provisions under Article 7 of the Act revising the EPC of 29 November 2000 (Special Edition No.1 OJ EPO 2007, 197). Accordingly, claim 1 is to be interpreted as a product claim, with the consequence that the multi-valent immunogenic composition has to be suitable for conferring protection against disease caused by both H. influenzae and M. catarrhalis.

22. According to established case law of the Boards of Appeal an invention is only disclosed in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art if at least one way of enabling the person skilled in the art to carry out the invention is disclosed, and if this allows the invention to be performed in the whole range claimed (Case law of Boards of Appeal of the European Patent Office, 7th edition 2013, sections II.C.4.2 and II.C.4.4). The appellant submitted that neither requirement was fulfilled by the subject-matter of claim 1 (see section XIX above).

23. The patent in suit discloses (see example 7 and Figure 9) that a multi-component vaccine comprising the four antigens H91A Hin 47, rHMW, rHia and r200 kDa provides excellent protection in a chinchilla nasopharyngeal colonization challenge model, which is the relevant animal model for establishing protective efficacy against infection with H. influenzae. There is no relevant animal model for infection by M. catarrhalis but a bactericidal antibody assay has been developed as a surrogate assay. The patent in suit also discloses (see example 8, Tables III and IV) that antisera raised against the multi-component vaccine comprising the four antigens H91A Hin 47, rHMW, rHia and r200 kDa possess bactericidal antibody activity in this bactericidal antibody assay.

24. The board is satisfied that the evidence provided by examples 7 and 8 of the patent in suit shows that a multi-valent immunogenic composition falling within the scope of claim 1 is suitable for conferring protection in a host against a disease caused by both H. influenzae and M. catarrhalis. Therefore, in the board's judgement, the patent in suit provides at least one way to carry out the invention.

25. Appellant's further argument that not a single embodiment had been provided by the patent in suit in which no antigenic interference was observed is not found persuasive. The board notes that claim 1 requires that the composition is suitable to provide dual protection but is silent as regards the avoidance of antigenic interference. In other words, claim 1 does not extend to compositions in which the components interfere to an extent that dual protection is no longer provided. Importantly, according to the patent in suit there was no apparent enhancing or inhibiting effect on the anti-r200 kDa response with the addition of the other vaccine components, i.e. H91A Hin47 + rHMW + rHIA (see paragraph [109]). Moreover, the patent in suit also discloses that the relative bactericidal antibody activity of anti-r200 kDa and an anti-4 component (H91A Hin47 + rHMW + rHia + r200 kDa) antisera was compared and found to be equivalent (see paragraph [0123]). Therefore, the board is satisfied that the patent in suit provides compositions which provide dual protection and in which the antigens are combined such that antigenic interference is avoided.

26. As regards the second requirement (see point 22 above), i.e. performance over the whole range claimed, the board notes that present claim 1 differs from claim 1 of the main request, for which the appellant had raised and substantiated its objection, in that all 4 antigens are now defined proteins. Extensive guidance regarding these proteins is provided in the patent in suit (see paragraphs [0005] to [0010] and [0012] to [0017]). The patent in suit provides moreover animal models which allow the skilled person to assess the protective ability of any multi-component composition comprising these proteins (see examples 7 and 8).

27. In the board's judgement, it can therefore reasonably be assumed that a skilled person, following the guidance provided in the patent in suit, would be in a position to prepare appropriate immunogenic compositions, to test them and to select those which are suitable for conferring protection in a host against a disease caused by both H. influenzae and M. catarrhalis and, thus, that the skilled person could put the invention into practice over the whole scope of the claim without undue burden.

28. Accordingly, the board is satisfied that the requirements of Article 83 EPC are satisfied.

Novelty

29. The appellant has not raised any objection under Article 54 EPC and the board is satisfied that none of the documents on file anticipates the claimed subject-matter, such that the requirements of Article 54 EPC are satisfied.

Inventive step

Closest prior art

30. In the decision under appeal document (D5) was considered to represent the closest prior art. On appeal, the appellant failed to identify one single closest prior art document but submitted that "in general combinations of antigens from M. catarrhalis and H. influenzae to make M. catarrhalis/ H. influenzae vaccines were known at the priority date", while the respondent considered that document (D30) constituted the closest prior art.

31. The present invention aims at providing a multi-valent immunogenic composition which confers protection in a host against a disease caused by both H. influenzae and M. catarrhalis. The closest prior art for assessing inventive step is normally a prior art document disclosing subject-matter conceived for the same purpose or aiming at the same objective as the claimed invention and having the most relevant technical features in common.

32. Document (D5) relates to the synthesis and characterisation of lipooligosaccharide-based conjugates as vaccine candidates for M. catarrhalis. It discloses that the detoxified LOS (dLOS) was coupled to high-molecular weight proteins (HMP) from non-typeable H. influenzae and that the dLOS-HMP conjugate was immunogenic (see abstract). The HMP protein is used as a carrier and document (D5) neither mentions protection against H. influenzae nor aims at providing protection against both H. influenzae and M. catarrhalis.

33. Document (D30) aims at providing a vaccine capable of protecting against both H. influenzae and

M. catarrhalis (see page 45, lines 10 to 15) and provides a conjugate in which the UspA2 of

M. catarrhalis serves as a carrier for an H. influenzae type b oligosaccharide (HbO). Therefore, in the board's judgement, document (D30) qualifies as the closest prior art because it is directed to the same purpose as the invention, while document (D5) is not. The immunogenic and bactericidal effects of the HbO-UspA2 conjugate are reported in example VI of document (D30). The conjugate elicited antibodies against the pneumococcal oligosaccharide (see Table XXV) as well as bactericidal antibodies to M. catarrhalis (see Table XXVII). While the immunogenicity data provided in Table XXV allow no conclusion as regards the protective ability of the antibodies against H. influenzae, the bactericidal activity indicates a protective effect against M. catarrhalis.

Technical problem to be solved

34. Starting from document (D30) as closest prior art the board considers the problem to be solved as the provision of a multi-valent vaccine which is protective against both H. influenzae and M. catarrhalis.

35. Claim 1 proposes as solution to this problem a composition comprising at least (a) an analog of

H. influenzae Hin47 protein having a decreased protease activity which is less than 10% natural Hin47 protein, (b) a H. influenzae adhesin (Hia) protein of a non-typeable strain of H. influenzae, (c) a high molecular weight (HMW) adhesin protein of a strain of non-typeable H. influenzae, and (d) an outer membrane adhesin protein of M. catarrhalis having an apparent molecular mass of 200 kDa, as determined by SDS-PAGE. In the light of the experimental data provided in the patent in suit (see examples 7 and 8) the board is satisfied that the problem is solved by the subject-matter of claim 1.

Obviousness

36. It remains to be addressed whether the skilled person, when faced with the technical problem defined in point 34 above, would have modified the teaching in the closest prior art document (D30) - possibly in the light of other teachings in the prior art - so as to arrive at the claimed invention in an obvious manner.

37. Document (D30) discloses the HbO-UspA2 conjugate and its ability to raise antibodies against the H. influenzae oligosaccharide in mice as well as bactericidal antibodies against M. catarrhalis. Document (D30) neither teaches nor suggests to include further proteins and in particular adhesins of H. influenzae or of M. catarrhalis to provide a multi-valent vaccine which is protective against both H. influenzae and M. catarrhalis. Accordingly, the claimed solution is not obvious from document (D30) alone.

38. Document (D36) investigates the role of the 200 kDa protein of M. catarrhalis as an antigen and mentions that another use of the protein is to act as a carrier for polysaccharide antigens of other organisms, including H. influenzae (see page 16, lines 1 to 12). However there is nothing in document (D36) that suggests that the glycoconjugates so formed are intended to be protective against both M. catarrhalis and H. influenzae. Finally, although document (D36) provides immunogenicity data (see examples 3, 5 and 6), it provides no data relating to a possible protective capability of the 200 kDa protein and in particular no experimental data regarding the bactericidal activity of antibodies raised against the protein. Therefore, in the board's judgement, the skilled person would not derive any motivation from document (D36) to include the 200 kDa protein in the combination known from document (D30), when faced with the problem of providing a multi-valent vaccine which is protective against both H. influenzae and M. catarrhalis.

39. Document (D33) discloses (see abstract) that immunisation with HMW of non-typeable H. influenzae modifies experimental otitis media in chinchillas and concludes that although protection following immunization was incomplete, these data suggest that the high-molecular weight adhesion proteins are potentially important protective antigens which might represent one component of a multi-component non-typeable Haemophilus vaccine.

40. Document (D34) discloses the identification of a second family of high-molecular-weight adhesion proteins expressed by non-typeable H. influenzae and designated Hia protein. Document (D34) suggests the possibility of developing vaccines based upon a combination of HMW1/HMW2-like proteins and Hia-like proteins which could be protective against diseases caused by most if not all non-typeable H. influenzae (see abstract).

41. Document (D35) discloses that a H91A mutant of HtrA (also known as Hin47, see paragraph [0012] of the patent) was found to be partially protective in animal protection models and therefore H91A HtrA may be a good candidate antigen for a vaccine against invasive H. influenzae disease and otitis media.

42. Documents (D33), (D34) and (D35) relate to H. influenzae antigens and none of these documents even mentions M. catarrhalis or the possibility of providing a vaccine affording dual protection against H. influenzae and M. catarrhalis.

43. In summary, the board concludes that none of the documents relied on by the appellant provides any hint that would have motivated the skilled person to modify the teaching of document (D30) to abandon altogether the chosen M. catarrhalis antigen (UspA2) and to replace it with the 200 kDa M. catarrhalis antigen or even to add the 200 kDa M. catarrhalis antigen when faced with the problem of providing a multi-valent vaccine which is protective against both H. influenzae and M. catarrhalis so as to arrive at the claimed invention in an obvious manner.

44. The appellant submitted that each of the antigens disclosed in the patent, i.e. the HMW, Hia/Hsf, Hin47 from H. influenzae and the 200 kDa protein from M. catarrhalis, was known to be a vaccine candidate and that in general combinations of antigens from M. catarrhalis and H. influenzae to make M. catarrhalis/H. influenzae vaccines were known at the priority date. The combination of these antigens was a mere aggregation of antigens and each antigen represented a partial problem. The solution to each of these problems was obvious in view of documents (D33), (D34), (D35) and (D36).

45. According to established case law of the Boards of Appeal partial problems exist if the features or sets of features of a claim are a mere aggregation of those features or sets of features (juxtaposition or collocation) which are not functionally interdependent, i.e. do not mutually influence each other to achieve a technical success over and above the sum of their respective individual effects, in contrast to what is assumed in the case of a combination of features. What has to be established is whether each set of features is separately obvious in the light of the prior art (Case Law of the Boards of Appeal of the EPO, 7th edition, 2013, I.D.9.2.2).

46. As pointed out in the patent in suit (see paragraph [0044]): "The composition of multi-component vaccines is important. The vaccine components must be compatible and they must be combined in appropriate ratios to avoid antigenic interference and optimize any possible synergies." Document (D15) relates to clinically relevant vaccine-vaccine interactions and confirms (see lines 6 to 10 of the summary on page 443) that "Many vaccines should not be administered together because of adverse reactions known as vaccine-vaccine interactions, a phenomenon where one vaccine affects another vaccine, thus potentially causing loss of immunogenicity, loss of protective efficacy or induction of adverse reactions". The skilled person thus knew that additional components could not just be added to vaccines in the expectation that the protective ability afforded by the individual components would be maintained. In the present case, the dual protection against diseases caused by H. influenzae and M. catarrhalis is effected by the combination of antigens recited in claim 1 and the contribution of the individual antigens can not be separated. In the board's judgement, the partial problem approach is therefore not appropriate for the subject-matter of present claim 1.

47. Moreover, the board notes that the appellant failed to establish that the inclusion of each antigen as defined in present claim 1 was separately obvious in the light of the prior art. Taking protein 200 kDa of M. catarrhalis as an example, document (D36) which is the sole document in these proceedings relating to this protein, does not disclose any data showing a protective activity of this protein. Therefore, the skilled person had neither a motivation nor any reasonable expectation of success that inclusion of that particular protein in the composition known from document (D30) would solve the problem formulated above (see point 34).

48. The above considerations in respect of claim 1 also apply to the subject-matter of claims 2 to 6. For these reasons auxiliary request 2 complies with the requirements of Article 56 EPC.