T 0296/93 (HBV antigen production) 28-07-1994

Reasons for the Decision

1. Admissibility and other procedural questions

The appeal is admissible.

The submissions by Respondent II and by the Appellant on 10. August 1994 and 16 August 1994, respectively, are disregarded because they were filed after closing of the debate (in this respect see decision T 595/90 of 24 May 1993, to be published in the OJ of the EPO, in particular point 1 of the Reasons) and, what's more, after the announcement of the decision (see G 12/91, OJ EPO 1994, 285, points 2 and 3).

2. Admissibility of intervention (Article 105 EPC)

2.1. The Board firstly observes that the Opposition Division, through its announcement of the decision on 28 October 1992 to revoke the patent, had effectively severed itself from the case, and therefore could not take any decision on the intervention matter. Had no appeal been lodged against the decision to revoke, the intervention would have had no standing at all (see G 4/91, OJ EPO 1993, 707). This matter therefore must be dealt with by the Board. In G 1/94 of 11 May 1994 (to be published in the OJ of the EPO), the Enlarged Board of Appeal further established that an intervention at the appeal stage is admissible.

2.2. Article 105(1) EPC reads as follows:

"In the event of an opposition to a European patent being filed, any third party who proves that proceedings for infringement of the same patent have been instituted against him may, after the opposition period has expired, intervene in the opposition proceedings, if he gives notice of intervention within three months of the date on which the infringement proceedings were instituted. The same shall apply in respect of any third party who proves both that the proprietor of the patent has requested he cease alleged infringement of the patent and that he has instituted proceedings for a court ruling that he is not infringing the patent."

2.3. In the negotiations leading up to the adoption of the EPC, the question of intervention was raised in 1971 in Working Group I, who decided to propose the introduction of such an opportunity for third persons to enter into opposition proceedings, the object being to make it possible for an alleged infringer to avoid having to defend himself before a national court although central opposition proceedings were still pending before the EPO (BR/144/71, points 75 to 77).

In subsequent meetings to discuss further details, proposals were made to ensure that interventions would not lead to delays of the opposition proceedings (BR 168/72, BR 169/72, and BR 177/72). These time considerations led to a fixed period of three months after the institution of infringement proceedings before a national court.

In preparation for the Munich Diplomatic Conference in 1973, the Swiss delegation proposed a separate possibility to intervene, in the situation where no infringement action had been instituted by the Patentee, but he had requested - for example in an ordinary letter - a third party to stop infringing the patent and the third party had initiated proceedings for a court ruling that he was not infringing the patent (M/31, 28 May 1973). This proposal was adopted by the Conference (M/PR/I, page 51), although one delegation questioned whether this further opportunity would not indeed cause delays in the opposition proceedings.

2.4. The Board cannot agree with the Intervener that the above cited travaux préparatoires indicate a right to choose at will which starting point for calculating the time period for intervention to invoke.

The second possibility of intervention was only introduced to make it possible at all for a third party to enter the centralised proceedings before the EPO, although no formal infringement action had been raised. The situation for this second category of Interveners is in fact identical to the first, with the very important difference that he otherwise could not avail himself of the centralised EPO proceedings. This was not considered justified in the case where a patentee chooses not to start a court action, thereby preempting the Intervener. The latter would then have to institute national proceedings himself, proceedings which could prove to be needless, i.e. if the patent were later to be revoked by the EPO.

2.5. The provision of the institution of court actions as starting dates for the calculation of the time periods for interventions guarantees an indisputable official date. As the Appellant rightly pointed out, it is not customary in procedural law that a party who wants to avail itself of a time limit also holds the means by which the starting point for its calculation can be controlled.

The principle behind Article 105 EPC is that, as soon as any court action has been brought, the sole available period for intervention starts running. Any other interpretation would open the possibility of abuse of the intervention opportunity by the filing of national invalidity actions in order simply to trigger a new time limit under Article 105 EPC, regardless of earlier circumstances.

2.6. Consequently, the Board finds that the two alternatives offered under Article 105(1) EPC, first and second sentence respectively, are mutually exclusive for the same case of infringement. With regard to the same patent, an alleged infringer can only belong to one category, the decisive factor being which court action was the first to be instituted.

2.7. In the present case, therefore, the time period for intervention was triggered by the writ of summons of 1 July 1992. Not having been filed within three months of that date, the notice of intervention does not meet the requirements of Article 105(1), first sentence, EPC, and must therefore be rejected as inadmissible.

3. Formal allowability of the amended claims (Article 123(2) and (3) EPC)

The deletion of Claims 5 to 7 (Claims 5 and 7 for AT) as well as the consequent renumbering and changes in dependencies of the remaining claims resulted neither in an extension of the protection nor in the generation of new subject-matter. Thus, there are no objections under Article 123(2) and (3) EPC to the amended claims.

4. Entitlement to priority (Article 87 EPC)

4.1. The right to priority is governed by Article 87, which requires that the European patent application and the application whose priority is claimed relate to the same invention. Thus, the main criterion in this respect is whether the claimed invention is disclosed in the priority document as a matter of substance, i.e. with all its essential features. According to decision T 81/87 (loc.cit.) the disclosure of the essential elements "must be either express, or be directly and unambiguously implied by the text. Missing elements which are to be recognized as essential only later on are thus not part of the disclosure". This view was confirmed in a number of decisions of the Boards of Appeal (see, for example, T 301/87, loc.cit.).

4.2. The claimed subject-matter

Claim 1 (non-AT) at issue is essentially directed to a recombinant DNA molecule in which a DNA sequence coding for a polypeptide (or a fragment thereof) displaying HBV antigen specificity is operatively linked to an expression control sequence so as to be expressed in a suitable transformed host cell.

Claim 2 further specifies that the expressed polypeptide also displays HBV antigenicity.

Claims 3 and 4 specify that the said DNA sequence codes for a polypeptide (or fragment thereof) displaying the HBV antigen specificity of HBcAg and HBsAg, respectively.

Claims 5 to 23, which each refers back to one or more of the Claims 1 to 4, concern transformed host cells, the polypeptides thereby produced, compositions for stimulating the production of antibodies to HBV, means and a method for detecting HBV infections in blood serum, DNA sequences encoding HBV antigens.

4.3. The subject-matter of the BI priority document

The BI priority document relates to the transformation of host microorganisms with vectors containing HBV DNA, appropriately cleaved and inserted, so that they produce polypeptides with the specificity of HBV antigens (see page 3, lines 10 to 25). The intended purpose thereof is the provision of HBV antigen for vaccine studies and for use in the detection of the infection (see page 3, lines 2 to 5 and page 4, lines 12 to 16).

The said document teaches in general terms cleaving HBV DNA at only a single, or at most a few sites, with a restriction enzyme such as Kpn I, Bgl II, Bam HI, Ava I and Eco RI, inserting at least one of the resulting fragments into a vector such as a bacterial plasmid, transforming host microorganisms therewith, culturing the said transformed hosts and collecting the polypeptide from the culture (see page 4, line 3 to page 5, line 8).

In a specific worked example (see pages 5 to 9), HBV DNA is prepared from Dane particles and cleaved with Kpn I. The digestion products are inserted into the Pst site of pBR322. E.coli host cells are transformed with the resulting vectors, screened by colony hybridisation and tested for the production of HBV specific antigens by means of a radioimmunoassay with HBV antibodies. Cultures designated as deposit A are found to give a positive response both in the colony hybridisation and in the test for the viral antigen (see page 11). As established in the parallel case T 886/91 (loc.cit., see point 4.2 of the Reasons), this deposit corresponds to deposit A (NCIB 11548), which in the European patent specification is shown to produce a polypeptide with HBcAg antigen specificity.

In another worked example (see page 10), E.coli host cells transformed with vectors containing Bam HI fragments of HBV DNA designated as deposit B are also found to give a positive response both in the colony hybridisation and in the test for the viral antigen (see page 11). As established in the parallel case T 886/91 (loc.cit., see point 4.2 of the Reasons), this deposit corresponds to deposit B (NCIB 11549), which in the European patent specification is shown to produce a polypeptide with HBcAg antigen specificity.

Other examples of successful insertion of HBV DNA fragments into a plasmid, as measured by the positive signal in the colony hybridisation assay, are reported (see page 10, line 19 to page 11, line 14). However, no data with respect to viral antigen expression are reported in this case.

4.4. The essential elements of the disclosure in the BI priority document are:

- the cleavage of isolated HBV DNA with selected restriction enzymes;

- the insertion of the resulting fragments into a vector carrying selectable markers (drug resistance genes);

- the transformation of host cells with the resulting recombinant DNA molecule, their culture and selection on the basis of drug resistance;

- the screening of the transformants by colony hybridisation;

- detection and characterization of recombinants by means of immunological methods.

It is directly and unambiguously implied by the text that the expressed product could be a protein displaying the antigen specificity and antigenicity of one or more of the known HBV antigens, e.g. HBcAg and HBsAg, depending on the HBV DNA fragment used (see page 4, lines 17 to 20), and that detection and characterization should therefore be carried out by means of the corresponding specific antibodies (see inter alia page 9, lines 15 to 16). Such antibodies were admittedly available in the art at the BI priority date.

Compositions for stimulating the production of antibodies to HBV, means and methods for detecting HBV infections are also implied by the text of the BI priority document (see, for example, page 4 lines 12 to 16).

4.5. The fact that no actual demonstration of expression of either HBcAg or HBsAg is provided in the BI priority document is used by the Respondents as an argument to show that not all essential elements are disclosed therein.

In the Board's opinion, the lack of actual data on the production of a polypeptide with the antigen specificity and antigenicity of one or the other HBV antigen does not necessarily lead to the conclusion that essential elements of the claimed invention are missing in the disclosure of the BI priority document.

The worked examples in the BI priority document demonstrate that, by following the said experimental approach, expression in a recombinant DNA system of polypeptides displaying HBV antigen specificity can indeed be achieved. In this respect, it must also be kept in mind that expression of HBV antigen in general, not the efficiency of expression is at issue here.

None of the Respondents has succeeded in discharging the onus of proof by demonstrating that, by proceeding experimentally as indicated in the BI priority document, expression of proteins having the antigen specificity and antigenicity of either HBcAg or HBsAg cannot be achieved to some extent. The Respondents have been unable to point to one or more essential elements recognised as essential only later which are missing in the BI priority document. Their objections derive mainly from the lack of actual data on the polypeptides which are or can be expressed, not from any proven inadequacy of the disclosed experimental approach.

The evidence on file rather indicates that, by proceeding experimentally as taught in the BI priority document, expression of proteins having the antigen specificity and antigenicity of either HBcAg or HBsAg was achieved to some extent. The European patent specification confirms the validity of the approach and demonstrates inter alia that deposits A and B express polypeptides with the antigen specificity of HBcAg. The witness statement by Prof. K. Murray (attachment 7 submitted by Respondent IV) shows that some recombinant colonies gave positive signals in immunological assays also for surface antigen (see, for example, items 94 to 96). The cautious nature of Prof. K. Murray's statements in respect of the latter results [see, for example, attachment B(1); cf. Section XI a), above] are fully understandable when due account is taken of the complexity of the project and of the need to avoid a false interpretation of the results by carrying out further verifications. None of the Respondents, however, could successfully demonstrate that expression of polypeptides with HBsAg antigen specificity (even at a faint level) was impossible when following the teaching of the BI priority document. The criticism by the Respondents stems essentially from the fact that the results referred to by Prof. Murray were preliminary and indicative. However, it must be remembered that what is at issue here is the expression of the desired polypeptides as such at any level (from faint to strong), not the improvement of any already known expression system.

4.6. In conclusion, the Board is not convinced by the Respondent's arguments that priority document BI is deficient in respect of relevant technical information necessary for reducing the claimed invention to practice by the person skilled in the art without undue burden (see points 4.4 and 4.5). If no essential elements (i.e. features) of the claimed invention can be said to have been recognised or added only later on in the sense that they are not part of the disclosure of the priority document, the claims under discussion and the priority document on which they are based must be regarded as relating to the same invention within the meaning of Article 87(1) EPC. Consequently, in line also with the existing EPO jurisprudence on this matter (see, for example, T 81/88, T 73/88 and T 301/87, loc.cit.), the said claims are considered to be entitled to the BI priority date.

4.7. As for the request put forward by Respondent IV to refer the legal question quoted above in section XI, item (a), last paragraph, to the Enlarged Board of Appeal, the present Board considers it unnecessary because it is already evident that, under the present EPO jurisprudence, the answer to the said question is that a broad claim must find adequate support for all its essential elements in the priority document (see point 4.1, above). However, this is a matter of substantive nature which must be decided in each particular case on its own merit.

In the present case, for the reasons given above, the Board has come to the conclusion that the claims at issue are entitled to the BI priority date.

5. The citability of document (3)

5.1. Document (3), published in the issue No.16, of Volume 287 of the "C.R.Acad.Sc. Paris", bears the date 18. December 1978. A footnote on page 1456 mentions "the meeting of 6 November 1978".

The Appellant submitted evidence aimed at showing that no oral presentation of the contents of the document (3) was made at any public session of the Academy of Sciences and that the published article was not sent out until 1 February 1979.

The Respondents agreed that the date of 6 November 1978 was in relation to the internal procedure of evaluation of the articles by the Reading Committee of the Academy which occurred under conditions of confidentiality. Thus, there is consensus on the fact that the said date is meaningless for the purpose of Article 54(2) EPC.

However, Respondent II insisted that document (3) must have been available at least at the Académie des Sciences, a public institution, on the date which it carried, i.e. on 18 December 1978. In its opinion, the testimonial letter of Mr Paul Germain, Permanent Secretary of the Institut de France, Académie des Sciences, did not exclude this (see exhibit 8). Moreover, in its submission, none of the letters from different technical libraries (see exhibit 9) provided information on the date on which document (3) had been received. Respondent II submitted evidence which, in its opinion, showed that the "dépôt légal" with the Ministry of the Interior of the issues of the Journal "C.R.Acad.Sc.Paris" published under the title of the year 1978 was made in 1978.

5.2. As stated in decision T 381/87 (OJ EPO 1990, 213), in relation to the question when a document was first made available to the public, the Board "must decide what happened having regard to the available evidence, on the balance of probability; i.e. it must decide what is 'more likely than not' to have happened" [see point 4.(4) of the Reasons].

In the present case, document (3) published by the "Institut de France - Académie des Sciences" carries the date of 18 December 1978. It being a public institution, the possibility cannot be discounted that a copy of it could have been made available to the public on the very same date e.g. in the public library of the said Academy. However, the Board observes that no declaration and/or affidavit to this effect has been submitted by the Respondents.

On the other hand, the Appellant submitted the quoted testimonial letter of Mr Paul Germain (see exhibit 8) stating that the date of 18 December was not the date on which the issue was received by the subscribers and the libraries and that only starting on 1 February 1979 was the said issue available to their readers. Furthermore, the Appellant submitted attestations from a number of different European libraries stating that the issue No.16, of Volume 287 of the "C.R.Acad.Sc. Paris" was received or registered on a date after 1 February 1979 (see exhibit 9).

The Respondents have not submitted any counter- attestation of other libraries showing that the issue No.16, of Volume 287 of the "C.R.Acad.Sc. Paris" was received or registered on a date before 1 February 1979, in particular on a date before 22 December 1978, which is the BI priority date, or that the document was otherwise available at this priority date.

The Board firstly notes that there is a gap in the chain of evidence as regards the period from 18 December 1978 to 1 February 1979. It is therefore not clear whether during this period third persons would have been in the position to take part of the document.

As for the late evidence submitted by Respondent II concerning the "dépôt légal" [see section XI, b), below], the Board considers that it has no bearing on this matter because it does not indicate a specific date (day of the month) on which the said "dépôt légal" was actually made.

The Board further notes the lack of express evidence from the Académic des Sciences that documents would have normally been available to the public as of the publication date printed thereon. On the contrary, there is evidence on file (see exhibit 8) indicating the opposite.

5.3. Having regard to the available evidence, noting in particular the evidence regarding the distribution to subscribers, the Board is satisfied that the contents of document (3) were not available to the public before or at the BI priority date.

Consequently, document (3) is not state of the art citable under Article 54(2) EPC against any subject matter which is entitled to the BI priority date.

6. Novelty (Article 54 EPC)

None of the cited documents made available to the public before the BI priority date discloses the claimed subject-matter which is, therefore, novel under Article 54(1)(2) EPC.

Document (20), a European patent application, claims a priority date later than the BI priority date. Thus, this document is not taken into consideration under Article 54(3) EPC.

7. Inventive step (Article 56 EPC)

7.1. Document (16) represents the closest prior art for the claims-at-issue. This document is a review on the information about HBV and Dane particles: the number of viral gene products, the size, structure and complexity of Dane particle DNA, the mechanism of the DNA polymerase reaction; the pattern of viral gene expression in infected cells. From the different pieces of information a working model for the structure of the HBV genome is proposed according to which Dane particles are viewed as defective, genetically heterogeneous hepatitis B virions which replicate by complementation in multiply infected cells (see Figure 2). The conclusion drawn at the end of the document is that "further research will be needed to confirm or refute the model" (see page 375).

Document (16) reports also the work disclosed in document (23) (see paragraph bridging pages 366 and 367; reference no.51) and, therefore, constitutes a more complete prior art document than the latter.

7.2. In the light of document (16) the technical problem to be solved can be seen in the provision of HBV DNA or fragments thereof in sufficient amounts for the elucidation of its structure and for the production of HBV antigens.

7.3. This problem is solved by providing the recombinant DNA molecules referred to in the present claims (see, for example, Claims 1 to 4). In view of the detailed information contained in the patent-in-suit on the preparation of polypeptides displaying HBV antigen specificity and antigenicity by use of the said recombinant DNA molecules, the Board is satisfied that the above-stated technical problem has been solved.

7.4.1. It is observed that, in spite of the good amount of knowledge which was available in the prior art in respect of HBV and its genome [see document (16)], the skilled person was still faced with a number of uncertainties such as, for example,:

- the actual size of the HBV genome [see document (16), page 358, third paragraph and page 371, item 2];

- the complex structure of the Dane particles in which the amount of DNA exceeded the amount of DNA in a single circular molecule, but was less than that in two such molecules [see document (16), page 372, item 4], indicating the structure of a circular DNA single stranded over approximately one third of its length (see therein Figure 1);

- whether or not the proteins containing HBV antigen reactivity were all specified by viral genes [see document (16), page 371, item 2];

- whether or not the total amount of unique nucleotide sequence in the DNA from Dane particles was sufficient to specify the HBV-specific proteins [see document (16), page 372, lines 2 to 5];

- whether or not Dane particles were directly infectious [see, for example, document (16), page 375, lines 2 to 5].

The observation of these uncertainties brought the authors of document (16) to the conclusion that further research into the structure of Dane particles and HBV genome was necessary. This per se demonstrates that at the BI priority date the skilled person would not have considered the cloning of the HBV genome, not to mention its expression in a host cell, to be readily achievable with a reasonable expectation of success. Before entering into the unexplored area of cloning and expression of HBV DNA, the average skilled person would have had to acquire further information about the Dane particles and HBV genome.

This is even more true, if due account is taken also of the additional uncertainties with regard to the technology available for expressing higher eukaryotic genomic DNA, which in late 1978 was still in its infancy. The Appellant and the Respondents essentially agree that there was a number of open issues in relation to cloning and expression, but disagree on the extent to which they would have conditioned the activity of the skilled person (compare affidavit of Dr Old with affirmation of Prof. Almond). In the Board's view, if the said general uncertainties are added to the particular ones in respect of HBV, it can only be concluded that the skilled person in late 1978 had no reasonable perspectives of readily achieving expression of polypeptides displaying HBV antigen specificity and antigenicity by the genetic engineering route.

7.4.2. The parallel drawn by the Respondents with the studies on the virus SV40 (see attachment 3, submitted by Respondent IV) is misplaced because, firstly, the skilled person would not have seen a direct analogy between the two viruses [in this respect, see, for example, the statement on page 375, lines 10 to 12 in document (16)] and, secondly, no expression of fragments of SV40 genome had been reported.

7.4.3. Only with hindsight is it now possible to suggest a series of possible routes [for example, the experimental approach of document (8)] which could theoretically have lead the skilled person to the desired result. The facts in the present case rather indicate that, notwithstanding the available information, the studies of the primary structure of the HBV genome were quite precarious and that even predictions as to the possibility of cloning the genome were not possible; even less so as regards the possibility of achieving expression of fragments of the HBV genome.

7.4.4. Furthermore, the arguments put forward by Respondent IV based on the allegedly looser restrictions on recombinant DNA work in the United Kingdom and on the number of teams working in competition on the same project are immaterial to the issue of inventive step.

Neither the fact that a person (or a team) (here: the Appellant) was working under more favourable conditions nor that other persons (or teams) were concurrently performing research in the same area lessens the inventive step of any subject-matter claimed in a patent specification by the said first person (or team) in relation to the said research work, if this subject- matter is not obvious to a person skilled in the art, having regard to the state of the art.

The fact that other persons (or teams) were also working on the same project might suggest that is was "obvious to try" or that it was "an interesting area to explore", but it does not necessarily imply that there was "a reasonable expectation of success". "A reasonable expectation of success", which should not be confused with the understandable "hope to succeed", implies the ability of the skilled person to reasonably predict, on the basis of the existing knowledge before the starting of a research project, a successful conclusion to the said project within acceptable time limits. The more unexplored a technical field of research is, the more difficult is the making of predictions about its successful conclusion and, consequently, the lower the expectation of success.

7.4.5. In the Board's view, the successful achievement of the expression of HBV genes in a recombinant DNA system, regardless of whether it was just a "lucky strike" or the result of "looking for the unexpected" or of a planned strategy, was a major breakthrough in HBV research which, for the reasons given above, no prior art document had anticipated or rendered obvious.

7.4.6. For these reasons, the Board concludes that the subject- matter of the main request involves an inventive step. Thus, the said main request (Claims 1 to 23 for non-AT States and Claims 1 to 11 for AT) is allowable.