T 0534/07 (CD8 T cells/OXXON THERAPEUTICS) 25-11-2008

Procedural matters

Admissibility of the appeal filed by appellant II, PowderJect

Vaccines Inc.

1. Appellant II appealed the decision of the opposition division of 31 January 2007 on 5 April 2007 and paid the appeal fee on the same day. However, no statement setting out the grounds of appeal was filed. The notice of appeal contains nothing which could be regarded as constituting grounds of appeal.

2. In the present case the provisions of the EPC 1973 on the assessment of the admissibility of the appeal are to be applied. For the reasons determining the board's finding in this respect, it is referred to decision J 10/07, OJ EPO 2008, 567, points 1 et seq. of the reasons. In this decision, the Legal Board of Appeal explained in detail why the provisions of the EPC 1973 are to be applied on the assessment of the admissibility of an appeal if the time limit for setting out the grounds of appeal had already expired when the EPC 2000 came into force.

3. Pursuant to Article 108, third sentence, EPC 1973 in conjunction with Rule 65(1) EPC 1973, the Board of Appeal shall reject the appeal as inadmissible, if no grounds of appeal have been filed before the expiry of the time limit laid down in Article 108, third sentence, EPC 1973. Such is the case here.

Admissibility/validity of the appeal filed by appellant I, the patent proprietor Oxxon Therapeutics, and identification of which company is now appellant I

4. One month before the oral proceedings before the board appellant III, Danisco (former Genencor), raised an objection against the admissibility of the appeal filed by appellant I, the patent proprietor Oxxon Therapeutics. The objection was based on the allegation that as a result of Oxxon Therapeutics having been taken over by Oxford BioMedica on March 12 2007, i.e. before the present appeal was filed, the appeal had been filed by a non-existing party. Following an invitation by the board to file evidence showing that Oxxon Therapeutics still exists as a legal person or, in case of a universal succession (e.g. a merger) having taken place, which company is the legal successor of Oxxon Therapeutics, appellant I submitted a print-out from the Companies House Register in which the status of Oxxon Therapeutics Limited, i.e. of appellant I, is stated as "active".

5. Appellant III based its allegation that Oxxon Therapeutics had ceased to exist on a news release dated 12 March 2007. However, that news release only mentions that Oxford BioMedica (opponent 03) had acquired the patent proprietor company. It contains no information to the effect that the acquisition took place in the form of a merger or any other form of universal succession entailing as a consequence that appellant I would have ceased to exist. As the print-out from the Companies House Register submitted by appellant I confirms, appellant I is still an active company. There are therefore no doubts that the appeal has been validly filed by Oxxon Therapeutic Ltd. being an existing legal person and that that company continues to be the appellant I in the present appeal proceedings.

Exclusion of representatives from representation

6. Appellant III alleged the existence of a conflict of interest in the person of the representative having formerly represented appellant III (opponent 06) and formally still representing opponent 03 and now representing appellant I, the patent proprietor. The board notes first of all that even though the representative has not formally withdrawn from representation as regards opponent 03, he has not acted for opponent 03 in the present appeal proceedings. Opponent 03 is only a party as of right and has not taken position in the appeal proceedings, i.e. after having acquired the patent proprietor, which appears perfectly normal in the circumstances.

7. Appellant III did not indicate on which legal basis the board could be entitled to accede to its request and exclude the representatives of the office of Carpmaels and Ransford from further representing any of the parties, in particular appellant I, the patent proprietor, and the board also sees none.

8. The existence of a conflict of interest, if any, concerns the relation between the representative and his client and may, depending on the circumstances of the case, entail disciplinary measures being taken against the representative under the Regulation on discipline. This would not be a matter for the board.

9. By contrast, the validity of procedural acts undertaken by the representative for his client is not affected by the existence of a conflict of interest. Nor is there any legal basis for excluding a professional representative whose name appears on the list of professional representatives from representing a party in proceedings before the EPO (see also T 1009/97, supra; Headnote and point 2 et seq. of the Reasons). On the contrary, Article 134(5) EPC stipulates that persons whose names appear on the list of professional representatives shall be entitled to act in all proceedings established by the EPC. So are the representatives of the office of Carpmaels and Ransford.

Substantive matters

Article 54 EPC; novelty of claim 1 of the main request filed as "First Auxiliary Request- amended" on 24 October 2008.

10. The teachings of documents (3), (2), (45), (29), (26) and (56) were argued to be detrimental to novelty. In the following, their relevance will be assessed in the given order.

11. Document (3) teaches the use of a priming composition made of a non-replicating recombinant vaccinia virus expressing the model tumor associated antigen beta-galactosidase (MVA-LZ) and of a boosting composition comprising the non-replicating recombinant fowlpoxvirus vector FPV.bg40k also expressing beta-galactosidase, for the production of a potential anti-cancer vaccine (page 390).

12. Appellant I readily agreed that the replicative abilities of these two vectors were the same as those of the vectors contained in the prime/boost compositions for the now claimed use. The question relevant to novelty is whether or not the skilled person would regard the teaching of document (3) as a teaching - explicit or otherwise - of a regimen whereby the antigen used would trigger a CD8+ T cell immune response. It is without doubt that no reference at all is made in document (3) to such a response having taken place. For the skilled person, would it then be implicit that it did ?

13. Document (3) discloses that spleenocytes from mice primed with MVA-LZ reveal elevated levels of e.g. IFN-gamma (page 390, passage bridging the left- and right- hand columns). Furthermore, an experiment was carried out to compare the efficiency of homologous versus heterologous boosting. It led to the result that heterologous boosting is more efficient, at least in the experimental set-up where MVA-LZ is used for priming and FPV-bg40k is used for boosting. The reverse combination, however, does not generate any improvement in the immune response, notwithstanding that both vectors express beta-galactosidase (page 390, right-hand column).

14. Together with its statement of grounds of appeal, appellant I produced a diagram showing that the capacity of inducing cytokine secretion, e.g. IFN-gamma , belonged not only to CD8+ T cells but also to CD4+ T cells and NK cells, a point which was not challenged by appellant III in its comments on appellant I's grounds of appeal of 3 March 2008. Thus, the production of IFN-gamma observed in the experiments carried out in document (3) does not constitute a satisfactory albeit indirect proof that a CD8+ T cell immune response has taken place.

15. As for the observation that improvement of the immune response will or not be achieved depending on the order in which the vectors are used, beta-galactosidase being in any case expressed, it is possible to consider it as evidence that, when observed, the improvement is not due to the presence of beta-galactosidase. Otherwise stated, this observation suggests that beta-galactosidase does not contain "effective" CD8+ T cell epitopes in the given experimental circumstances since such epitopes would be expected to contribute to the improvement. In this context, it is worth mentioning that the statement at the end of the second full paragraph on page 390, right-hand column:

"Due to the aggressive nature of the tumor it is perhaps not surprising that treatment at a relatively late stage of tumor growth would not have a dramatic effect on survival even if heterologous boosting was advantageous."

is not sufficiently clear to have any kind of bearing - positive or negative- on the findings above.

16. In its letter dated of 3 March 2008 - dealing with the novelty issue -, appellant III did not argue that a CD8+ T cell immune response took place in any of the experiments described in the documents of the prior art, nor that it might have been a matter of common general knowledge that it would. The arguments rather went to the fact that the patent in suit did not demonstrate a CD8+ T cell immune response in any of the examples given. Of course, this may be of relevance to sufficiency of disclosure, but it does not change any of the findings in points 5 and 6 supra as regards the implicit teaching of document (3).

17. For these reasons, the board concludes that the skilled person would not have found in document (3) the explicit or implicit teaching of a CD8+ T cell immune response. Novelty is, thus, acknowledged.

18. Documents (2) and (45) provide the same teaching, the earlier being the published abstract of part of the content of the latter, a poster presentation. Both teach that heterologous boosting is better than homologous boosting to generate an immune response. Prime/boost vectors are tested, which possess the same replicative properties as those of the vectors for the now claimed use. In document (45), reference is made to two model antigens, beta-galactosidase and influenza nucleoprotein which are shown to generate an antibody response and a CTL response. However, the origin of the CTL response (CD8+ T cells, CD4+ T cells, NK cells) is not investigated. There is, thus, no clear and unambiguous disclosure of CD8+ T cells being involved in the immune response. Novelty is not affected by any of these documents.

19. Document (29) is concerned with studying antibody immune responses arising from a vaccination regimen comprising vectors with the same replicative abilities as the vectors for the now claimed use, the antigen being the hemagglutinin antigen of influenza virus. A reference to CTL responses is made on page 329:

"Although primary CTL responses against HA could not be demonstrated with one immunization, moderate CTL responses were obtained in primed spleen cells upon restimulation with influenza virus in vitro."

In the board's judgement, this statement falls well short of a clear and unambiguous disclosure that a CD8+ T cell immune response has taken place. For this reason and in accordance with the case law (T 509/04 of 5 July 2005 and T 836/01 of 7 October 2003), this document is not considered as relevant to novelty.

20. Document (26) is state of the art for the purpose of assessing novelty under Article 54(3) EPC 1973. It is concerned with the isolation of recombinant pox viruses capable of expressing cell-encoded tumor associated antigens e.g. gp100 and MART-1. Replicating vaccinia viruses and non-replicating fowlpox viruses are disclosed on page 7 as "useful in practising the present invention". The passage bridging pages 10 and 11 which is the only one dealing with prime/boost vaccination regimens reads as follows:

"A specific immune response to a tumor associated antigen can be generated by administering between about 10**(5)-10**(9) pfu of the recombinant pox virus .... The boosting antigen may preferably be administered using a second pox virus vector from a different pox genus..."

There is no mention in the document of the kind of immune responses to be expected, let alone of a CD8+ T cell immune response. The examples provided describe the isolation of specific vectors but not their use. In the board's judgement, the teachings of this document as regard vaccination with viral vectors are simply much too vague to be affecting novelty.

21. Document (56) teaches that human cytotoxic T cells may be generated where a sufficient amount of recombinant pox virus vector carrying the relevant antigen is introduced into a host and the host is thereafter contacted with additional antigen expressed from a second pox virus different from the first one. On pages 10 and 11, information is given as to which sites on the pox virus vector should be used to insert the DNA encoding the antigenic sequence without affecting viral viability. The prime/boost immunization protocols tested involve the recombinant vaccinia-CEA viral vector either for priming or for boosting (see e.g. Table 6). This vector is listed on page 15 amongst the pox viruses of interest and these are all life viral vectors. If only for this reason, document (56) is not novelty destroying for the subject-matter of claim 1 which is limited to non-replicative vectors. It must also be noted that no mention is made in document (56) of the cytotoxic response being due to CD8+ cells.

22. For the reasons given in points 11 to 21 supra, novelty is acknowledged.

Sufficiency of disclosure

23. Appellant III argued lack of sufficient disclosure on the basis of post-published documents (81) and (83). Document (81) is concerned with a vaccine efficacy trial against malaria infection. This trial involves a prime/boost regimen with DNA prime vectors and MVA viral boost vectors expressing an antigenic peptide comprising, amongst others, 14 CD8+ T cell epitopes (page 129). On page 128, it is stated that:

"DNA/MVA prime-boost vaccination is safe and highly immunogenic for effector T-cell induction in a malaria endemic area. But despite having produced a substantial reduction in liver-stage parasites in challenge studies of non-immune volunteers, this first generation-cell inducing vaccine was ineffective at reducing the natural infection rate in semi-immune African adults."

And on page 134:

"Second-generation prime-boost vaccine strategies for malaria currently in or near to clinical evaluation include the following: use of a different viral vector as the priming agent that may lead to proportionately greater CD8+ rather than CD4+ T cell induction..."

Document (83) is concerned with a vaccine efficacy trial against HIV infection. HIV specific CD8+ immune responses are observed in 18% of all vaccinated volunteers.

In short, documents (81) and (83) confirm the role of CD8+ T cells in generating a immune response against malaria or HIV disclosed in the patent in suit.

24. It cannot be denied that the results obtained in field trials are not perfect as they do not show absolute protection against the disease. However, in accordance with the case law (e.g. T 315/03, OJ EPO 2006, 15), no such stringent criteria need be fulfilled for sufficiency of disclosure to be acknowledged. On the contrary, it is enough that on the basis of the information given in the patent, one may reasonably assume that the claimed use may be carried out. Of course, one will expect that further work be required to adjust to real life conditions but, unless proven otherwise, this work is considered of a routine kind well within the capacities of the skilled person.

25. The patent in suit (e.g. Examples 1 and 6 illustrating the invention in mice and chimpanzees) describes the involvement of CD8+ T cells in the protective immune response observed with prime/boost regimens comprising a source of malarial or HIV epitopes carried by non-replicative vector/non-replicative pox virus vector. The reproducibility of the assay (Elispot assay) which needs to be carried out to identify suitable CD8+ T cell epitopes has not been challenged.

26. For these reasons, sufficiency of disclosure is acknowledged.

Article 56 EPC; inventive step

27. In accordance with the case law (e.g. T 606/89 of 18 September 1990), the closest prior art is generally 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. The closest prior art must, thus, be a document which describes the induction of a CD8+ T cell protective immune response in a vaccination regimen, i.e. as already mentioned in the board's communication under Article 15(1) RPBA, document (57).

28. Document (57) is concerned with testing the effectiveness of several recombinant influenza and vaccinia viruses to induce a malaria specific immune response which is quantitatively evaluated with regard to epitope-specific humoral and CD8+ T cell responses and their capacity to confer protection against malaria. On page 4637, the authors explain that their primary aim had been to evaluate the worth of life viral vectors in vaccination regimens and, indeed, all recombinant viruses tested - even when attenuated - are life viral vectors. The results obtained show that comparable levels of epitope-specific CD8+ T cells are induced by influenza and vaccinia vectors carrying the entire circumsporozoite protein of Plasmodium yoelii or a small sequence representing only the T cell epitope (page 4646). Protective immunity - measured as the inhibition of liver stage development of malaria parasites - is enhanced when priming with recombinant influenza viruses is followed by boosting with recombinant vaccinia (page 4644). Interestingly from the point of view of vaccine development, when a highly attenuated recombinant vaccinia virus is used as a boost, 81% of the mice are fully resistant to malaria challenge (passage bridging pages 4646 and 4647). In the discussion section of the article, it is mentioned on page 4647:

"The fact that a highly attenuated recombinant vaccinia virus expressing a key malaria Ag is highly immunogenic makes this vector an attractive and viable vaccine candidate for human use."

and it is concluded as follows:

"From a more general point of view, our results underscore the considerable potential of life carriers for the development of vaccines".

29. Starting from the closest prior art, the problem to be solved may be defined as the provision of a further prime/ boost system for generating a protective CD8+ T cell immune response.

30. The solution provided is the prime/boost system of claim 1, making use of non-replicative vectors/non-replicative pox virus vectors to carry the antigen bearing CD8+ T cell epitopes.

31. Document (57) does not suggest such a prime/boost regimen. In fact, in the light of its teachings which emphasize the potential of life viral vectors, the skilled person would have rather been motivated to test further different prime/boost regimens involving life viral vectors. In view of the obvious advantages of attenuated life viral vectors in terms of safety - mentioned in document (57) -, he/she may have chosen to devise prime/boost systems with attenuated viral vectors. This, however, does not amount to choosing vectors which are non-replicative because attenuation may be achieved in many different ways - as shown in document (57) itself. Thus, document (57) on its own does not render obvious the claimed subject-matter.

32. Other documents of the state of the art do not specifically deal with an immune response due to CD8+ T cells and, therefore the combination of document (57) with either one of them cannot render the claimed invention obvious.

33. For these reasons, inventive step is acknowledged.

34. For sake of completeness, the relevance of document (2) for inventive step will also be reviewed as document (2) was considered to be the closest prior art in the earlier stages of the proceedings. Document (2) is a very short abstract which teaches the use of non-replicating vectors in prime/boost regimens for vaccination purposes (see point 18, supra). Various regimens are tested for their ability to induce a CTL reaction. The technical feature that the prime/boost combinations generate a protective CD8+ T cell immune response is not disclosed. No evidence has been provided that the skilled person would necessarily come to the conclusion that they did.

35. In the board's judgement, it would be an obvious desideratum when developing a vaccination protocol to achieve as high a level as possible of immune responses of all kinds. And, indeed, this is reflected in document (2) and the other documents of the state of the art by the fact that they teach to measure "generic" cytolytic activity - generated by CD8+ T cells but also CD4+ T cells and NK cells - as well as antibody responses as parameters reflecting the effectiveness of the vaccination regimen. Thus, it is only with the hindsight knowledge of the invention that this "generic strategy" can be regarded as making obvious the "specific strategy" of preferentially inducing CD8+ T cell immune responses. Document (2) does not affect the inventive step of the claimed subject-matter.

36. In its submissions dated 3 March 2008 in response to appellant I's statement of grounds of appeal, appellant III refers to its arguments against inventive step elaborated for the auxiliary request accepted by the opposition division as equally valid for the requests filed on appeal. These arguments presented on 11 June 2007 all deal with the obviousness of using the specific vectors MVA virus, Ty virus-like particles or adenovirus in the priming compositions. They are not relevant to present claim 1 which is not directed to the use of such specific priming compositions.

37. The objection was also raised that the CTL assays described in the patent in suit were not suited for distinguishing between CD8+ T cells, CD4+ T cells or NK cells. This is certainly true but in the patent in suit, the characterisation of the CD8+ T cells response is not made on the basis of a CTL assay but on the basis of the Elispot assay.

38. For the reasons given in points 27 to 32 supra, the requirements of Article 56 EPC are fulfilled.