T 2048/10 (B7-H3 splice variants, antagonist antibodies/BRISTOL-MYERS SQUIBB) 21-07-2015

Summary of Facts and Submissions

I. European patent no. 1 292 619, based on European patent application 01 941 978.7 and filed as International patent application PCT/US2001/018257 (published as WO 2001/094413; hereinafter "the application as filed"), was opposed by two parties on the grounds set forth in Articles 100(a), (b) and (c) EPC. The opposition division considered the Main Request and Auxiliary Request 1 to contravene Article 54 EPC. Auxiliary Request 2 was considered to fulfil the requirements of the EPC. All requests were filed on 30 June 2010 at the oral proceedings before the opposition division.

II. An appeal was lodged by opponent 01 (appellant). With the statement of Grounds of Appeal, the appellant filed new documentary evidence (documents D52-D65).

III. In reply thereto, the patentee (respondent) filed new Auxiliary Requests I to XV and documentary evidence (D66-D75). The respondent requested that documents D58 and D59 were not admitted into the appeal proceedings and, if they were admitted, that the case be remitted to the department of first instance for further prosecution.

IV. With letter of 19 April 2011, the appellant filed further submissions ("Declaration of Professor Christopher Rudd" and annexes; document D76).

V. With letter of 21 July 2011, the respondent requested the board not to consider these new submissions.

VI. With letter of 16 August 2011, the appellant submitted further arguments to admit documents D58/D59 and D76 into the appeal proceedings.

VII. No submissions were filed by opponent 02 (party as of right).

VIII. In a communication pursuant to Article 15(1) of the Rules of Procedure of the Boards of Appeal (RPBA) annexed to Summons to oral proceedings, the parties were informed of the board's preliminary, non-binding opinion on the issues of the case.

IX. In reply to this communication, the respondent maintained its Main Request (set of claims upheld by the opposition division) and filed new Auxiliary Requests I to VI to replace all previous Auxiliary Requests.

X. The appellant did not reply to the board's communication.

XI. With letter dated 11 May 2015, opponent 02 informed the board that it would not be represented at the oral proceedings.

XII. Oral proceedings were held on 21 July 2015. During these proceedings, the respondent withdrew its Main Request and made Auxiliary Request I its new Main Request.

XIII. Claims 1 and 4-5 of the Main Request read as follows:

"1. A nucleic acid molecule or a nucleotide sequence selected from the group consisting of:

(a) a nucleic acid molecule encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 11 or 13;

(b) a nucleic acid molecule encoding the amino acid sequence consisting of amino acids 1 to 465 of SEQ ID NO: 7;

(c) a nucleic acid molecule encoding a B7-related polypeptide comprising the amino acid sequence of SEQ ID NO: 11 which is altered to incorporate one polymorphism in the amino acid sequence;

(d) a nucleic acid molecule encoding a B7-related polypeptide comprising the amino acid sequence of SEQ ID NO: 13 which is altered to incorporate one polymorphism in the amino acid sequence;

(e) a nucleotide sequence comprising polynucleotides encoding amino acids 1 to 698 of SEQ ID NO: 9;

(f) a nucleotide sequence comprising polynucleotides encoding amino acids 2 to 698 of SEQ ID NO: 9;

(g) a nucleotide sequence comprising polynucleotides encoding amino acids 69 to 698 of SEQ ID NO: 9;

(h) a nucleotide sequence comprising nucleotides 1 to 2094 of SEQ ID NO: 8;

(i) a nucleotide sequence comprising nucleotides 4 to 2094 of SEQ ID NO: 8;

(j) a nucleotide sequence comprising nucleotides 205 to 2094 of SEQ ID NO: 8;

(k) a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO: 6, 10, 12 or PTA-1993;

(l) a nucleotide sequence encoding a polypeptide comprising the amino acid sequence encoded by the DNA contained in PTA-1987 or PTA-1988;

(m) nucleic acid molecule which is complementary to the sequence of the nucleic acid molecule according to any one of (a) to (k); and

(n) a nucleotide sequence encoding an extracellular domain of an amino acid sequence selected from the group consisting of SEQ ID NO: 7, 11 and 13 and a nucleotide sequence encoding an Fc domain of immunoglobulin G.

4. A polypeptide encoded by the nucleic acid molecule according to (a) to (i), (l) and (n) of claim 1 or by the nucleic acid molecule of SEQ ID NO: 10 or 12.

5. An antibody that binds to the polypeptide according to claim 4, wherein said antibody blocks the activity of immune or inflammatory response cells."

Claims 2 and 3 are directed to a vector and host cell comprising the nucleic acid of claim 1. Claim 6 relates to a hybridoma cell producing the antibody according to claim 5. Claim 7 refers to the products of claims 1 and 3-5 for use as a pharmaceutical. Claims 8-9 and 11-12 relate to methods of identification and diagnosis using the products of claims 1 and 4-5. Claim 10 is directed to the use of the products of claims 1 and 3-5 for the preparation of a pharmaceutical composition.

XIV. The following documents are cited in this decision:

D1: WO 01/18204 (publication date: 15 March 2001);

D2: US 60/183,578 (18 February 2000);

D10: J. Henry et al., Review Immunol. Today, June 1999, Vol. 20, No. 6, pages 285 to 288;

D39: Open Biosystems. Clone information. incl. Annex as filed by opponent 01/appellant on 15 January 2009;

D58: WO 01/18021 (publication date: 15 March 2001);

D59: US 60/200,346 (filing date: 28 April 2000).

XV. Appellant's arguments, insofar as they are relevant to the present decision, may be summarized as follows:

Admissibility of the Main Request

The Main Request was filed as Auxiliary Request I one month before the oral proceedings and thus, it was late filed. Although filed in reply to the board's communication, it intended to overcome objections that had been in the proceedings from the very beginning. Since it did not overcome these objections, the Main Request did not simplify the proceedings.

Main Request

Article 100(c) EPC

Annex B of the patentee/respondent's submissions filed on 19 August 2009 showed the fragment 1-465 to contain not only the BSL2/B7-H3 extracellular domain (ECD) but also other domains. Likewise, the legend of Figure 3B of the application as filed referred to this fragment as containing the ECD but not equating it to the ECD. Nowhere in the application as filed was the ECD individualized as such. Claim 9 of the application as filed referred to fusion proteins comprising the ECD but no exact values/positions defining this domain were given therein, nor were these values disclosed in the application as filed. The fragment 1-465 could not be associated to the references in the application as filed to soluble forms of BSL2/B7-H3, since this fragment was disclosed as a mere arbitrary fragment among many other possible fragments available to the skilled person. Thus, the reference to fragment 1-465 in claim 1(b) of the Main Request was taken out of context in the claim and had no formal basis in the application as filed. Moreover, this objection applied to all claims dependent on claim 1(b), such as claim 5 directed to antibodies raised against fragment 1-465. The case law referred to in the board's communication did not apply to the present case. Contrary to the cases underlying the cited decisions where the specific values/positions were identified, in the present case such identification was missing.

New arguments/objections under Article 123(2) EPC

There was no basis in the application as filed for the feature "one polymorphism" in claims 1(c) and 1(d). The term "one" was disclosed only as part of "one or more" and, as shown on page 36 of the application as filed, the presence of "one or more polymorphisms" was linked to an intended purpose (enhance BSL2/B7-H3 stability/reactivity) that was not present in claims 1(c) and 1(d). This objection had already been raised in the opposition procedure.

Finally, anti-BSL2/B7-H3 antibodies were described, on page 78 of the application as filed, as "specifically react[ing]" with the BSL2/B7-H3 antigen. This requirement had been omitted in claim 5, which constituted an unallowable extension of the subject-matter as originally filed.

Admissibility of a new objection under Article 123(3) EPC

Whereas in the context of the application as filed the feature "one polymorphism" was clear and not open to interpretation, this feature was taken out of context and open to interpretation in claims 1(c) and 1(d). In these claims, this feature could be understood as allowing the presence of at least one polymorphism. The scope of these claims was accordingly broader than the scope of the corresponding granted claims that was limited by a specific degree of identity. Although this objection was raised for the first time in the oral proceedings before the board, it was highly relevant and should therefore be considered.

Article 100(a) EPC (Article 54 EPC)

Claims 1(k) and 1(m) and claim 2

The Incyte Genomics clone 4616811 (designated in the patent BSL2-4616811, carried on plasmid pINCY:BSL2-4616811 and deposited as ATCC PTA-1993) was a commercially available clone from the LIFESEQ database. This clone contained sequence SEQ ID NO: 6 which encoded sequence SEQ ID NO: 7, as shown in Example 1 of the patent. Evidence was on file, including document D39 and the statements of the patent itself, that established the public availability of the LIFESEQ database and the Incyte Genomics clone 4616811.

Claim 1(b) and claim 5

The BSL2/B7-H3 amino acid/nucleic acid sequences were disclosed in Figure 3 of document D1. The structure of BSL2/B7-H3 was disclosed in detail, with identification of its domains and a hydrophobicity plot analysis in Figure 5. The BSL2/B7-H3 transmembrane domain was identifiable and both, the BSL2/B7-H3 cytoplasmic and extracellular domains, were identifiable in this figure. As shown by an expanded copy of Figure 5, submitted at the oral proceedings, the ECD was identical to the fragment 1-465 in claim 1(b). Document D1 disclosed anti-BSL2/B7-H3 antibodies, in particular antibodies blocking the co-stimulation of T-cells, which were useful for treating autoimmune diseases. Thus, the functional feature given in claim 5 was anticipated by document D1.

Although document D2 did not contain the complete disclosure of document D1, the BSL2/B7-H3 amino acid/nucleic acid sequences and the hydrophobicity plot analysis were disclosed in Figures 1 and 4 of document D2. References were made to the BSL2/B7-H3 structure, including the transmembrane domain and the four Ig-like domains within the ECD (Figure 3), which anticipated the subject-matter of claim 1(b). BSL2/B7-H3 was identified in document D2 as a member of the B7 family. Members of the B7 family were known, as disclosed in document D2 and exemplified in document D10, to have costimulatory T-cell activity. Thus, antibodies of therapeutic interest for treatment of autoimmune disease were antagonist antibodies with the functional feature cited in claim 5. Indeed, the skilled person knew that there were only agonist and antagonist antibodies and, depending on the intended use, the appropriate antibodies were selected. Thus, the disclosure of document D2 was identical to that of document D1, although in an implicit manner.

Admissibility of documents D58/D59

Documents D58/D59 were filed with the Grounds of Appeal, at the earliest stage of the appeal proceedings. They were known to the respondent more than four years before the oral proceedings and, in this sense, were not late filed. The documents were filed in direct reply to the amendment, i.e. the introduction of the functional feature into claim 5, introduced into claim 5 at the oral proceedings before the opposition division. Thus, the first possibility to react to this amendment was with appellant's Grounds of Appeal. Also in this sense, documents D58/D59 were not late filed. These documents were highly relevant which was the overriding criterium for admitting them into the proceedings. It was against the public interest not to admit highly relevant documents into the appeal proceedings and to maintain a non-valid patent. The contents of documents D58/D59 were not complicated and their relevance was easily established. Indeed, claim requests were on file showing that the respondent had already taken them into account.

Remittal to the first instance

Documents D58/D59 were filed at the earliest stage of the appeal proceedings. The respondent had ample opportunity to prepare its case, react to these documents and, if appropriate, change its claim requests. Indeed, claim requests were on file intending to overcome objections based on these documents. It was not in the public interest, four and a half years after the onset of the appeal procedure, to further delay the proceedings and to remit the case to the first instance for further prosecution. There was no absolute right for remittal and a patentee could not, always and in all cases, rely on it.

XVI. Respondent's arguments, insofar as they are relevant to the present decision, may be summarized as follows:

Admissibility of the Main Request

The Main Request was based on the request upheld by the opposition division which had been in appeal proceedings from the beginning. Amendments introduced into the Main Request, made in reply to the board's communication, were straightforward (deletion of a claim directed to cell lines and the change of dependency of the antibody claim to exclude antigens encoded by complementary nucleic acid sequences).

Main Request

Article 100(c) EPC

The fragment 1-465 was individualized, as such, in the application as filed and identified as containing the ECD of BSL2/B7-H3, as described in the legend of Figure 3B. The skilled person would have recognized this fragment as a preferred soluble fragment of BSL2/B7-H3. The more so, since in Example 4 of the application as filed, this fragment was used for constructing a fusion protein and was equated to the ECD of BSL2/B7-H3. The amino acid sequence corresponding to this fragment could be identified within the sequence of the fusion protein shown in Figure 4B. Since fragment 1-465 had a basis in the application as filed, there was also a basis for claim 5, directed to antibodies raised against this fragment.

New arguments/objections under Article 123(2) EPC

The objections related to the feature "one polymorphism" and to the omission of the feature "specifically react" were raised at the oral proceedings, i.e. at the latest possible stage of the appeal proceedings. Although the feature "one polymorphism" was discussed at first instance, the decision of the opposition division on this issue, as stated in the board's communication, was not contested by the appellant. The appellant did not reply to this communication. As for the omission of the feature "specifically react", according to the case law of the Boards of Appeal (cf. T 189/01 of 15 June 2004), the notion of specificity was inherent to the nature of antibodies and therefore, it was inherent to the antibodies defined in claim 5. In any case, the objection was never raised before and its introduction at the oral proceedings before the board should not be admitted.

Admissibility of a new objection under Article 123(3) EPC

The feature "one polymorphism" was not taken out of context in claims 1(c) and 1(d). When these claims were read in a reasonable manner, this feature had the same meaning as in the application as filed, namely the incorporation of only one, single polymorphism into the amino acid sequences. In any case, this objection was raised for the first time at the latest possible stage of the appeal proceedings and referred to an amendment that had been introduced into the claims at the beginning of the opposition proceedings. The objection should not be admitted into the appeal proceedings.

Article 100(a) EPC (Article 54 EPC)

Claims 1(k) and 1(m) and claim 2

The Incyte Genomics database was not publicly available and, in the post-published document D39, only an expressed sequence tag (EST) of 255 nucleotides was disclosed but not the sequences cited in claims 1(k) and 1(m). Two LIFESEQ databases were provided by Incyte, a free database containing only a limited number of sequences and a proprietary database containing more sequences but subjected to confidentiality. Claims 1(k) and 1(m), relating to sequences SEQ ID NO: 6 and 7 and to PTA-1993, were not anticipated by Incyte Genomics clone 4616811. Even if the Incyte Genomics database had been available, the specific clone 4616811 could not have been retrieved without the corresponding sequence at hand. There was no annotation on this EST sequence informing a skilled person that it encoded a polypeptide of the B7 family. According to the case law (cf. T 18/09 of 21 October 2009, T 301/87 of OJ EPO 1990, page 335), neither the library nor the EST sequence, if publicly available, anticipated claims 1(k) and 1(m).

Claim 1(b) and claim 5

Figure 5 of document D1 showed the hydrophobicity plot analysis for the full-length sequence of BSL2/B7-H3. There was no disclosure of any BSL2/B7-H3 fragment in this analysis, let alone of the specific fragment 1-465. The structure of BSL2/B7-H3 was defined only in a general manner and there was no disclosure of the positions defining the BSL2/B7-H3 transmembrane domain. This disclosure was also not derivable from appellant's expanded copy of Figure 5. Position 465 was not identified as the last position of a fragment containing the ECD nor was position 466 identified as starting the BSL2/B7-H3 transmembrane domain, other positions (467, 468, etc.) were also possible. Thus, the fragment 1-465 cited in claim 1(b) was not disclosed in document D1. The BSL2/B7-H3 function/activity was not characterized in document D1, which referred only to a general modulation of immune responses. References to therapeutic antibodies were given in a general manner, without characterizing the antibodies as antagonist or agonist antibodies. Indeed, the activity of an antibody depended on the nature of the antigen used for their production, i.e. either the complete BSL2/B7-H3 or only fragments thereof, such as a BSL2/B7-H3 fragment containing only the ECD, which was not even disclosed in document D1. Thus, document D1 did not anticipate antibodies with the functional feature cited in claim 5.

Document D2 contained less information than document D1. The reference to a therapeutic use of BSL2/B7-H3 for treating patients suffering from autoimmune disorders contradicted the identification of BSL2/B7-H3 as a member of the B7 family, since members of this family were known to have a costimulatory T-cell activity. The general reference in document D2 to antibodies for use in therapeutic methods was not a disclosure of antibodies with the functional feature cited in claim 5. These claimed antibodies were a particular sub-group of antibodies which was not derivable from document D2.

Admissibility of documents D58/D59

Documents D58/D59 clearly related to members of the B7 family as seen from their title and they could have been easily retrieved and filed at an earlier stage of the proceedings. The amendments introduced into claim 5 at the oral proceedings before the opposition division were no excuse for the late-filing of these documents, since claims referring to (increased/decreased) BSL2/B7-H3 activity were already present in the set of granted claims and in all claim requests filed at first instance proceedings. The relevance of this activity for therapeutic uses was known to a skilled person. If documents D58/D59 were admitted into the appeal proceedings, they rendered the case more complex, raised new issues and required a remittal to the first instance, which all went against the need for procedural economy.

Remittal to the first instance

Although there was no absolute right to two instances, in the circumstances of the present case, this right should be accepted by the board. The delay in the proceedings arose from the late-filing of documents D58 and D59. As a reaction, the respondent had filed auxiliary requests as fall-back positions, since it was aware that it had no absolute right to two instances. However, it was not fair to be punished for the precautionary filing of auxiliary requests and to be deprived from arguing and discussing their merits before the opposition division. The filing of auxiliary requests could not put the respondent in a worse position than if it had not filed them.

XVII. The appellant requested that the decision under appeal be set aside and that the patent be revoked.

XVIII. The respondent requested that the decision under appeal be set aside and that the patent be maintained on the basis of the Main Request filed at the oral proceedings before the board. The respondent further requested that documents D58/D59 not be admitted into the appeal proceedings and, if they were admitted, that the case be remitted to the department of first instance for further prosecution.

XIX. No requests were on file from opponent 02, party as of right.