T 0100/01 (Variant proteins/GENENTECH, INC.) 05-02-2004

Reasons for the Decision

Admissibility of 15 new documents in the proceedings

1. On 29 January 2004, ie seven days before the oral proceedings, the Respondents filed seven new documents. The time limit of one month before the oral proceedings set up by the Board for the filing of new submissions was not observed. These documents are considered to be late filed and, thus, are not admitted in the proceedings.

2. On 5 January 2004, ie within the time limit set up by the Board, the Appellants filed five new documents and three declarations.

3. One of these declarations is an expert's opinion on the inherent content of the passage on page 48, lines 37 to 48 of document (1). It does not bring any useful information in addition to that already on file. The other two declarations include new experimental data which in accordance with the case law (cf, for example, T 397/02 of 10 October 2003, see in particular point 2 of the reasons), should not be admitted at this late stage. For these reasons, the Board decides not to admit any of them in the proceedings.

4. Four of the documents are post-published. They are meant to throw light on the inherent content of the above mentioned passage which is argued to destroy the novelty of the method of claim 1 under Article 54(3)(4) EPC when this inherent content is taken into account.

5. In accordance with Article 54 EPC, the only kind of documents which may be taken into consideration when assessing novelty are those belonging to the state of the art at the date of filing and those European patent applications which were filed before that date and published thereafter. If it is necessary to refer to the above mentioned four documents, this could only be because they add information not present in document (1). If it is not necessary to refer to them, it would be unsafe to do so and merely confuse the issue as they are post-published documents which cannot themselves be used in assessing novelty. Consequently, the four post-published documents are not admitted in the proceedings.

6. The Appellants' argument that proving the inherency of a given feature in a method disclosed under Article 54(3)(4) EPC necessarily required the use of post-published documents is not convincing. According to the consistent view in the case law on novelty, when considering how far the teaching in a written description of an allegedly novelty-destroying document also makes available certain features which are not explicitly stated, ie implicit or intrinsic features, all that matters is the whole contents of the said document alone as read and interpreted by the skilled person on the background of common general knowledge, ie the knowledge generally available at the relevant filing date, not later. This excludes the consideration of post-published documents even for assessing background common general knowledge at the priority date. This principle must also apply to situations where novelty under Article 54(3)(4) EPC has to be assessed. In this context, it is noticed that bacteriophage display was a technique already known in the art at the priority date (patent in suit, passage bridging pages 2 and 3).

7. Document (46) belongs to the prior art, it was submitted in the context of assessing inventive step because it disclosed an expression plasmid vector, ie pEH-90-10am (column 20, line 5 onwards), which comprises a first and second genes separated from each other by a suppressible terminator codon. In view of the similarity between the structure of this plasmid and that of the phagemid DNA in claim 13, it was decided to accept the document in the proceedings so that its relevance could be assessed in more detail.

Article 54(3)(4) EPC; novelty

Claim 1

8. Document (1) was argued to be novelty destroying for the subject-matter of claim 1 under Article 54(3)(4) EPC. The teachings of said document which may be taken into account are those also contained in its third priority document: GB 9024503.6 with a filing date of 12 November 1990 since the earliest priority date of the patent in suit is 3 December 1990.

9. Both document (1) and GB 9024503.6 relate to the production of viral particles having the ability to present antibodies or receptor molecules at their surface and to various methods of use of said particles. It is thus disclosed that:

(a) "..., a cDNA library could be constructed and inserted into the bacteriophage and this library be screened for the ability to bind a ligand." (GB third priority document: page 8, lines 8 to 12, corresponding passage in document (1): page 11, lines 45 to 49).

(b) "... the present invention also provides novel screening systems and assay formats. In these systems and formats, the gene sequence encoding the binding molecule (eg the antibody) of desired specificity could be separated from the general population having a range of specificities by the fact of its binding to a specific target (eg antigen or epitope)" (GB third priority document: page 11, lines 31. to 37; corresponding passage in document (1): page 21, lines 45 to 51).

(c) "A useful and novel set of applications makes use of the binding protein in the phage to target the phage genome to a particular cell or group of cells". (GB third priority document: page 8, lines 21 to 25; document (1): page 12, lines 23 to 25).

(d) "... a specific receptor could be expressed on the surface of the phage so that it could bind its ligand. The receptor could then be modified by, for example, in vitro mutagenesis and variants having higher binding affinity for the ligand selected." (GB third priority document: page 7, lines 14 to 17; corresponding passage in document (1): page 10, lines 23. to 25). The same approach is also disclosed in relation to antibody display (GB third priority document: passage bridging pages 6 and 7, corresponding passage in document (1): page 7, lines 15 to 18).

10. Examples common to both document (1) and the third priority document comprise:

(a) the construction of vectors facilitating the cloning of various foreign DNA sequences (Examples 1 and 5 in both documents).

(b) the insertion of foreign DNA sequences in the bacteriophage vector (Examples 2, 3, 9, 11, 13 and 15 in document (1) corresponding to Examples 2, 3, 9, 13, 15. and 11 in the GB priority document).

(c) experiments for testing the properties of the foreign protein once expressed at the bacteriophage surface (Examples 4, 6, 7 and 12 in document (1) corresponding to Examples 4, 6, 7 and 14 in the GB priority document).

(d) the isolation of a preferred recombinant bacteriophage from a mixture (Examples 8 and 10 in both documents).

11. A passage referring to phagemids is found in Example 1 (GB third priority document: page 25, lines 4 to 14; document (1)): page 48, lines 37 to 48) which reads as follows:

"Clearly alternative constructions will be apparent to those skilled in the art. For example, M13 and/or its host bacteria could be modified such that its gene III could be disrupted without the onset of excessive cell death; the modified fd gene III, or other modified protein, could be incorporated into a plasmid containing a single stranded phage replication origin, such as pUC119, superinfection with modified phage such as K07 would then result in the encapsulation of the phage antibody genome in a coat partially derived from the helper phage and partly from the phage antibody gene III construct."

12. It is on the basis of this sole passage in document (1) that the method of claim 1 was argued by the Appellants not to be novel. It is immediately apparent that no explicit disclosure is provided of a method step corresponding to step (b) of the method in claim 1: "mutating the vector at one or more selected positions within the first gene thereby forming a family of related plasmids.". This fact is not contested by the Appellants who argue that when reading the description as a whole, the skilled person would necessarily understand this step to be included in the method described on page 48 since it was described on pages 7 and 10 in relation to using bacteriophages.

13. This argument is not found convincing. As mentioned in point 9 supra, document (1) as a whole describes at least four methods making use of bacteriophage display. Only one of them (method (d); point 9 supra) requires that the foreign DNA (encoding a receptor or an antibody) be mutated once present in the bacteriophage DNA; the three other methods (methods (a) to (c) supra)) do not necessitate such a step. Furthermore, Example 1 which the passage on page 48 belongs to, only mentions mutagenesis in the context of constructing new appropriate vectors. As for the other examples, none of them are concerned with the mutagenesis of the DNA encoding the fusion protein (point 10, supra).

14. For these reasons, the skilled person would not directly and unequivocally derive from reading document (1) as a whole that a step of mutagenesis necessarily is present when constructing either bacteriophages or phagemids for the purpose of protein display. These findings are sufficient to conclude that document (1) does not clearly and unambiguously disclose a method as claimed in claim 1 comprising step (b) and that therefore, it cannot destroy the novelty of the subject-matter of said claim.

15. Having reached this conclusion on the basis of step (b), there is no need for the Board to investigate whether or not the other steps of the claimed method are disclosed in the passage on page 48, lines 37 to 48 of document (1).

Claims 22 and 26

16. These claims relate to methods which comprise a mutagenesis step corresponding to step (b) of the method of claim 1. If only for this reason their subject-matter is novel.

17. The subject-matter of the granted claims fulfils the requirements of Article 54 EPC.

Article 56 EPC; inventive step

Claim 13

18. The closest prior art is document (7) which describes an enrichment method for variant proteins with altered binding properties. The gene encoding human growth hormone is fused to the 3' end of the gene III encoding a minor coat protein of bacteriophage M13. The hybrid construct is cloned into a plasmid containing origins of replication for E.coli and for filamentous phage. Upon superinfection of the bacterial host carrying the recombinant plasmid with bacteriophage M13 K07, phagemid particles are produced which usually carry no more than one copy of the fusion protein along with four copies of wild-type gene III on their surface.

19. Starting from the closest prior art, the problem to be solved is defined as producing alternative phagemids for protein display. The need for different phagemids is not suggested in document (7). Yet, the Board derives from reading the background art as summarized in the patent in suit that at the priority date, it was of great concern to the scientific community to develop several efficient screening systems for binding molecules. Thus, it is accepted that the formulation of this problem would have been obvious to the person skilled in the art.

20. The solution given in claim 13 consists in phagemids the DNA of which includes the gene of interest fused to the gene encoding at least part of a coat protein with a suppressible codon being inserted at the junction in the gene fusion. A suppressor- host containing the phagemid DNA expresses the protein of interest in unfused form. When superinfected with a filamentous phage, a suppressor+ host containing the phagemid DNA produces phagemid particles which carry the protein of interest on its surface because said protein is expressed as part of the coat protein. Thus, by using one phagemid expression vector, one is able to produce the protein of interest as well as to test its binding properties. The claimed phagemids are, thus, distinctly advantageous over those disclosed in document (7).

21. The Appellants argued that this improvement would have readily come to the skilled person's mind taking into account the teachings of document (46). As already mentioned in point 7 above, this document was accepted into the proceedings as prima facie possibly relevant because it disclosed a plasmid which carried a DNA fragment with the same structure as that present in the phagemid particles of claim 13, ie wherein a gene of interest is fused to a "carrier" gene, a suppressible codon being inserted at the junction in the fusion (pEH-90-10am, column 20). An in-depth reading of the document shows that this construct is expressed in a suppressor+ host in order to produce the protein of interest, simultaneously in fused and unfused forms. In fact, as the purpose of the experiment is to stabilize the unfused form by co-aggregation with the fused form, an essential part of the concept underlying the experiment is that the two forms must be expressed in the same host.

22. Document (46) does not relate to the field of phagemid display nor to the field of gene expression per se: it is rather concerned with protein stabilisation once the protein has been expressed. The above mentioned concept is not relevant to the invention as claimed in claim 13. Indeed, the fact that when the phagemid DNA is present in a suppressor+ host, fused and unfused proteins are most probably concomitantly produced was never argued to have a bearing on the display on the phage surface.

23. For these reasons, the Board concludes that, even if the skilled person had come across document (46) while working in the field of phage display (which is not entirely certain), he/she would have had no incentive to combine its teachings with those of document (7) in order to isolate alternative phagemids to those described in this last document.

24. There is no other documents on file the teachings of which could be combined with those of document (7) to make obvious the subject-matter of claim 13. Inventive step is, thus, acknowledged.

Issues raised for the first time on appeal

Inventive step of claim 1

25. In the opposition proceedings, the only ground under which the validity of claim 1 had been challenged was lack of novelty over document (1), which was part of the state of the art only under Article 54(3) EPC. Pursuant to Article 56 EPC, document (1) is not to be considered in deciding whether there has been an inventive step so there can be no basis for alleging that an attack in the opposition proceedings based on lack of novelty over document (1) was also implicitly an attack on the ground of inventive step.

26. As made clear in decisions G 1/95 and G 7/95 of the Enlarged Board of Appeal (OJ EPO 1996, 615 and 626 respectively) when expanding on what had already been said in opinion G 10/91 (OJ EPO 1993, 420), the totality of Articles (namely Articles 52 to 57 EPC) within the meaning of Article 100(a) EPC do not constitute a single objection to the maintenance of the patent, but a collection of different objections. Further a fresh ground for opposition is to be interpreted as referring to a new legal basis for objecting to the maintenance of the patent, which was not both raised and substantiated in the notice of opposition and which was not introduced into the proceedings by the opposition division.

The attack of lack of novelty does not have the same legal basis as the attack of lack of inventive step, though, as stated in decision G 7/95, lack of novelty in relation to documents which are prior art pursuant to Article 54(2) EPC is also relevant when assessing the legal ground of lack of inventive step.

27. The Board concludes that in this case attempting to argue for lack of inventive step of claim 1 on appeal amounts to raising a fresh ground of opposition. The situation is not analogous to one in which the ground of inventive step had been originally alleged and substantiated, and the appellant merely seeks to rely on other or additional documents. Nor does the fact that in the opposition proceedings lack of inventive step was argued against independent claim 13 assist the Appellants, since it remains the fact that no attack of lack of inventive step against the claim now under consideration, claim 1, had been raised, let alone substantiated, in the opposition proceedings.

28. Since the Respondents have not given consent to consideration of the issue of lack of inventive step of claim 1, it cannot be considered in the appeal proceedings. The Board would in any case have been reluctant to consider an issue which does not appear to have been properly substantiated even in the appeal proceedings.

Insufficiency in relation to claim 1

29. Insufficiency in relation to claim 1 was not raised, let alone substantiated, during the opposition proceedings. Since the Respondents have not given consent to consideration of this issue, it cannot be considered in the appeal proceedings.

30. The case put forward would in any case not appear to be one that the subject matter of claim 1 cannot be carried out. Not even the Appellants have seriously argued this. Rather the Appellants used it in the form of a squeeze argument when arguing lack of novelty: either claim 1 and document (1) both disclosed the same process, in particular feature (e) and thus, document (1) was detrimental to the novelty of claim 1, alternatively, if document (1) did not disclose feature (e), then in the same manner, the patent in suit did not provide an enabling disclosure of said feature. However the Board's finding of novelty is based on feature (b) of claim 1 not being found in document (1), so this squeeze argument is not enough to establish lack of sufficient disclosure.

Reference of a question to the Enlarged Board of Appeal

31. What can or cannot be considered on appeal has already been made clear in Enlarged Board opinion G 10/91 and decisions G 1/95 and G 7/95, above referred to, and following the reasoning of these decisions it is clear that attacks of lack of inventive step and insufficiency against claim 1 cannot be considered in this appeal. Since the law is clear the Board sees no occasion for the referral of any question to the Enlarged Board of Appeal.

32. Regarding the specific question suggested by the Appellants, the Board does not accept that the patentee- respondent here has raised in its defence to one ground of opposition an issue which has an adverse implication for the validity of the patent under a ground which has not been pleaded.

Remittal to the first instance

33. The Board sees no issue here that requires remittal to the first instance for further prosecution, nor any reason for setting aside the decision under appeal.

34. The Appellants refer to decision T 1066/92 of 5 July 1995. Only the legal context of that decision is of relevance, not the technical details involved. The opposition there was directed only to granted claims 3 to 5. The opposition division maintained the patent only on the basis of granted claims 1 and 2, while refusing granted claims 3 to 5 for lack of novelty, and claims 6 to 10 for lack of inventive step. On appeal the patentee-appellant argued for the allowability of a claim combining the features of granted claims 3 and 5 on the basis of new evidence relating to the special meaning that a person skilled in the art would attribute to a test in such claim, and for the allowability of claims 6 to 10 as not being subject of the opposition. The respondent sought to introduce as a new issue the ground of insufficiency against the claim combining claims 3 and 5 as granted, justifying the lateness of this argument because the objection only became apparent as a result of the new evidence on the meaning of the test, first put forward by the patentee on appeal.

35. The competent board in case T 1066/92 held, following G 9/91 (OJ EPO 1993, 408 having the same text as, but a different order than, G 10/91 referred to above) that the revocation of claims 6 to 10 was ultra vires the powers of the opposition division, and that the board could not itself consider the new ground of insufficiency without the consent of the appellant. However it exercised its discretion under Article 111(1) EPC to remit the case to the opposition division for further prosecution, pointing out that before novelty and inventive step were considered, the objection of insufficiency under Article 100(b) EPC which appeared prima facie highly relevant should be decided, and that under the principles laid down in G 9/91 the opposition division did have the power to raise on its own motion a ground for opposition not covered by the statement pursuant to Rule 55(c) EPC.

36. The board thus had reasons for setting aside the decision under appeal, and it also exercised its discretion under Article 111(1) EPC to remit a claim for further prosecution that had in effect been revoked for lack of novelty by the opposition division, but which on the basis of new evidence filed on appeal might be found allowable subject to consideration of insufficiency, novelty and inventive step.

37. Decision T 1066/92 certainly cannot be taken as establishing or even advocating any principle that a newly raised ground which a board of appeal cannot itself consider should be remitted to the opposition division for consideration. Such remittal must remain a matter for the discretion of the board considering each individual case. In the present case the Board sees no reasons for setting aside the decision under appeal, and no case which requires remittal to the first instance.