T 0339/93 (Modified vaccinia virus/HEALTH RESEARCH, INC.) 18-04-1996

Admissibility of opposition and appeal

1. The Opposition Division had decided that the opposition was admissible, yet the Respondents again disputed this before the Board without themselves appealing. The Respondents relied on decision T 289/91 (OJ EPO 1994, 649, see point 2.1) which had said that an objection that the opposition is inadmissible, in that case also because the opponent was not entitled to file an opposition, could be raised at any stage of the proceedings, i.e. even at a late stage before the Board of Appeal, because the admissibility of the opposition was an indispensable procedural requirement for any substantive examination of the opposition submissions, and must therefore be examined by the EPO of its own motion. The Respondents also relied on the fact that as the Opposition Division upheld the patent as granted in accordance with their main request, they were not adversely affected for the purpose of Article 107 EPC and thus were neither entitled nor obliged to file an appeal to raise this issue of admissibility. The appellants asked that this challenge to the admissibility of the opposition, and hence the admissibility of the appeal, be found inadmissible by the Board.

2. For the Board to follow the request of the appellants, to find inadmissible the challenge itself to the admissibility of the opposition, would be a departure from what has been decided in previous cases. To ensure uniform application of the law, such departure should not take place without referring the question of the admissibility of the challenge to the Enlarged Board of Appeal. However the answer of the Enlarged Board would be neither necessary nor decisive for the outcome of this case, if this Board can come to the conclusion on the facts that the opposition is admissible. Accordingly the Board will first consider admissibility on the facts.

3. Article 99(1) EPC states that any person may give notice of opposition. There is no requirement that he have an interest. It is already a gloss on this to require that such person file the opposition in his own name, but following decision T 289/91 the Board is prepared to assume that the true identity of the opponent must be stated.

4. Here on the evidence the Board has no doubt that the named opponent is the true opponent. The board has had the benefit of a declaration from the opponent explaining the circumstances, and finds this borne out by the Respondents' witnesses themselves. As decision T 289/91 relied on by the Respondents makes clear, the Board can only ask for clarification by declaration if there are concrete grounds for believing that the identity of the opponent was in doubt, as was the case considered in decision T 635/88 (OJ EPO 1993, 608), where a third party had stated in writing that it was the opponent. The presumption that the named opponent is the true opponent is a strong one. Further in case T 590/93 (OJ EPO 1995, 337) the Board held that it followed from the expression "any person" in Article 99(1) EPC that the EPO was fully entitled to take declarations of identity at their face value and was not obliged to make enquiries into the opponent's real identity by questioning the veracity of his declaration. Hearsay evidence, as given here by one inventor, that the opponent apologized to him for filing the opposition because of a specific third party, is not such a concrete ground. The precise wording used is in dispute, but the Board finds that this incident merely shows that the Appellant did file the opposition, albeit possibly at the urging of that specific third party.

5. The evidence that the opponent and the specific third party are represented by the same attorneys does not serve to throw any doubt on the identity of the opponent. One can file an opposition, but would still like to persuade others to assist in substantiating it and possibly paying any legal costs. An opposition is not assignable as such, so that it and any appeal must usually be continued in the name of the original opponent, even if others may later have a greater interest in the outcome.

6. The Respondents seem rather to be arguing for a requirement going far beyond that of Article 99 EPC, namely that it must be shown that the person with the greatest interest filed the opposition. There is no warranty for such a requirement in the European Patent Convention.

7. As there might conceivably be a need for identifying hidden opponents who were contractually debarred from filing an opposition, the Respondents were asked by the Board whether the alleged true opponent, the specific third party, would have been under some contractual obligation not to oppose the patent. The answer was no. Thus no exceptional circumstances exist here, that might possibly make further investigation necessary on some ground of public policy of seeking to ensure the fulfilment of contracts.

8. In the circumstances the Board concludes that the opposition is admissible, and that neither the questions put forward by the Respondents nor any others need be put to the Enlarged Board to resolve this case. The request by the Respondents to refer its two questions to the Enlarged Board of Appeal is rejected.

Late filed documents

9. Six documents were filed during the written part of the appeal procedure which help in understanding the nature of the invention and the state of the art relating to vaccinia viruses. The Board decides to allow them into the proceedings. One further document was filed by the Appellant at oral proceedings (section IX, supra). After considering it, the Board came to the conclusion that it was not of any relevance and, therefore, decided to make use of its discretion under Article 114(2) EPC to refuse the request that it should be introduced into the proceedings.

Main request

Novelty (Article 54 EPC)

10. During the oral proceedings before the Opposition Division, the Appellant (then Opponent), as appears from the minutes, dropped his novelty objection once the Opposition Division had stated that it was evident that the subject matter of the requests before them had not been disclosed in the prior art, and also withdrew his objection under Article 83 EPC. The Opposition Division nevertheless in its decision indicated the basis on which it acknowledged that novelty over document (1) existed. While the Board agrees with the conclusion that novelty over document (1) exists, the Board does so on different reasoning. As this document (1), and the reasons why it does not destroy novelty, also need to be taken account of when considering inventive step, it appears convenient first to give the reasoning on which novelty exists.

11. The Opposition Division based its assessment of novelty over document (1) on the assumption that rabbit pox viruses should be considered as vaccinia viruses, relying on a statement in document (1) that rabbit pox viruses are sufficiently closely related to vaccinia as to be regarded as a subspecies. The Appellant identifies both viruses as serologically related, having 86.9-97.1% identity at the DNA level and restriction patterns which are 60% homologous. The Board takes the view that although closely related, the viruses are not the same and, therefore, will start the analysis of novelty on the basis that the two viruses are different.

12. Document (1) describes a "marker rescue" experiment whereby cell monolayers are concomitantly infected with rabbit pox DNA fragments and vaccinia virus temperature sensitive mutants. The viral progeny is selected for at high temperature (40 C). Any vaccinia viruses capable of growing at that temperature must necessarily have been "rescued", that is they have had the temperature sensitivity defect of their parent repaired. The mechanism by which this "rescue" occurs is the replacement of the defective piece of vaccinia DNA by insertion into the vaccinia genome of the equivalent non-defective rabbit pox DNA restriction fragment by a recombinant process. Thus, taking into account that the defect must have been located in an essential region of the genome, as a virus will not grow at high temperature, if it cannot perform an essential function at that temperature, document (1) shows the insertion of "foreign" rabbit pox DNA into an essential region of the vaccinia viral genome.

13. However, claim 1 requires the insertion of the foreign DNA fragment into a non-essential region of the genome. It is on this basis that the Board considers that document (1) does not destroy the novelty of the subject-matter of claim 1.

Inventive step (Article 56 EPC)

14. The Board agrees with the parties view that the closest prior art is document (2). It discloses that vaccinia virus exists in two forms, the L (large) and S (small) variants which may be distinguished by the size of their DNAs. Upon co-infection of sensitive CV-1 cells with the S variant and with specific restriction fragments carrying the DNA unique to the L variant, insertion of L variant-DNA into the S variant-genome is observed. Document (2) suggests that these results raise the possibility of utilizing pox viruses as vectors for foreign DNA.

15. The technical problem to be solved is making S variant vaccinia virus recombinant cloning or expression vectors.

16. The solution consists in a recombinant vaccinia virus which contains in a non-essential region of the genome a DNA segment which does not naturally occur in said virus, and which recombinant vaccinia virus has the properties specified in one of parts (a) to (c) of claim 1. The solution is arrived at in two steps, namely:

- flanking the foreign DNA to be ultimately carried by the vaccinia viral DNA with sequences derived from the non-essential regions of the viral genome,

- co-infecting sensitive cells with the molecule so obtained and an infective vaccinia virus.

17. Vaccinia viruses had already been used for approximately two hundred years for inoculation against smallpox. They were, thus, known as non-oncogenic viruses which could be expressed in mammals. Document (2) teaches that DNA can be recombined into them and suggests that they should be used as cloning vectors. In the Board's view, the skilled person would not have failed to appreciate the importance of these results, which implied that vaccinia viruses could become efficient and safe tools for introducing any DNA into mammals and obtaining expression thereof in mammals. Thus, it would have been obvious to try to find out if indeed vaccinia viruses could be made into cloning vectors.

18. The question to be asked with regard to inventive step is whether the skilled person would have reasonably expected that the project could be successfully brought to completion. In the Board's view, the skilled person on the basis of common knowledge available on vaccinia viruses, in particular, on the restriction patterns of the S and L variants (see document (11)) would have been aware that the L variant restriction fragments which could be recombined into the S variant genome were those which also carried at both extremities a substantial amount of DNA homologous to S variant-DNA, and would have concluded from Document (2) that for the L variant-DNA to be inserted into the S variant-genome, a recombination event had to take place between homologous portions of said DNA and genome.

19. Moreover, the skilled person considering this would also have taken into account document (1), which reports that ectromelia DNA may be inserted into the genome of the rabbit pox virus by a recombination process. Rabbit pox virus is known to be very similar to vaccinia virus, so that the skilled person would expect that a similar insertion of foreign DNA into the vaccinia viral genome should be possible. In document (1) two types of experiments are reported, of which the first related to rabbit pox whole genomic DNA and ectromelia viruses being co-infected into monolayers of sensitive cells. Ectromelia virus is unable to grow at 40 C, but it does produce haemagglutinin. Rabbit pox virus, on the other hand, grows at 40 C but does not produce haemagglutinin. The progeny coming out of the infection was selected for at 40. C. 3,3% of the viruses which grew at that temperature were positive in the haemadsorption test for haemagglutinin. According to the authors these viruses were recombinant rabbit pox viruses which had inserted in them and which expressed the ectromelia haemagglutinin gene.

20. During oral proceedings, the Respondents however submitted that as the experiment did not involve extensive purification of viral progeny, the possibility remained that the viral progeny was made of viral pseudotypes or of a mixture of rabbit pox and ectromelia viruses, i.e. of contaminants and not of genuine recombinant progeny. The Board cannot, of course, rule out that some contamination had taken place. However, the Board cannot, for the reasons given below, believe that readers would seriously believe that no recombination had taken place:

- It appears from reading document (1)(page 143:"..in a normal genome rescue experiment, there was some complementation of the coinfecting virus (data not shown)"), that the authors were aware that the design of their experiment enabled some ectromelia viruses to grow. Yet despite this, the authors did not consider that the plaques observed at 40 C would be contaminants.

- The work has been published in a respected scientific journal, which implies that it had been reviewed by peer scientists who, it can be expected, would have refused publication, had they been of the opinion that no recombination had been observed or that there was sufficient doubt for further verification to be required.

- One of the authors of document (1) has provided the Board with a declaration (document (23)) in which the experiments of document (1) were discussed, which leaves the Board in no doubt that chimeric pox viruses could be formed by co-infecting whole cells with one type of poxvirus and naked DNA from another type of poxviruses.

- One of the inventors has in 1988 published an article (document (24)), in which it is stated that the work of documents (1) or (2) had opened the way to setting up a vaccinia virus cloning system. It must, thus, be that, at that point in time, the scientific community at large believed that document (1) did show recombination.

21. Furthermore, it is the Board's opinion that readers of document (1) would have understood from the fact that recombinant rabbit pox viruses formed plaques, that the haemagglutinin encoding DNA had been inserted into a non-essential region of the rabbit pox genome.

22. The second experiment disclosed the marker rescue of rabbit pox DNA restriction fragments in ectromelia viruses. It was found that only some of the rabbit pox DNA restriction fragments are marker rescued in the ectromelia viruses which, then, became capable of growth at 40 C. In the Board's view, these ectromelia viruses cannot have been contaminants precisely because they were only obtained in the marker rescue of certain specific rabbit pox DNA fragments. Indeed, if they were contaminants, they should equally have been found in all marker rescue experiments, independently of the nature of the restriction digests. Furthermore, the Board does not believe that the fact that some rabbit pox restriction digests did not enable the ectromelia viruses to grow at 40 C, should be considered as evidence that recombination cannot occur. It should rather be kept in mind that for growth at 40 C to occur, expression of the rescued rabbit pox markers is also needed. It, thus, may just be that in the rabbit pox DNA restriction enzyme digests which do not enable growth at 40 C, the region of DNA which is necessary for growth was destroyed by the restriction enzyme. If any conclusion can be drawn from this second experiment, it is that recombination is possible between ectromelia and rabbit pox DNA, which agrees well with the results of the first experiment that ectromelia DNA can be inserted into rabbit pox DNA by a recombination process.

23. The Board concludes that the experiments reported in document (1) would be taken by the skilled reader at face value.

24. Further the Respondents have argued that the existence of the two variant forms of vaccinia viruses (document (11)) would be taken as evidence that the vaccinia viral genome was inherently unstable and, therefore, unsuitable as vector DNA, so that in spite of the teachings of document (1) and (2) the skilled person would have had a prejudice to the effect that it was not feasible to set up a cloning system with vaccinia viruses as vectors. In the Board's view, the existence of two vaccinia variants should rather be considered as an indication that DNA can be inserted into vaccinia with reasonable stability, because if the variant with a higher molecular weight were unstable, it could probably never have been isolated.

25. Document (2) thus provides the information that vaccinia viral DNA is capable of recombination with a DNA segment which is homologous to the vaccinia DNA in its extremities, and the suggestion that this raises the possibility of utilizing pox viruses as vectors for foreign DNA. Document (1) provides the information that foreign DNA is expressed when it is introduced into a non-essential region of the genomic DNA of a virus which is extremely close to vaccinia virus.

26. The skilled person starting from document (2) with the wish to solve the problem of making S variant vaccinia virus into recombinant cloning or expression vectors, would take into account document (1) relating to the very closely related rabbit pox viruses, and would derive from this the information with a reasonable expectation of success that vaccinia viruses are capable of recombination with a DNA segment which is homologous to the vaccinia DNA in its extremities, and that a vector made up of extremities homologous to vaccinia DNA and a cental part made up of foreign DNA should with a reasonable expectation of success allow this foreign DNA to be expressed in infected eukaryotic cells or host organisms and to encode an antigen or a biological product other than an antigen, that is to fulfil characteristic (b) of claim 1.

27. Characteristic (b) is the most broadly worded of the criteria (a), (b) or (c) stated in Claim 1 as properties that the recombinant vaccinia must have. The respondents have not alleged that any special measures need be taken to ensure the successful introduction or expression of foreign DNA in vaccinia virus by homologous recombination, nor is this apparent from the patent specification.

28. It would, thus, appear that, at the priority date, setting up a cloning system with vaccinia viruses as vectors would have been perceived as an endeavour likely to succeed and that isolating the recombinant vectors did not pose such problems as to prove that this assumption was wrong.

29. The Board is thus convinced that the skilled person at the priority date would have been able to arrive at a recombinant vaccinia virus characterized in that it contains in a non-essential region of the vaccinia genome a DNA segment which does not naturally occur in vaccinia viruses and which meet characteristic (b) of claim 1, and would have had a reasonable expectation of success in being able to do so. This means that Claim 1 of this request does not meet the requirements of Article 56 EPC, and it is not necessary, for this request, to consider whether the skilled person would also have a reasonable expectation of success for achieving characteristic (a) expression in a vaccinated mammal and of foreign DNA encoding an antigen which is capable of inducing an antibody-response or characteristic (c) the capacity of modifying, replacing or repairing defective genes in the infected eukaryotic cell or organism.

30. For the above reasons, the Board decides to reject the main request as not fulfilling the requirement of Article 56 EPC.

Auxiliary request I

31. Claim 1 differs from claim 1 of the main request in that the method of obtaining the claimed virus which is the subject-matter of granted claim 10 has been added as a further paragraph at the end of the claim, and the word "stably" has been inserted in the first line of the claim which, thus, reads: " A recombinant virus characterized in that it stably contains...", (emphasis added, see section X).

32. The method disclosed in claim 10 of the main request is the one used in the application as filed to isolate the claimed recombinant virus. The word "stably" does not appear as such in said application. The provided example shows, however, that the HA gene of influenza virus can be expressed from the vaccinia virus in cultured cells as well as in mammals. In the Board's view, these results imply that the insert must be stable. Furthermore, it is stated on page 9, lines 32 to 34 of the application as filed that other exogenous genes can similarly be introduced and expressed.

33. It is, thus, the Board's opinion that the amendments introduced into claim 1 do not result in the skilled person being presented with an information which is not directly and unambiguously derivable from the application as filed. Moreover, the amendments do not result in an extension of the subject-matter of the patent application. Accordingly, the auxiliary request fulfills the requirements of Article 123(2)(3) EPC.

34. In the Board's view, the word "stably" when used to define a DNA insertion has a definite although not necessarily quantitative meaning which is evident to the skilled person who will only be able to work with the recombinant virus if the inserted DNA remains in its place. It can, thus, be considered that the requirements of Article 84 EPC are fulfilled.

35. As for claim 1 of the main request no question as regards novelty arises.

36. The method of production of the recombinant virus by homologous recombination and the possibility that a prejudice existed in the art against viral stability have both been taken into account when assessing the inventive step of the main request. The reasoning developed in points 26 to 30, supra is, thus, equally valid for the claim 1 of this request. Accordingly, the same conclusion is reached that claim 1 of auxiliary request I does not fulfill the requirements of Article 56 EPC.

37. The Board decides to reject the auxiliary request I for lack of inventive step.

Auxiliary request II

38. Claim 1 of auxiliary request II differs from claim 1 of the main request by the insertion of the word "stably" in the first line of the claim and the addition of the expression "under vaccinia control" after the words "mammal", "host organisms" and " is" in parts (a), (b) and (c) respectively (see section XI, supra).

39. The origin of transcription of the herpes virus TK gene in the vaccinia virus recombinant is discussed on page 30 and 28 of application as filed. On page 32, the information is given that the HSV TK fragment is incorporated into the vaccinia virus in the cell and is then capable of replication and expression under vaccinia control. However, it is stated on page 28 where the experiment is described in more detail that a vaccinia virus promoter or the internal TK promoter could equally be responsible for the initiation of transcription of the TK gene. There is, thus, no unambiguous disclosure in the application as filed that the exemplified gene is expressed under vaccinia control. Nor is there any suggestion as to which specific control region should be used for the expression of other foreign genes.

40. The Board is of the opinion that the information that the foreign DNA segment should be expressed under vaccinia control is not directly and unambiguously derivable from the application as filed. The claim contains subject-matter which extends beyond the content of said application. The auxiliary request II is, thus, rejected as not fulfilling the requirements of Article 123(2) EPC.

Auxiliary request III

41. Claim 1 of this request is based on a combination of claims 1, 10 and 14 as granted, and directed to a vaccine comprising a recombinant vaccinia virus characterized in that it stably contains in a non-essential region of the vaccinia genome a DNA segment which does not naturally occur in vaccinia viruses limited to characteristic (a) of Claim 1 as granted, and obtainable by the method of claim 10 as granted. The addition of the word "stably" here may be supported on the reasoning given in relation to Auxiliary request I above, and at first sight the requirements of Articles 123(2) and (3) EPC appear to be met.

42. The Board is thus prepared to allow the request into the proceedings, but the Board does not consider it appropriate to carry out the examination required under Article 102(3) EPC itself, but decides to use its powers under Article 111(1) EPC to remit the case to the Opposition Division for further prosecution. This will allow both the Respondents and the Appellants to direct their arguments on this request, in the knowledge of the reasoning on which the Board refused the other requests.