T 2589/16 (Cross-species CD3 antibody/AMGEN) 16-11-2021

Summary of Facts and Submissions

I. The patent proprietor and opponents 1 to 4 filed appeals against the decision of the opposition division that, account being taken of the amendments in the form of auxiliary request 18, European patent No. 2 155 783 and the invention to which it related met the requirements of the EPC. The patent, entitled "Cross-species-specific CD3-epsilon binding domain", had been granted on European patent application No. 08 735 001.3, which was filed as an international application under the PCT, published as WO 2008/119567 (the "application as filed"). It claimed priority from European patent application Nos. 07 006 990.1 (P1), 07 006 988.5 (P2) and 08 004 741.8 (P4) and US patent application 60/931,688 (P3).

II. Originally, seven parties had filed oppositions.

Opponent 5 withdrew the opposition during the appeal proceedings. Since no issues other than substantive issues arose in this appeal, opponent 5 ceased to be a party to the appeal proceedings.

Opponents 6 and 7 are respondents in these proceedings.

For ease of reference, in this decision the board refers to the parties as patent proprietor and opponents 1 to 7 or "appellants-opponents" when referring to opponents 1 to 4.

III. The patent was opposed as a whole under Article 100(a) EPC on the grounds of lack of novelty (Article 54 EPC), lack of inventive step (Article 56 EPC) and lack of industrial applicability (Article 57 EPC), and under Article 100(b) and (c) EPC.

IV. In the decision under appeal, the opposition division dealt with a main request (the patent as granted) and 18 auxiliary requests. It held, inter alia, with respect to the main request, that the subject-matter claimed did not extend beyond the content of the application as filed but that the subject-matter of some claims lacked novelty in view of the disclosure of document D6, which was prior art in accordance with Article 54(3) EPC; with respect to the set of claims of auxiliary request 18, it held that the subject-matter was entitled to the earliest priority date claimed, thus excluding document D6 as prior art under Article 54(2) EPC, and that the claimed invention was sufficiently disclosed and involved an inventive step with regard to document D3 as representing the closest prior art.

V. With the statement of grounds of appeal, the patent proprietor filed sets of claims of a main request and 21 auxiliary requests and several new documents. Auxiliary request 21 is identical to auxiliary request 18 considered allowable by the opposition division.

VI. The appellant-opponents filed statements of grounds of appeal, some of them including new documents.

VII. The patent proprietor and opponents 1 to 7 submitted replies to the statements of grounds of appeal.

VIII. Opponent 4 subsequently filed a further submission.

With the letter dated 11 July 2019, opponent 2 filed a further submission, accompanied by decision T 628/15.

IX. By letter dated 4 September 2019, the patent proprietor submitted sets of claims of further auxiliary requests 16A, 18A, 19A, 20A, 20B, 20C, 20D, 22 to 25, 22A to 25A and 25B.

X. The board appointed oral proceedings in view of corresponding requests of the parties.

XI. Opponents 1 and 6 subsequently filed one further submission each.

XII. By letter dated 4 March 2020, the patent proprietor filed sets of claims of auxiliary requests 22-R, 22A-R, 23-R, 23A-R, 24-R and 24A-R.

XIII. In a communication pursuant to Article 15(1) RPBA 2020 dated 26 October 2020, the board took note of the parties' requests submitted in writing, including the withdrawal of auxiliary requests 1 to 19, 16A, 18A, 19A, 25, 25A and 25B, and informed the parties of its preliminary opinion, inter alia, that document D6 disclosed embodiments encompassed by claim 1 of the main request.

XIV. Subsequently, one further substantive submission was filed by the patent proprietor indicating, inter alia, a new hierarchy of the claim requests.

XV. Further submissions were also filed by opponents 1, 2, 4, 6 and 7.

XVI. After several postponements, inter alia due to the COVID-19 pandemic, the oral proceedings took place on 15 and 16 November 2021 as an in-person hearing. All parties to the appeal proceedings attended the oral proceedings.

At the beginning of the oral proceedings, the patent proprietor withdrew the main request filed with the statement of grounds of appeal and stated that auxiliary request 20 was the new main request.

At the end of the oral proceedings, the Chair announced the board's decision.

XVII. The following claim requests were considered at the oral proceedings: main request (filed as auxiliary request 20 with the statement of grounds of appeal), and auxiliary requests 20A, 20B, 20C, 20D (all filed with the letter dated 4 September 2019) and 21 (filed with the statement of grounds of appeal; being the same as the request held by the opposition division to comply with the requirements of the EPC).

XVIII. Claims 1, 3 and 4 of the main request read:

"1. A polypeptide comprising a binding domain which is an antibody capable of binding to an epitope of human and Callithrix jacchus, Saguinus oedipus or Saimiri sciureus CD3epsilon chain, wherein the epitope is part of an amino acid sequence comprised in the group consisting of SEQ ID NOs:2, 4, 6, or 8 and comprises at least the amino acid sequence Gln-Asp-Gly-Asn-Glu, wherein the antibody is a scFv, wherein said scFv does not comprise CDR-L1 having the sequence RSSTGAVTTSNYAN, CDR-L2 having the sequence GTNKRAP, and CDR-L3 having the sequence ALWYSNLWV and CDR-H1 having the sequence TYAMN, CDR-H2 having the sequence RIRSKYNNYATYYADSVKD and CDR-H3 having the sequence HGNFGNSYVSWFAY or CDR-H3* comprising the amino acid sequence "VSWFAY", and wherein the polypeptide further comprises a second binding domain capable of binding to a cell surface antigen which is a tumor antigen.

3. A polypeptide comprising a binding domain which is an antibody capable of binding to an epitope of human and Callithrix jacchus, Saguinus oedipus or Saimiri sciureus CD3epsilon chain, wherein the epitope is part of an amino acid sequence comprised in the group consisting of SEQ ID NOs:2, 4, 6, or 8 and comprises at least the amino acid sequence Gln-Asp-Gly-Asn-Glu, wherein the antibody is a scFv or a single domain antibody, wherein the first binding domain comprises a VL region comprising CDR-L1, CDR-L2 and CDR-L3 selected from:

(a) CDR-L1 as depicted in SEQ ID NO:27, CDR-L2 as depicted in SEQ ID NO:28 and CDR-L3 as depicted in SEQ ID NO:29;

(b) CDR-L1 as depicted in SEQ ID NO:117, CDR-L2 as depicted in SEQ ID NO:118 and CDR-L3 as depicted in SEQ ID NO:119; and

(c) CDR-L1 as depicted in SEQ ID NO:153, CDR-L2 as depicted in SEQ ID NO:154 and CDR-L3 as depicted in SEQ ID NO:155,

and wherein the polypeptide further comprises a second binding domain capable of binding to a cell surface antigen which is a tumor antigen.

4. A polypeptide comprising a binding domain which is an antibody capable of binding to an epitope of human and Callithrix jacchus, Saguinus oedipus or Saimiri sciureus CD3epsilon chain, wherein the epitope is part of an amino acid sequence comprised in the group consisting of SEQ ID NOs:2, 4, 6, or 8 and comprises at least the amino acid sequence Gln-Asp-Gly-Asn-Glu, wherein the antibody is a scFv or a single domain antibody, wherein the first binding domain comprises a VH region comprising CDR-H1, CDR-H2 and CDR-H3 selected from:

(a) CDR-H1 as depicted in SEQ ID NO:12, CDR-H2 as depicted in SEQ ID NO:13 and CDR-H3 as depicted in SEQ ID NO:14;

(b) CDR-H1 as depicted in SEQ ID NO:30, CDR-H2 as depicted in SEQ ID NO:31 and CDR-H3 as depicted in SEQ ID NO:32;

(c) CDR-H1 as depicted in SEQ ID NO:48, CDR-H2 as depicted in SEQ ID NO:49 and CDR-H3 as depicted in SEQ ID NO:50;

(d) CDR-H1 as depicted in SEQ ID NO:66, CDR-H2 as depicted in SEQ ID NO:67 and CDR-H3 as depicted in SEQ ID NO:68;

(e) CDR-H1 as depicted in SEQ ID NO:84, CDR-H2 as depicted in SEQ ID NO:85 and CDR-H3 as depicted in SEQ ID NO:86;

(f) CDR-H1 as depicted in SEQ ID NO:102, CDR-H2 as depicted in SEQ ID NO:103 and CDR-H3 as depicted in SEQ ID NO:104;

(g) CDR-H1 as depicted in SEQ ID NO:120, CDR-H2 as depicted in SEQ ID NO:121 and CDR-H3 as depicted in SEQ ID NO:122;

(h) CDR-H1 as depicted in SEQ ID NO:138, CDR-H2 as depicted in SEQ ID NO:139 and CDR-H3 as depicted in SEQ ID NO:140;

(i) CDR-H1 as depicted in SEQ ID NO:156, CDR-H2 as depicted in SEQ ID NO:157 and CDR-H3 as depicted in SEQ ID NO:158; and

(j) CDR-H1 as depicted in SEQ ID NO:174, CDR-H2 as depicted in SEQ ID NO:175 and CDR-H3 as depicted in SEQ ID NO:176,

and wherein the polypeptide further comprises a second binding domain capable of binding to a cell surface antigen which is a tumor antigen."

XIX. Claim 1 of auxiliary request 20A reads (additions as compared to the main request highlighted by the board by underlining)(claims 3 and 4 remained unamended):

"1. A pharmaceutical composition comprising a polypeptide comprising a binding domain which is an antibody capable of [...]"

XX. Claim 1 of auxiliary request 20B reads (differences to the main request highlighted by the board using underlining for additions and strike-through for deletions)(claims 3 and 4 remained unamended):

"1. A pharmaceutical composition comprising a polypeptide comprising a binding domain which is an antibody capable of [...] wherein said scFv does not comprise CDR-L1 having the sequence RSSTGAVTTSNYAN, CDR-L2 having the sequence GTNKRAP, and CDR-L3 having the sequence ALWYSNLWV and CDR-H1 having the sequence TYAMN, CDR-H2 having the sequence RIRSKYNNYATYYADSVKD and [deleted: CDR-H3][deleted: having the sequence ][deleted: HGNFGNSYVSWFAY][deleted: or] CDR-H3* comprising the amino acid sequence "VSWFAY", [...]"

XXI. Claim 1 of auxiliary request 20C reads (differences to the main request highlighted by the board using underlining for additions and strike-through for deletions)(claims 3 and 4 remained unamended):

"1. A pharmaceutical composition comprising a polypeptide comprising a binding domain which is an antibody capable of [...] wherein said scFv does not comprise CDR-L1 having the sequence RSSTGAVTTSNYAN, CDR-L2 having the sequence GTNKRAP, and CDR-L3 having the sequence ALWYSNLWV and CDR-H1 having the sequence TYAMN, CDR-H2 having the sequence RIRSKYNNYATYYADSVKD and CDR-H3 having the sequence HGNFGNSYVSWFAY [deleted: or ][deleted: CDR-H3*][deleted: comprising the amino acid sequence "VSWFAY"], [...]"

XXII. The set of claims of auxiliary request 20D corresponds to that of the main request where claims 1 and 2 were deleted and claims 3 and 4 were renumbered to claims 1 and 2, respectively.

XXIII. Claim 1 of auxiliary request 21 reads:

"1. A polypeptide comprising a binding domain which is an antibody capable of binding to an epitope of human and Callithrix jacchus, Saguinus oedipus or Saimiri sciureus CD3epsilon chain, wherein the epitope is part of an amino acid sequence comprised in the group consisting of SEQ ID NOs: 2, 4, 6, or 8 and comprises at least the amino acid sequence Gln-Asp-Gly-Asn-Glu, wherein the polypeptide further comprises a second binding domain capable of binding to a cell surface antigen which is a tumor antigen, wherein the first binding domain comprises a VL region comprising CDR-L1, CDR-L2 and CDR-L3 selected from:

(a) CDR-L1 as depicted in SEQ ID NO:27, CDR-L2 as depicted in SEQ ID NO:28 and CDR-L3 as depicted in SEQ ID NO:29;

(b) CDR-L1 as depicted in SEQ ID NO:117, CDR-L2 as depicted in SEQ ID NO:118 and CDR-L3 as depicted in SEQ ID NO:119; and

(c) CDR-L1 as depicted in SEQ ID NO:153, CDR-L2 as depicted in SEQ ID NO:154 and CDR-L3 as depicted in SEQ ID NO:155; and

comprises a VH region comprising CDR-H1, CDR-H2 and CDR-H3 selected from:

(a) CDR-H1 as depicted in SEQ ID NO:12, CDR-H2 as depicted in SEQ ID NO:13 and CDR-H3 as depicted in SEQ ID NO:14;

(b) CDR-H1 as depicted in SEQ ID NO:30, CDR-H2 as depicted in SEQ ID NO:31 and CDR-H3 as depicted in SEQ ID NO:32;

(c) CDR-H1 as depicted in SEQ ID NO:48, CDR-H2 as depicted in SEQ ID NO:49 and CDR-H3 as depicted in SEQ ID NO:50;

(d) CDR-H1 as depicted in SEQ ID NO:66, CDR-H2 as depicted in SEQ ID NO:67 and CDR-H3 as depicted in SEQ ID NO:68;

(e) CDR-H1 as depicted in SEQ ID NO:84, CDR-H2 as depicted in SEQ ID NO:85 and CDR-H3 as depicted in SEQ ID NO:86;

(f) CDR-H1 as depicted in SEQ ID NO:102, CDR-H2 as depicted in SEQ ID NO:103 and CDR-H3 as depicted in SEQ ID NO:104;

(g) CDR-H1 as depicted in SEQ ID NO:120, CDR-H2 as depicted in SEQ ID NO:121 and CDR-H3 as depicted in SEQ ID NO:122;

(h) CDR-H1 as depicted in SEQ ID NO:138, CDR-H2 as depicted in SEQ ID NO:139 and CDR-H3 as depicted in SEQ ID NO:140;

(i) CDR-H1 as depicted in SEQ ID NO:156, CDR-H2 as depicted in SEQ ID NO:157 and CDR-H3 as depicted in SEQ ID NO:158; and

(j) CDR-H1 as depicted in SEQ ID NO:174, CDR-H2 as depicted in SEQ ID NO:175 and CDR-H3 as depicted in SEQ ID NO:176."

XXIV. The following documents are referred to in this decision:

D3: WO 2005/061547

D6: WO 2007/042261

D11: Kontermann R.E., Acta Pharmacologica Sinica 26(1), 2005, pp. 1-9

D18a: Experimental results - SP34 binding experiments prepared by opponent 2

D19: Experimental report on SP34 binding prepared by opponent 1

D39: Archived webpage from 7 September 2006 - Beth Israel Deaconess Medical Center

D48: WO 2000/041474

D50: Schlereth B. et al., Cancer Research 65(7), 2005, pp. 2882-2889

D52a: Results of alanine-scanning experiment of the terminal 27 amino acids of CD3 epsilon using SP34, A2J and H2C, filed by opponent 2 during opposition proceedings

D101: Experimental report "CD3 epsilon epitope mapping" filed on 21 March 2016 by opponent 2

D103: Experimental report "Cytokine secretion data I and II" filed on 27 April 2016 by the patent proprietor

D112: Experimental report "Epitope mapping of A2J, E2M, H2C, F12Q, H1E, F7O, I2C, F6A, G4H antibodies" dated 28 February 2017 filed by the patent proprietor

XXV. Further documents filed in this appeal proceedings are not referred to in this decision because they were filed either in relation to an issue which the board need not decide or in relation to an issue decided in favour of the party filing them without the need for the board to take them into account.

XXVI. The arguments of the patent proprietor, in so far as relevant to this decision, may be summarised as follows.

Main request

Admittance into the appeal proceedings (Article 12(4) RPBA 2007)

This claim request had been filed with the statement of grounds of appeal and had thus been long in the procedure. It was based on auxiliary request 15 considered in the decision under appeal.

The deletion of the alternative "single domain antibody" from claim 1 constituted a simplification.

The word "having" used in the definition of the CDRs meant "consisting". This meaning was used for example in document D6. This amendment aimed at providing a self-contained claim.

Auxiliary request 20A

Admittance into the appeal proceedings (Article 13(1) RPBA 2007)

This claim request was filed in reaction to the filing by opponent 2, with the letter dated 11 July 2019, of decision T 628/15 of the current board concerning, allegedly, closely related subject-matter. The decision dealt with the issue of Article 123(2) EPC with respect to a claim defining a combination of light chain and heavy chain CDRs.

By the addition of the expression "a pharmaceutical composition comprising", the claim now had the format of a purpose-limited product claim according to Article 54(4) EPC.

Auxiliary requests 20B and C

Admittance into the appeal proceedings (Article 13(1) RPBA 2007)

These claim requests were filed in reaction to the objection put forward in opponent 6's reply to the appeal (see point 7.4.).

Auxiliary request 20D

Admittance into the appeal proceedings (Article 13(1) RPBA 2007)

This request should be admitted into the appeal proceedings as a reaction to the new objection of opponent 2 under Article 123(2) EPC raised for the first time in appeal proceedings.

Claims 1 and 2 of this request were identical to claims 4 and 5 as granted. These claims were also present in the main request as claims 3 and 4. No objections to these claims had been raised by the opponents during the opposition proceedings. Thus, the request did not add to the complexity of the case.

Auxiliary request 21 - claim 1

Amendments - Article 123(2) EPC

Admittance of an objection under Article 123(2) EPC (Article 12(4) RPBA 2007)

The amendment during the opposition proceedings by which the sequences of the CDRs of the light and heavy variable regions were inserted into claim 1 of the then auxiliary request 18 had not been objected to during the opposition proceedings. In fact, the decision under appeal stated that no objections under Article 123(2) EPC were raised in respect of this request.

This objection constituted an amendment of the opponents' case. The objection could have been brought forward in opposition proceedings and should not be admitted in the appeal proceedings.

Further objection under Article 123(2) EPC

The epitope in claim 1 was the pentapeptide Q-D-G-N-E disclosed on page 26, line 11 of the description by the three-letter amino acid code Gln-Asp-Gly-Asn-Glu.

The application disclosed that the epitope was part of amino acid sequences having SEQ ID NOs: 2, 4, 6 and 8 (see page 26, first two paragraphs). However, from the sequence alignment provided in document D20b of the N-terminal 27 amino acids of these sequences, it was apparent that in none of those sequences the amino acid "D" followed the pentapeptide sequence Q-D-G-N-E, i.e. the pentapeptide recited in the claim. Thus, the epitope could not be the hexapeptide Q-D-G-N-E-D, i.e. the one in brackets on page 26, line 11 of the application, and the pentapeptide was the correct sequence of the epitope.

Moreover, the passage on page 8, lines 23 to 30 also disclosed the epitope with only the five amino acids.

Furthermore, it was common practice in the technical field to repeat the three-letter code sequence in abbreviated form, i.e. in the one letter code, in brackets. Therefore, that passage of the application did not disclose a list of two sequences for the epitope. Instead, the same sequence was given in a three-letter code followed by its abbreviation in a one-letter code, and no selection needed to take place.

Sufficiency of disclosure (Article 83 EPC)

Admittance of the objection of lack of sufficient disclosure into the appeal proceedings (Article 12(4) RPBA 2007)

The statement of grounds of appeal of opponent 1 (point 4.1) briefly referred to a communication of the examining division. This did not comply with the requirements for substantiation of an objection. Thus, the objection should not be admitted into the appeal proceedings.

Sufficiency of disclosure

The skilled person was aware of binding domains derived from molecules other than antibodies. An example of such a binding domain was lipocalin (letter of reply to the appeals, section B).

The opponents had not provided verifiable facts to substantiate serious doubts.

Inventive step (Article 56 EPC)

Admittance of the objection based on antibody SP34 as representing the closest prior art

No arguments were provided in this respect.

Admittance of the objection based on document D48 as representing the closest prior art

The objection raised by opponent 4 for the first time at the oral proceedings should not be admitted. This document had previously been addressed in the context of novelty but had not been put forward as representing the closest prior art. Thus, a line of argument on inventive step starting from this disclosure had never been submitted until the oral proceedings before the board.

Moreover, no reasons had been presented why this disclosure would be closer to the claimed subject-matter than the disclosure in each of documents D3, D11 and D50.

Inventive step in view of document D6 as representing the closest prior art

Priority (Article 87 EPC)

The application as filed and the patent applications P1 and P2 disclosed the same Q-D-G-N-E epitope. Furthermore, the context-independence of the N-terminal amino acids 1 to 27 of CD3, where the epitope was located, the epitope being linked with the effect on T cell redistribution, was already disclosed in the applications P1 and P2.

Both of these priority applications disclosed binding domains binding to human and non-chimpanzee primate CD3 epsilon (P1, page 22, third full paragraph and P2, page 7, first full paragraph). The term "antibody", referring to the CD3 binding domain, included various embodiments such as chimeric and humanised antibodies, and the generation of mouse antibodies and their humanised versions was disclosed (P1, page 18 and examples 1 and 2). Thus, the subject-matter was not restricted to binding domains derived from humans.

Hence, since claim 1 validly claimed priority from P1 and P2, document D6 did not constitute prior art according to Article 54(2) EPC and could therefore not be taken to represent the closest prior-art document in the assessment of inventive step.

Inventive step in view of document D3, document D11 or document D50 as representing the closest prior art

Closest prior art and objective technical problem

The claimed bispecific polypeptide differed from that disclosed in the prior-art documents D3, D11 and D50 by the epitope to which it bound on CD3.

The binding to this epitope resulted in two technical effects: the ability of the antibody to cross-react with human and New World monkey CD3 and an increased efficacy due to reduced T cell redistribution.

Thus, the objective technical problem was to be formulated as the provision of a cross-species reactive antibody with increased efficacy in BiTE (bispecific T cell engager) therapy.

Obviousness

Even when the objective technical problem was formulated without taking into account the second effect, it was nevertheless not obvious to provide the claimed polypeptide.

Given that the binding domains of antibody SP34 already presented cross-species reactivity, there was no need to provide further cross-species reactive antibodies by modifying antibody SP34.

The skilled person would not have used antibody SP34 for providing a binding domain for CD3 for the following reasons:

(i) There was a prejudice against using cross-reactive CD3 antibodies because they would cause T cell activation and/or T cell redistribution. Thus, the skilled person would not have used antibody SP34 due to its cross-species reactivity.

(ii) If the skilled person had used a cross-species reactive antibody, the antibody SP34 would not have been the only choice since other antibodies with cross-species reactivity were known, as shown in documents D61 and D24.

(iii) Knowledge of the epitope to which SP34 bound could not be used for the assessment of inventive step as it was only determined by the opponents in knowledge of the patent or application.

Furthermore, there were alternative solutions, for example polypeptides binding to CD5 instead of CD3 or polypeptides binding to a different epitope on CD3.

It was not obvious to provide variants of the CD3 binding domains of antibody SP34. The epitope bound by SP34 was not known at the earliest date of priority claimed. Thus, it was not routine to provide such variants. There was no reasonable expectation of success; only mere hope.

Modifications to the CDRs of antibody SP34 could result in binding to a different epitope. There was no guidance on how to arrive at the alternative CDRs in the claim.

XXVII. The arguments of the appellant-opponents and the respondents, opponent 6 and opponent 7, may be summarised as follows.

Main request

Admittance into the appeal proceedings (Article 12(4) RPBA 2007)

This request should not be admitted into the appeal proceedings because the amended wording used to define the CDRs introduced clarity issues which had not been addressed in the decision under appeal.

Furthermore, the disclaimer did not comply with the requirements of Articles 123(2) and 84 EPC.

The request was thus not prima facie allowable.

The patent proprietor had not put forward any reasons why this request could not have been filed in the proceedings before the opposition division, neither had any indication been given as to which ground for opposition the request was meant to address.

Auxiliary request 20A

Admittance into the appeal proceedings (Article 13(1) RPBA 2007)

This request should not be admitted into the appeal proceedings because the claims did not fulfil the requirement of clear allowability. The issues raised in the context of the main request under Articles 123(2) and 84 EPC, arising from the amended wording "having" in the definition of the CDRs as well as from the disclaimers, applied equally here.

The insertion of the wording "pharmaceutical composition" did not address the issues concerning the scope of the disclaimer and added to the complexity of the case.

The objection under Article 123(2) EPC had been submitted with the opponents' statements of grounds of appeal and therefore could not justify the timing of the filing of this request.

Auxiliary requests 20B and C

Admittance into the appeal proceedings (Article 13(1) RPBA 2007)

These requests should not be admitted into the appeal proceedings for the same reasons as put forward for auxiliary request 20A.

Auxiliary request 20D

Admittance into the appeal proceedings (Article 13(1) RPBA 2007)

Claim 1 of this request defined the polypeptide in terms of either the VH or the VL CDRs. Such subject-matter had not been addressed earlier in the proceedings and required considerations of the biological properties imparted to the polypeptide by the sequences of the VH or the VL regions separately, the combination no longer being required. Thus, this request should not be admitted into the appeal proceedings because it added to the complexity of the case.

Furthermore, the request constituted a reaction to the objections of lack of novelty based on document D6 which were already in the proceedings before the opposition division. Therefore, the request could and should have been filed earlier.

The objection under Article 123(2) EPC was submitted with the statements of grounds of appeal and therefore could not justify the timing of the filing of this request.

Auxiliary request 21 - claim 1

Amendments - Article 123(2) EPC

Admittance of an objection under Article 123(2) EPC (Article 12(4) RPBA 2007)

The board had discretion to admit the objection.

The objection was prima facie highly relevant in view of the decision in case T 628/15.

Analysing the objection involved no complexity, and the impact in terms of procedural economy was low as no documents were involved other than the patent application.

The patent proprietor had had time to react to the objection in advance of the oral proceedings.

Further objection under Article 123(2) EPC

The three species Callithrix jacchus, Saguinus oedipus and Saimiri sciureus constituted a selection from those disclosed on pages 14 to 18 of the application as filed.

The peptide Gln-Asp-Gly-Asn-Glu also constituted a selection from two possibilities on page 26, line 11 of the application as filed. Thus, claim 1 included a combination of two selections.

From the passage on page 26 of the application, it was not clear whether a pentapeptide or a hexapeptide was meant.

Multiple corrections were possible for the hexapeptide. Besides the correction consisting of the deletion of the last amino acid in the hexapeptide, a possible correction would be its replacement with the amino acid E, glutamic acid. Such a hexapeptide would fall within SEQ ID NOs 2, 4, 6 and 8. Therefore, the hexapeptide could not be corrected by deletion of the last amino acid, and two possibilities were disclosed in this passage of the description.

Sufficiency of disclosure (Article 83 EPC)

The examining division in the communication of 7 February 2011 (point 6.1) had raised an objection of lack of sufficiency of disclosure for binding domains other than derived from antibodies (see statement of grounds of appeal of opponent 1, point 4.1).

Inventive step (Article 56 EPC)

Admittance of the objection based on antibody SP34 as representing the closest prior art

In opponent 4's letter of 17 March 2021 on pages 5 and 6, an objection was developed selecting as the closest prior art the commercially available antibody SP34.

No arguments were provided in relation to admittance of this objection into the appeal proceedings.

Admittance of the objection based on document D48 as representing the closest prior art

The disclosure in document D48 was addressed in opponent 1's letter dated 17 July 2017 (points 3.16 and 7.39). A reference to inventive step was made in points 3.60 and 7.10 of that letter. The claims as a whole had been objected to under inventive step. Since this included the dependent claims of the then main request, it followed that also the features of claim 1 of auxiliary request 21 had been objected to.

This document represented the closest prior art because it referred to antibody SP34, and therefore the claimed subject-matter differed from it merely in the specific CDR sequences.

Inventive step in view of document D6 as representing the closest prior art

Priority (Article 87 EPC)

Priority was not claimed in respect of the same invention as disclosed in earlier applications P1 and P2 for two reasons.

The earlier applications did not disclose that the epitope resulted in less T cell redistribution during the starting phase of the treatment, as disclosed in the application (page 6, line 24 to page 8, line 7). This effect resulted in a functional definition of the epitope in addition to the structural definition consisting of the amino acid sequence recited in the claim. The skilled person was thus presented with new information, not directly and unambiguously derivable from the earlier patent applications (see decision G 2/98).

Moreover, including the effect of T cell redistribution in the formulation of the objective technical problem was impermissible because it took into account knowledge not available at the priority date.

All the relevant passages in each of the priority applications required that the binding domain be a human binding domain (e.g. on pages 1, 6 to 11, 21, 165 and 171 of patent application P1). However, this requirement was not present in the claims. Thus, none of the claimed subject-matter was entitled to the priority date claimed from applications P1 and P2.

Hence, since priority from earlier applications P1 and P2 was not validly claimed for the subject-matter of claim 1, document D6 constituted prior art according to Article 54(2) EPC and could therefore be taken to represent the closest prior-art document in the assessment of inventive step.

Inventive step in view of document D3, document D11 or document D50 as representing the closest prior art

Closest prior art and objective technical problem

The closest prior art could be represented by the bispecific CD3-binding molecules disclosed in each of documents D3, D11 and D50.

The claimed subject-matter differed from these by the epitope to which the polypeptides (antibodies) bound and their CDR sequences.

Binding to the particular epitope resulted in the ability of the antibody to cross-react with human and New World monkey CD3.

No effect in terms of increased efficacy of the antibody due to reduced T cell redistribution could be acknowledged, for the following reasons:

(i) The meaning of "reduced T cell redistribution" was not clear - a term which had no recognised meaning in the art should not be incorporated into the formulation of the objective technical problem.

(ii) It was not clear how to measure "reduced T cell redistribution" - in the patent, T cell counts were the property measured.

(iii) The experimental data in the patent did not unambiguously substantiate such an effect for the bispecific constructs tested - the experiments for comparing the constructs according to the claim with other constructs differed by several parameters.

(iv) If present, such an effect would inevitably be present for the antibody SP34 since, according to the patent proprietor, the effect of reducing T cell redistribution resulted from binding to the specific epitope. Since antibody SP34 bound to the same epitope, such an effect would thus be merely a bonus effect present in the obvious bispecific construct based on antibody SP34.

(v) As an alternative to the previous point, it had to be assumed that the effect was not achieved by all antibodies binding to the epitope as defined in the claim, and consequently not all constructs falling within the scope of the claim achieved this technical effect.

(vi) The experimental results provided in document D103 showed that such a technical effect could not be attributed to the epitope.

The objective technical problem was thus to be formulated as the provision of a bispecific CD3 and tumour antigen binding polypeptide which presented cross-species reactivity with human and New World monkey CD3. Alternatively, the objective technical problem could be formulated as the provision of improved CD3-binding BiTE molecules or as the provision of CD3-binding bispecific polypeptides reacting with the three species indicated in claim 1.

The objective technical problem defined by the patent proprietor, or that adopted by the opposition division, amounted to two distinct problems, one being the "cross-species reactive" problem and the other being the "reduced adverse events/reduced T cell redistribution" problem.

Should the problem be formulated with both parts, if the solution to one part had been obvious, the provision of a solution to the other part would merely have been a bonus effect.

The objective technical problem as formulated by the opposition division was not solved over the whole scope of the claim - cross-species reactivity was shown only for four antibodies, i.e. only for some of the CDR combinations covered by the claim, and T cell redistribution results were shown for only one of the antibodies. Moreover, for none of the specific antibodies in the patent were there experimental results with regard to both technical effects.

The two problems in the problem as formulated by the opposition division were in fact partial problems.

Obviousness

To provide a cross-species reactive CD3-binding bispecific polypeptide, the skilled person would have used antibody SP34 for the CD3 binding domain because it was the only CD3 antibody known to present cross-reactivity.

The CD3 binding domain in claim 1, as defined by the CDR sequences, bound to the same epitope as antibody SP34. The particular CDRs within the binding domains claimed were mere arbitrary alternatives to the obvious CDRs within the SP34 binding domains.

The fact that the particular CDRs were not predictable in advance did not make them contribute to inventive step. No technical effect was known associated with the differences in the CDR sequences versus those in antibody SP34. Decisions T 735/00 (Reasons 26) and T 2637/11 (Reasons 20) were relevant in this context. In particular, in decision T 735/00, the board held that the preparation of antibodies was routine. Also, mutagenesis of known CDRs was routine.

The skilled person would have been motivated to provide polypeptides with cross-species reactivity and thus would have modified the prior-art bispecific polypeptides to provide them with binding domains based on antibody SP34. It was not necessary to know the epitope bound by this antibody.

Because the skilled person would have used antibody SP34, the resulting polypeptide would have bound to the same epitope as SP34, as required by the claim.

The claimed variants could easily be generated without any technical difficulties, for example by mutagenesis of the CDRs and selection for cross-reactivity. Document D48 disclosed in-vitro mutagenesis for modifying CDRs (page 9, lines 12 to 16, paragraph 3 and page 10, first paragraph). Only routine methods were involved.

Although the epitope bound by antibody SP34 was not known in the prior art, it could be determined.

Each of the multiple steps indicated by the opposition division was routine and therefore did not lead to the presence of an inventive step.

Requests of the parties relevant for the present decision

XXVIII. The patent proprietor requested that the decision under appeal be set aside and that the patent be maintained in amended form on the basis of the set of claims of the main request, filed as auxiliary request 20 with the statement of grounds of appeal or, alternatively, on the basis of one of the sets of claims of auxiliary requests 20A, 20B, 20C and 20D, all filed with the letter dated 4 September 2019 or, further alternatively, on the basis of the set of claims of auxiliary request 21, filed with the statement of grounds of appeal, auxiliary request 21 being identical to the version considered allowable by the opposition division, thus implying that the appeals of the opponents be dismissed.

The patent proprietor further requested that documents D110 to D112 and D120 to D122 be admitted into the proceedings.

XXIX. Appellant-opponents 1 to 4 requested that the decision under appeal be set aside and that the patent be revoked in its entirety. They also requested that the main request and all auxiliary requests except for auxiliary request 21 not be admitted into the proceedings and that all documents filed by the opponents be admitted into the proceedings.

Respondent-opponents 6 and 7 requested that the patent proprietor's appeal be dismissed.