T 0870/14 (Meningococcal Hib vaccine/GLAXOSMITHKLINE) 20-07-2020

1. The appeal is admissible as it complies with the requirements specified in Articles 106 to 108 EPC and the further provisions referred to in Rule 101(1) EPC.

2. In view of its withdrawal of the opposition, the respondent ceased to be a party to the appeal proceedings as regards substantive issues. Other issues for which the respondent would have remained a party to the proceedings did not arise in the present case.

3. As the impugned decision resulted in the revocation of the patent, the withdrawal of the opposition had no procedural consequences for the appeal proceedings. The board must still examine the opposition division's decision in order to ascertain if it is to be set aside and whether the patent, with account being taken of the amendments made by the appellant in the form of the main request or auxiliary requests 1 to 8, and the invention to which it relates, meet the requirements of the EPC. In so doing the board may take into account the submissions and evidence filed by the respondent prior to its withdrawal of the opposition (see for example decision T 629/90, OJ EPO 1992, 654, point 2.2 of the Reasons).

4. In the decision under appeal the opposition division held, in addition to their finding that the claims lacked an inventive step, that claim 6 of the main request and auxiliary requests 1 to 3 as well as claim 1 of auxiliary request 4 did not comply with the requirements of Article 123(2) EPC. The present decision does not deal with this aspect in view of the board's negative decision in relation to inventive step.

5. The patent in suit concerns compositions for immunisation against meningitis caused in particular by Neisseria meningitidis and Haemophilus influenzae type B, in particular compositions comprising capsular saccharides from these bacteria. In this decision the board will in some instances refer to these as meningococcal saccharides and Hib saccharides, respectively. Accordingly, a conjugate of serogroup W135 capsular saccharide antigen of N. meningitidis is also referred to as "conjugated MenW135 saccharide" or "MenW135 saccharide conjugate" in the following. Abbreviations to "MenACWY" apply accordingly to saccharides of serogroups A, C, W and Y of N. meningitidis. Conjugate of H. influenzae type b capsular saccharide antigen is also referred to as "conjugated Hib saccharide" or "Hib saccharide conjugate" in the following.

Main request and auxiliary requests 1 to 3 and 5 to 8

6. Independent claims 1 to 5 of the main request and auxiliary requests 1 to 3 are identical to those of auxiliary requests 5 to 8, respectively (see section VII.).

7. Claim 1 of auxiliary request 1 is directed to a composition "consisting essentially of" individually conjugated capsular saccharides of MenW135, C and Y, as well as Hib. As such, this composition falls within claim 1 of the main request as well as that of auxiliary requests 2 and 3 and 5 to 8.

In the following, it is this subject-matter that is being analysed when the board refers to claim 1.

8. In the decision under appeal the opposition division concluded that 28 May 2004 was the valid priority date (page 7 of the decision). This has not been contested in the appeal proceedings.

Thus, documents D9a and D10, referred to below, belong to the state of the art according to Article 54(2) EPC.

Inventive step

The decision under appeal

9. The opposition division held that, in respect of auxiliary request 1 before it, the subject-matter of claim 1 lacked an inventive step with regard to document D7, considered to represent the closest prior art, in combination with the teaching of either document D13 or document D10.

10. The appellant disputes this decision on several accounts: the disclosure of document D7 does not constitute the closest prior art, the opposition division incorrectly formulated the problem by not having taken into account the effect provided by the composition, and the skilled person had no incentive to replace the meningococcal saccharides with the respective conjugates and yet still provide them in a composition with H. influenzae saccharide conjugate.

The closest prior art

11. Document D7 concerns the immune response to conjugated versus unconjugated polysaccharide vaccines (see title as well as "Objective"). For the study, patients were administered a composition comprising unconjugated polysaccharides from N. meningitidis serogroups ACYW135 and conjugated H. influenzae saccharide (see page 829, left-hand column, first full paragraph). Additionally the patients were administered multivalent pneumococcal polysaccharide compositions consisting of either conjugated or unconjugated forms of the saccharides. The document reports on the immune response to Hib, MenA and several pneumococcal serotypes (see page 828, "Design" and "Conclusion", as well as Table 3).

12. Thus, document D7 discloses a composition comprising both Hib saccharide conjugate and unconjugated MenACYW135 saccharides. This is not disputed by the appellant.

13. The board holds that document D7 constitutes an appropriate starting point for the assessment of inventive step since it addresses immunisation against both H. influenzae and N. meningitidis, which is also the purpose of the claimed compositions.

14. The appellant has not argued that this document belongs to a different technical field, but quite to the contrary acknowledged that all the prior-art documents referred to in the present case belong to the same technical field as the invention (see point 3.12 of the statement of grounds of appeal).

Instead, the appellant argued that the document was not directed to the same "purpose and effect" as the claimed invention. In particular, the document did not demonstrate the effect of the invention, namely a bactericidal response against MenW135, whereas both document D13 and document D6 did (see points 3.9 and 3.11 of the statement of grounds of appeal). One of these documents should therefore be considered to represent the closest prior art.

15. However, in the board's judgement, whether other documents constitute a more promising starting point is immaterial in the present case since the board holds that the claimed invention is obvious when starting from the disclosure in document D7.

As stated in decision T 967/97 (see point 3.2 of the Reasons, in particular the last paragraph), if inventive step is denied starting from a particular document as the closest prior art, the choice of starting point needs no specific justification.

Furthermore, a line of argument which leads to the finding of lack of inventive step cannot be successfully rebutted merely by submitting that there is closer prior art (see, for example, decision T 1742/12, point 10.3 of the Reasons).

16. In view of the above, further arguments by the appellant on the proper selection of the closest prior art need not be refuted. This applies to the appellant's argument based on the relative publication dates of the documents as well as that based on the technical effect achieved by the claimed invention.

Technical effect and objective technical problem

17. The claimed compositions are distinguished from the composition disclosed in document D7 in that the meningococcal saccharides are present in conjugated form.

18. The opposition division held that this difference resulted in improved immunogenicity of the saccharides such that the objective technical problem addressed by the claimed compositions was that of "improving the immunogenicity of the meningococcal saccharides in the vaccine of D7" (see page 20 of the decision).

19. The appellant argued that the effects achieved by the invention had not been taken into account by the opposition division when formulating the problem. On the one hand, in document D7 there was no disclosure of the bactericidal response against MenW135. On the other hand, the patent showed an improvement in such a response, as could be seen from comparing the compositions 2 and 3 in the tables on pages 26 and 27 of the patent (corresponding to pages 26 and 27 of the patent application). This improved response was present without there being significant interference with the immune responses to MenA, C and Y.

20. The board notes that the improvement put forward by the appellant relates to a comparison of MenACW135Y conjugate compositions in the presence and absence of Hib conjugate. It therefore does not relate to a comparison with the composition disclosed in document D7, which already includes a Hib conjugate.

It is, however, established case law of the boards of appeal that the nature of the comparison with the closest prior art must be such that it demonstrates that the technical effect has its origin in the feature distinguishing the claimed subject-matter from that prior art.

In the case at hand this feature is the conjugation of the MenA, C, Y and W135 saccharides. Since the comparison between compositions 2 and 3 in the patent and in the application, respectively, is not suitable for demonstrating an effect due to conjugation of the saccharides, it also cannot serve to demonstrate any effect of this distinguishing feature on the immune responses or on a lack of interference between the immune responses to the various saccharides.

21. As noted above, the opposition division held that the difference between the subject-matter under consideration here and the vaccine disclosed in document D7 resulted in an improved immunogenicity of the meningococcal saccharides. It came to this conclusion in the absence of comparative data. However, the board considers this effect of the difference to be plausible on the basis of the common general knowledge on the effective date, as disclosed in documents D9a, D10 and D11 for example, namely that conjugation of capsular saccharides of the meningitis-causing bacteria N. meningitidis, H. influenzae type B and S. pneumoniae increased their immunogenicity. The increase in immunogenicity by conjugation of the saccharides is attributed to the generation of helper T-cell responses and immunological memory (see for example document D10, below).

D9a, a textbook on vaccines, discloses that a multivalent pneumococcal conjugate vaccine including a MenC conjugated saccharide, as well as a multivalent meningococcal conjugate vaccine - MenACYW135 - were under development. The authors express the expectation that these vaccines will have a great impact on the control of meningitis (see paragraph spanning the two columns on page 980).

D10, a review on meningococcal conjugate vaccines, states that meningococcal conjugated vaccines present advantages over plain polysaccharide vaccines, especially in children and adolescents. It notes that conjugates of capsular saccharides of MenA, C, Y and W135 have been prepared similarly to conjugates of pneumococcal conjugate vaccines and those of Hib conjugate vaccines. Both the Hib conjugate vaccine and the MenC conjugate vaccine were successful in improving immunogenicity (see abstract and page 858, first full paragraph). D10 further states: "Protein-polysaccharide vaccines have the advantage over polysaccharide vaccines alone. They generate helper T-cell (Th1) responses and create immunological memory responses [...] In addition to improved immunogenicity, the conjugate vaccines have a dramatic herd immunity effect through decreased transmission and nasopharyngeal carriage as demonstrated with Hib and conjugate pneumococcal vaccines [...] Mucosal immune response to a conjugate meningococcal C vaccine, measured by increased salivary IgG levels [...] is improved in both adult and child vaccines compared to those receiving the polysaccharide A/C vaccine" (see page 858, first full paragraph).

D11, a review on therapies and vaccines for bacterial meningitis, highlights the introduction of conjugate vaccines as a major contribution to the control of meningitis caused by Hib and the expectation that it will lead to further improvements with regard to pneumococcal and meningococcal infection. In particular, a conjugate MenC vaccine had become available and a quadrivalent conjugate MenACW135Y vaccine was under development (see "Introduction", two last sentences and page 1055, last paragraph). According to this document, "[t]he major advances in prevention of bacterial meningitis have come from conjugate vaccine technology [...] New vaccines are being licensed for meningococci and pneumococci, which are likely to have similar efficacy to that which has been seen with Hib vaccine" (see page 1056, right-hand column, second full paragraph).

22. Thus, the board considers the objective technical problem to be the provision of a composition for immunisation against infection by N. meningitidis and H. influenzae with improved immunogenicity.

Obviousness

23. The opposition division reasoned that the conjugation of the saccharides in order to solve the problem would have been obvious because advantages of conjugation were well known. Each of documents D10 and D13 were referred to in this respect.

24. Document D13 is concerned with meningococcal vaccines conferring broad protection against N. meningitidis infection, against a background of either monovalent, conjugated MenC saccharide or multivalent, unconjugated polysaccharide vaccines which were, however, not providing a satisfactory immune response. With this aim, document D13 provides all the saccharides individually conjugated to a carrier protein (see abstract and paragraphs 10, 11 and 15). In particular this document discloses a clinical trial with a tetravalent conjugate vaccine - MenACW135Y - using diphtheria toxoid as the carrier for all capsular saccharides (see examples 6 and 9).

25. In the board's judgement, the skilled person seeking to provide a composition with improved immunogenicity would have modified the composition disclosed in document D7 by providing the meningococcal saccharides in conjugate form as disclosed in document D13, i.e. conjugation of all of the meningococcal polysaccharides to diphtheria toxin, in order to achieve the advantages disclosed in that document.

26. The appellant submitted that the skilled person would have had no reason to expect that such a composition would result in an improved bactericidal immune response against W135 serogroup, good bactericidal immune responses against serogroup A, C and Y, and without significant immune interference. In other words, the appellant argued that the skilled person would not have expected to provide the effects listed by the appellant. However, these differential effects are not those which the skilled person had set out to achieve in accordance with the objective technical problem formulated above, i.e. the provision of a composition for immunisation against infection by N. meningitidis and H. influenzae with improved immunogenicity. Hence, the appellant's argument is not relevant in relation to the problem as formulated.

27. The appellant further argued that, although the skilled person was aware of the advantages of conjugation from documents D10 and D13, they were also aware of the problem of immune interference and would have been concerned that providing different conjugates in one single composition would affect the immune response to individual conjugates.

28. The board is not persuaded by this argument. The evidence before the board does not support the view that the skilled person would have expected interference when combining meningococcal and Hib conjugates, as argued by the appellant. Such concerns in particular are not supported by document D2, as submitted by the appellant, for the reasons below.

The appellant referred to the passage on page 1, lines 7 to 11, of document D2. The passage in question states that the development of multivalent vaccines is complicated by the competition or interference between antigens. This generic and very brief statement does not mention conjugation at all. Moreover, the awareness of competition or interference did not deter the authors of the document from providing multivalent compositions, including compositions comprising Hib and meningococcal antigens, all individually conjugated to a carrier protein. In fact, the document discloses that combining the Hib antigens with antigens from other meningitis-causing agents led to an increase in the immunisation against Hib. In a clinical trial, a composition comprising Hib and MenAC conjugates was tested and the authors concluded that a good immune response against each antigen was observed (see example 3). More complex combinations were also tested, including, in addition to the above antigens, tetanus toxoid, diphtheria toxoid and a whole-cell pertussis component. A good immune response was observed here too (see example 3). Thus, reference to this document does not support the appellant's argument.

Document D5 also discloses combinations of Hib saccharide conjugates and meningococcal saccharide conjugates. It discloses kits comprising two or more separate vaccines, one of the vaccines being a composition comprising both a Hib conjugate and MenC and/or MenY conjugate (see page 5, lines 1 to 8). No teaching can be inferred from this document either which would have deterred the skilled person from combining a Hib saccharide conjugate with meningococcal saccharide conjugates.

29. Thus, the composition as claimed does not involve an inventive step, contrary to the requirements of Article 56 EPC.

Auxiliary request 4

30. Claim 1 of auxiliary request 4 differs from the embodiment considered in relation to claim 1 of the main request and of auxiliary requests 1 to 3 and 5 to 8 in that all meningococcal serogroup saccharides are conjugated to the CRM197 diphtheria toxin-mutant and that the composition comprises <= 30 myg meningococcal saccharide per dose.

31. For the reasons given in points 13. to 15. above, the board considers document D7 to be a suitable starting point for the assessment of inventive step for this subject-matter too.

32. The appellant has not referred to any technical effects in addition to those achieved by the composition as defined in claim 1 of auxiliary request 1, and an additional technical effect was not apparent to the board. Thus, the objective technical problem remains the same as formulated above, namely the provision of a composition for immunisation against infection by N. meningitidis and H. influenzae with improved immunogenicity.

33. With regard to claim 1 of auxiliary request 4 the appellant submitted - as for claim 1 of auxiliary request 1 - that none of the cited documents specifically suggested the combination of features and that the skilled person would not have had a reasonable expectation that a composition with these features would achieve an improved bactericidal immune response against W135 without significant immune interference.

This argument has not been found to be persuasive in relation to claim 1 of the auxiliary request 1 (see point 29. above). The two additional features by means of which the claimed composition is defined do not change the board's assessment of the argument.

34. The appellant has not argued that the amount of saccharide or the choice of carrier would not lie within the possibilities known to the skilled person. The same applies to the provision of all conjugates with the same carrier protein.

35. Nevertheless, the board refers to prior-art document D13, which provides all four saccharides conjugated to diphtheria toxin. It thus discloses the use of the same carrier protein for all conjugates.

The carrier protein in the composition as defined in claim 1 is a mutant of diphtheria toxin, namely CRM197. This is, however, one of the possibilities that is well known to the skilled person, as demonstrated by the list on paragraph 27 of document D13.

Thus, in the board's judgement, when faced with the problem above, the skilled person would have provided the meningococcal saccharides all conjugated to the same carrier, the carrier being either diphtheria toxin as used in the examples in document D13 or an alternative carrier chosen from those listed as equivalent alternatives in this document.

36. The composition defined in claim 1 further specifies the amount of meningococcal saccharide to be at most 30 myg in the composition.

However, the tetravalent conjugate vaccine exemplified in document D13 contains 4 myg of each meningococcal saccharide, resulting in a total of 16 myg of saccharide (paragraph 78). Thus, the range of amounts specified in the claim is within what the skilled person would have provided without exercising inventive skill.

37. In view of the above considerations, the subject-matter of claim 1 is obvious in view of the combined teachings of documents D7 and D13 and hence does not fulfil the requirements of Article 56 EPC.