T 0977/93 (Canine coronavirus vaccine) 30-03-1999

Reasons for the Decision

1. The appeal is admissible

Article 123(2) and (3) EPC

2. The passage in claim 1 "at least eight passages at a low virus to cell ratio of about 1:1000 to 1:10000, as measured by the TCID50 method" finds a basis on page 7, lines 10 to 15, of the application as filed. The wording in claim 1 "by parenteral administration" finds a basis on page 5, line 19, of the application as filed. These added features are restrictive in nature. The amendments in claims 11 and 17 (see section IX above) merely make it clear that the canine coronavirus vaccine has to be inactivated (see claim 1b) and that the claimed method relates to a vaccine according to claim 1a respectively. Consequently, the requirements of Article 123(2) and (3) are fulfilled.

Prior use

3. According to decision G 1/92, point 1.4 (supra), an essential purpose of a technical teaching is to enable the person skilled in the art to manufacture or use a given product by applying such teaching. Where such teaching results from a product put on the market, the person skilled in the art will have to rely on his general technical knowledge to gather all the information enabling him to prepare the said product. Where it is possible for the skilled person to discover the composition or the internal structure of the product and to reproduce it, then both the product and its composition or internal structure become part of the state of the art. The rationale emerging from this decision is that the properties of a product are considered not to have been made available to the public within the meaning of Article 54(2) EPC if the skilled person had no means of establishing the composition or the internal structure of the product and was not able to reproduce it, in spite of the product's being in the public's hands before the priority date of the patent.

4. The respondents have provided a great many documents to substantiate the prior use of the invention by the public availability of Duramune C® and Coronavac®. The board will deal first with the question of whether or not the prior use argued by the respondents satisfies the requirements of analysability and reproducibility prescribed by decision G 1/92 (supra). If it transpires that the prior use does not satisfy these requirements, then the task of establishing whether Duramune C® and Coronavac® were actually in the hands of a member of the public before the priority date of the patent in suit and fell within the scope of claim 1 at issue, becomes superfluous.

5. It should be established whether or not the skilled person having Coronavac® or Duramune C® in his/her hands could have derived therefrom any of the three features (1) to (3) indicated in claim 1 at issue (see paragraph IX supra), namely that:

(1) the vaccine contained CCV attenuated by at least eight passages through feline cells at a low virus to cell ratio of about 1:1000 to 1:10000, as measured by the TCID50 method (claim 1a), that

(2) the attenuated virus when administered to a dog by injection selectively infected the intestinal epithelium (claim 1a), and that

(3) upon parenteral administration, the avirulent antigenic product protected dogs from infection by virulent CCV (claim 1a and 1b).

6. As regards feature (1), it is common general knowledge that attenuation of a virus is performed in living material (eg animal cells) in order to induce specific genetic changes (mutations, deletions, etc.) reducing virulence of the virus while maintaining its immunogenicity. By each additional passage through the host cell, further genetic modifications occur influencing immunogenicity and/or infectivity of the virus. These changes depend upon the host cell in which attenuation is performed and on the conditions (inter alia the number of passages and the virus/cell ratio) applied. As to the possibility by a skilled person in possession of Coronavac® or Duramune C® before the priority date of the patent in suit of determining the conditions and the host cell in which the virus was attenuated, the board is convinced by the statement in paragraph 6 of document (64) that achieving this task was impossible. One major obstacle was obviously represented by the impossibility of correlating the genetic modifications to the number of passages, to the nature of the host cell or to the virus/cell ratio.

7. As for feature (2), namely the selective infection of the dog's intestinal epithelium upon parenteral administration of the claimed attenuated vaccine, the board agrees with the respondents that this feature is inherent (cf "the doctrine of inherency") in the interaction of the attenuated live CCV vaccine with the dog. Yet, this does not mean that the board is exempted from evaluating whether this feature was a "hidden" one or was accessible to the skilled person before the priority date of the patent in suit. This follows from the rationale emerging from decision G 2/88, OJ EPO 1990, 93, see point 10.1), which states: "Under Article 54(2) EPC the question to be decided is what has been "made available" to the public: the question is not what may have been "inherent" in what was made available (by a prior written description, or in what has previously been used (prior use), for example)".

8. The board notes that a prerequisite for feature (2) to have become accessible to the skilled person is that the exact mechanism through which Coronavac® or Duramune C® conferred protection on dogs had to be known to him/her. However, before the priority date of the patent in suit, nothing was even known about the immunity mechanism to the CCV and later document (15), published in August 1983, taken as an expert's opinion, shows this (see page 558, last full paragraph: "Still less is known about immunity to canine coronavirus"). What was known before the priority date was that virulent CCV infected the dog's intestine via the oral route (see document (10), page 26, under the heading "Route of infection") but that parenteral administration of the virus did not result in intestinal infection (ibid., page 28, left-hand column). This did not mean to the skilled person that an attenuated CCV had to behave in the same way. Especially where the attenuated virus was administered via the parenteral route, there was no certainty that this characteristic would remain active. Therefore it is the board's view that there was no means available by which this feature could have been established.

9. The respondents argue that feature (2) and a method for testing it had been revealed during Dr Acree's conference (see document (62), page 24/51, section IV.5.a, and page 25/51, section E.1). However, the board observes that document (62) merely reports that an undefined CCV vaccine administered parenterally elicits 95% intestinal protection. The document does not specify whether the vaccine is Coronavac® or Duramune C® or whether it is a live attenuated vaccine, an inactivated one or something else. Furthermore, "intestinal protection" is not necessarily linked to feature (2), namely "selectively infects the intestinal epithelium" since intestinal protection may be due to local antibodies and not to infection by the virus. It is also true that document (62) (see page 9/51, section 3) discloses a technique based on "fluorescent antibody staining of intestinal material". However, this technique is cited in the context of the diagnosis of canine coronavirus (see heading on page 9/51), not in the context of evaluating "intestinal protection" of the undefined CCV vaccine referred to therein. Thus, in conclusion, even assuming that combining document (62) with the prior use of Coronavac® or Duramune C® were permissible in a novelty issue, feature (2) remained concealed from the skilled person before the priority date of the patent in suit.

10. As regards feature (3), namely that the avirulent antigenic product emerging either from the live canine coronavirus attenuated according to claim 1a or from inactivated feline or canine cell propagated canine coronavirus (claim 1b) protected dogs by parenteral administration from infection by CCV, the board observes that before the priority date of the patent in suit diagnosis of CCV infection based only on the clinical signs was impossible. In fact, later document (15) (published August 1983), taken as an expert's opinion, confirms this on page 551 under the heading "Clinical Diagnosis". Document (62) also states on page 9/51 (point 2) that "a diagnosis of CCV gastroenteritis based on the symptoms can be misleading". Thus, field efficacy trials did not correlate with and thus could not be predictive of immunoprotection. This lack of correlation also applied to serological studies since humoral antibodies did not imply protection (see document (10), page 28, left-hand column, under "Immunity"). Thus, in order to overcome this obstacle, the skilled person had to turn to a reliable experimental challenge model for evaluating whether a given vaccine actually conferred protection. However, this experimental challenge model was not available to the skilled person before the priority date of the patent in suit. It was also kept secret during Dr Acree's conference (see document 62, page 25/51, section E.1: "The specific procedure used to evaluate the efficacy of a vaccine cannot be discussed"). This experimental challenge model was based on the finding of claim 25 of the patent in suit which consists in examining intestinal tract samples of the vaccinated dog and control dog both challenged with the CCV to determine the degree of replication of the challenge virus. Consequently, since the skilled person could not reliably evaluate before the priority date of the patent in suit whether or not feature (3) was shared by a given CCV vaccine, it must be concluded that feature (3) was also concealed from the skilled person.

Reproducibility

11.1 The respondents argue that availability of one of the prior use vaccines was possible by reproduction of the vaccine by departing from a single vial of eg Coronavac® used as a master seed stock and subjecting it to a limited series of passages in canine cells. However, in the board's view, two important reasons exist against the respondents' line of argument.

11.2 Firstly, point 1.4 of decision G 1/92 (see point 3 supra) states that an essential purpose of a technical teaching is to enable the person skilled in the art to manufacture or use a given product by applying such teaching. Thus, as a corollary, the manufacture or use of a given product requires that one has to understand the composition or the internal structure of the product. Hence reproducibility of a product requires that one has to understand before and after reproduction what one has in one's hands, otherwise "blindfold" reproduction will lead to something uncontrollable. But in the particular situation at issue, the skilled person did not and could not know whether features (1) to (3) above were present in the vaccine commercially available or in a reproduced vaccine (see points 6 to 10 supra). Therefore it was impossible to establish the identity of the reproduced vaccine with the starting vaccine.

11.3 Secondly, the probability of a genetic change in the virus' genome upon propagation in a living host cell was very high. Any virus when propagated may undergo genetic changes susceptible of altering eg the tissue tropism, the virulence, the attenuation markers or the thermal stability. This is in line with document (46), according to which, when propagating a live virus vaccine, only a limited number of passages have to be made to prevent undesirable mutations (see page 618, l-h column, second paragraph). But later documents show that single-stranded RNA viruses such as CCV are particularly predisposed to said mutations (see document (66), paragraph bridging pages 257 and 258 and document (63), bottom of page 65). As already pointed out under point 6 supra, these genetic alterations depend upon the host cell in which propagation is performed and on the conditions (inter alia the number of passages and the virus/cell ratio) applied.

12. Before the priority date of the patent in suit, the two facts mentioned above (ie the lack of understanding of the composition or the internal structure of the product by the skilled person and the high probability of a genetic change in the virus' genome upon propagation in a living host cell) thus combined to induce an uncontrollable situation, if an attempt was made to expand a commercially available CCV vaccine vial. For instance, since it was not possible to understand the true nature of the vial's content, other than that it was "a modified live CCV vaccine modified by special tissue procedures" (see page 72 of document (25), ie the leaflet accompanying the vial), there was also a lack of guidance as to the measures to be taken to propagate the CCV and the probability was high that the virus would have reverted to the virulent stage (see patent in suit, page 5, lines 25 to 29) if the skilled person did that. In conclusion, while it is not in dispute that it was possible to amplify the CCV virus by departing from a single vial of, for example, Coronavac® used as a "master seed stock" and subjecting it to a limited series of passages, the board cannot accept that this amplified CCV virus be qualified as the "claimed vaccine", in the absence of means to make sure that it is. Thus, there is a close connection between the requirements stated in decision G 1/92 (supra) that a product belonging to the public domain can be made and used and its analysability.

13. Thus, even presuming that Duramune C® and Coronavac® were in the hands of the public before the priority date of the patent in suit, features (1) to (3) referred to in the claim would not have been made available to the public within the meaning of Article 54(2) EPC since the skilled person had no means of establishing these features and was also not able to monitor reproduction so as to ensure that features of the "master feed stock" were maintained. The subject-matter of the claims at issue is therefore not affected by the mere existence in the public domain of Duramune C® and/or Coronavac®.

The board is also not in a position to identify further prior art disclosing the claimed subject-matter. It must be concluded that the claims of the sole request satisfy the requirements of Article 54 EPC.

Inventive step

Closest prior art

14. The respondents maintain that the closest prior art is represented by Dr Acree's oral disclosure (document (62)) and by Coronavac®'s and Duramune C®'s being available on the market, while the appellant views document (10) supplemented by later document (15), taken as an expert's opinion, as the closest prior art. Yet post-published document (15) cannot be taken into consideration for evaluating the inventive step. The board will also disregard in this context the vaccines Coronavac® and/or Duramune C® since, as stated above, the latter failed to reveal any intrinsic or extrinsic feature of the vaccine to the skilled person, and therefore it was not possible to produce and use them.

Document (10) is considered by the board as the closest prior art since it is concerned with CCV enteritis in dogs and immunity to CCV. It states that in previous experiments including parenteral administration of CCV preparations, whether attenuated or not, no full protection could be obtained and that a vaccine for protection against CCV was not available. It also states that local immunity in the intestine is essential for protection against CCV infection.

Document (62) reports that an undefined CCV vaccine administered parenterally elicits 95% intestinal protection, without specifying whether the vaccine is a live attenuated vaccine, an inactivated one or something else, and without teaching how the said vaccine is arrived at. Thus, in conclusion, this document does not provide any further technical teaching in comparison with document (10) but merely confirms what was already known from document (10), namely that local immunity at the intestinal level is essential for protection against CCV infection.

Problem to be solved and its solution

15. Departing from document (10), the technical problem to be solved by the patent in suit can be seen in the provision of effective protection for dogs from CCV infection and means for arriving at an effective vaccine. The board is satisfied that said problem has been solved by the vaccines according to claims 1 to 10, the process according to claims 11 to 16 and the methods according to claims 17 to 28, in view of the immunisation results referred to in eg Examples 5 and 15.

16. It has to be established whether or not the solution to the above problem followed in an obvious manner from document (10). In the board's opinion, document (10) provided no guidelines for arriving at the claimed vaccines other than the teaching that an effective vaccine had to confer local immunity at the intestinal level. Moreover, the statement made in document (10) (see page 28, r-h column), according to which parenteral administration of CCV preparations, whether or not attenuated, did not achieve full protection, would have discouraged the skilled person from embarking upon the development of a vaccine to be administered parenterally. Rather, the skilled person would have thought of developing an oral vaccine because it is stated on page 28, l-h column of document (10), that "dogs infected orally become immune".

17. As regards the inactivated CCV vaccine (claim 1b), not only did no prior art document suggest making an inactivated CCV vaccine, but, in the board's judgment, nor did the scientific community expect an inactivated CCV vaccine, let alone a parenterally administered one, to confer intestinal protection since there was a conviction within that community that only attenuated live CCV vaccine administered orally could have elicited a sufficient immunological response (see point 16 supra). Further, the influence of the inactivation procedure on the epitopes required for conferring protection was unpredictable.

18. The board also observes that arriving at the claimed vaccines was not straightforward because the important blockage emphasised in point 9 supra (an experimental challenge model was not available to the skilled person before the priority date of the patent in suit) had to be overcome. No prior art document pointed to the method for evaluating the effectiveness of a CCV vaccine according to claim 25 of the patent in suit which consisted in examining intestinal tract samples of the vaccinated dog and control dog both challenged with the CCV to determine the degree of replication of the challenge virus. Nor was the further technical information for arriving at the claimed vaccines suggested by any prior art document, namely that attenuation of the CCV had to be made according to independent method claim 23 at issue, ie by passaging CCV between 8 to 60 times in feline cells at a very low virus to cell ratio (between 1:1000 to 10000).

19. The respondents' argument based on document (62) and the availability on the market of the two vaccines Coronavac® and/or Duramune C® is also not convincing. This is because, on the one hand, document (62) did not specify whether the vaccine was a live attenuated vaccine, an inactivated one or something else, and more importantly it did not teach how the said vaccine was arrived at, and on the other hand, Coronavac® and/or Duramune C®, even if they were available to the public, would have been of no help (see points 9 to 10 supra).

20. The respondents further argued that there was a very high expectation of success that attenuating CCV would have led to an effective vaccine in view of document (3), which disclosed the manufacture of an attenuated TGEV live vaccine and an inactivated vaccine both conferring protection when administered parenterally. Yet the board observes that TGEV is not akin to dogs' coronaviridae but only serologically cross-reactive with CCV and the virus does not protect dogs from CCV infection (document (10), page 28, right-hand column). In the light of the fact that the even closer prior art relating to CCV (documents 10 and 62) did not provide any hint that protection upon parenteral administration of an attenuated CCV vaccine would be envisaged, the board does not consider the results obtained with TGEV to be transferable to CCV. In any case, document (3) does not teach or suggest the features indicated in claim 1.

21. In view of the above findings, the board concludes that the subject-matter of claim 1 and dependent claims 2 to 22 satisfy the requirements of Article 56 EPC. This conclusion also extends to the subject-matter of independent claims 23 and 25 because, as already discussed in point 18 supra, these claims are directed to a CCV attenuation method and a method for evaluating the effectiveness of a CCV vaccine respectively, not suggested by any prior art document on file. These are thus non-obvious means of arriving at the claimed vaccines, and also at claims 24 and 26 to 28 dependent thereupon.