T 0424/21 (Antibody Fc variants/ROCHE GLYCART) 08-04-2022

Reasons for the Decision

Main request (claims as granted)

Amendments (Article 100(c) EPC) - claims 4 and 5

1. Claim 4 as granted, which is dependent on claim 1 as granted, further defines the claimed antibody and Fc fusion protein to the effect that "the thrombocyte aggregation induced by the antibody or Fc fusion protein comprising the IgG1 Fc variant is reduced compared to the thrombocyte aggregation induced by the antibody or Fc fusion protein comprising the wild-type human IgG1 Fc region".

2. The respondent argued that the subject-matter of claim 4 was explicitly disclosed on page 2, lines 3 to 6 of the application, which reads: "In a further embodiment the thrombocyte aggregation induced by the polypeptide comprising the Fc variant is reduced compared to the thrombocyte aggregation induced by a polypeptide comprising a wild-type human IgG Fc region." The board does not agree because this disclosure is not linked to the specific set of P329G, L234A, L235A (PGLALA) mutations as defined in claim 1, but merely defines "a further embodiment" independent of any specific mutation. This passage does not refer specifically to an IgG1 Fc variant either.

3. The respondent further cited pages 44 and 45 and original claim 8 as a basis for the subject-matter of claim 4. However, the disclosure on pages 44 and 45 does not refer specifically to an IgG1 Fc variant either. Moreover, it refers to the PGLALA mutations not in general terms but in the context of a specific anti-CD9 antibody.

4. Claim 8 as filed, which refers to thrombocyte aggregation, is dependent on claim 1 as filed, which, apart from generally concerning an IgG Fc variant, also contains further functional requirements. Yet these are not present in claim 1 as granted. In particular, claim 1 as filed requires that "said polypeptide exhibits a reduced affinity to the human FcgammaRIIIA and/or FcgammaRIIA and/or FcgammaRI compared to a polypeptide comprising the wildtype IgG Fc region, and wherein the ADCC induced by said polypeptide is reduced to at least 20% of the ADCC induced by the polypeptide comprising a wild-type human IgG Fc region". The board does not agree with the respondent that the PGLALA mutations inherently imparted the above functional features on any antibody or Fc fusion protein. For the analysis of added subject-matter it cannot simply be assumed that all antibodies or Fc fusion proteins carrying the PGLALA mutations would achieve at least 20% reduced ADCC. Since the correlation is based only on measurements of one particular antibody (anti-CD20 (GA101); see Examples 4 and 5 and Figures 4a and 4b) the board finds that a reduction of ADCC to at least 20% is not directly and unambiguously derivable as an inherent feature of all the antibodies and Fc fusion proteins carrying the triple mutation.

5. Removing this requirement thus enlarges the group of antibodies and Fc fusion proteins falling under the scope of granted claim 1 and thus includes subject-matter which was not part of claim 1 as filed. Claim 8 as filed, which is dependent on claim 1 as filed, therefore does not disclose the subject-matter of claim 4 as granted.

6. Claim 5 as granted, which is dependent on claim 1 as granted, further defines the claimed antibody and Fc fusion protein to the effect that "CDC induced by the antibody or Fc fusion protein comprising the IgG1 Fc variant is strongly reduced compared to the CDC induced by the antibody or Fc fusion protein comprising the wild-type human IgG1 Fc region".

7. The respondent argued that the subject-matter of claim 5 was explicitly disclosed on page 2, lines 6 to 9 of the application, which reads: "In still a further embodiment, the polypeptide according to the invention exhibits a strongly reduced CDC compared to the CDC induced by a polypeptide comprising a wild-type human IgG Fc region." This passage does not provide a basis for the subject-matter of the claim, for the reasons set out in point 2.

8. The respondent further cited page 15, lines 15 to 20, page 39, lines 27 to 30 and original claim 9 as a basis. However, the disclosures on pages 15 and 39 do not mention the PGLALA mutations or an IgG1 Fc variant either. Moreover, claim 9 as filed depends on claim 1 as filed, which, as outlined above, contains additional functional features which have been omitted from granted claim 1 on which granted claim 5 is dependent. For the same reasons as outlined above for claim 8 as filed with regard to claim 4 as granted, claim 9 as filed does not disclose the subject-matter of claim 5 as granted.

9. Claims 4 and 5 add subject-matter.

Auxiliary requests 1 to 5

Amendments (Article 100(c) EPC) - claims 4 and 5

10. Claims 4 and 5 of these requests add subject-matter for the same reasons as outlined above for the main request.

Auxiliary request 6

Admission into appeal proceedings (Article 13(1) and (2) RPBA 2020)

11. Auxiliary request 6 was admitted into the proceedings. The reasons for this decision are as follows.

12. The set of claims in auxiliary request 6, filed by letter of 21 February 2022, i.e. after the notification of the summons to oral proceedings, differs from that in the main request in that dependent claims 4 and 5 have been deleted and claims 6 to 8 renumbered accordingly.

13. Article 13(2) RPBA 2020, which relates to the situation "after notification of a summons to oral proceedings", thus applies.

14. In a first step it needs to be assessed whether filing auxiliary request 6 amounts to an "amendment of the party's appeal case" within the meaning of Article 13(2) RPBA 2020.

15. A number of decisions have held that deleting a dependent claim that does not represent an amendment to the factual and legal framework of the case is not an amendment within the meaning of Article 13(2) RPBA 2020 (see e.g. T 884/18, Reasons 4; T 914/18, Reasons 4.1; T 995/18, Reasons 2; T 1480/16, Reasons 2.3).

16. In this board's view, however, a party's case should not be confused with the subject-matter that is presented for consideration of patentability. On the contrary, a new claim request normally represents a new line of defence against the opposition, and by adding this new line of defence to its case the respondent has undoubtedly changed its case.

17. In this respect, the present board agrees with the board in T 494/18, which found: "According to their wording, Articles 13(1) and 13(2) RPBA 2020 are both applicable to 'any amendment to a party's appeal case'. The provision as such however does not define what is to be regarded as an 'amendment to a party's appeal case', it is thus an undefined legal term. An 'amendment to the party's appeal case' is not identical to an amendment of the patent or of the patent application. Therefore, the provisions and decisions dealing with the latter (see for example G 3/14, OJ 2015, 102) and the definitions given in that context cannot be applied unchanged. However, the question of what can be defined as an 'amendment to a party's appeal case', and with that the question of whether Article 13 RPBA 2020 is applicable, can be answered in the systematic context of the provisions guiding appeal proceedings (see also J 14/19, reasons 1.4). In this context, Article 12(3) RPBA 2020 provides that the statement of grounds of appeal and the reply shall contain a party's complete appeal case. Accordingly, all requests shall be specified expressly at this stage. It follows from this that only those requests that have been filed with a party's statement of grounds of appeal or the reply form part of a party's appeal case.

Consequently, a new request filed afterwards with a set of claims that is different to that of the previous requests, is usually to be regarded as an 'amendment to a party's appeal case' within the meaning of Article 13 RPBA 2020. Following the systematic context of Articles 12(3) and 13 RPBA, a request in which claims have been deleted compared to the previous requests is therefore a new request and thus usually amounts to an 'amendment to the party's appeal case' according to Article 13 RPBA 2020." A similar conclusion was reached in decisions T 2091/18, Reasons 4.1 and T 2295/19, Reasons 3.4.5, for example.

18. In a second step, it has to be established whether there are "exceptional circumstances, which have been justified by cogent reasons", which allow the request to be admitted into the appeal proceedings.

19. The respondent argued that neither the opposition division's preliminary opinion nor the decision under appeal had addressed the question of added subject-matter with regard to claims 4 and 5. Before receiving the board's communication under Article 15(1) RPBA 2020, which drew attention to this issue, the respondent could therefore not have reasonably expected it to become relevant in the appeal proceedings. It would also not have been procedurally efficient to address all potential objections by filing as early as with the reply to the appeal auxiliary requests with individual dependent claims. The deletion addressed the objections with regard to claims 4 and 5 in full and did not change the assessment of any other issue of the appeal.

20. The appellant countered that the deletion of the claims changed the focus of the appeal and that the late filing of an amended claim request would give the patentee an unfair advantage. It was the purpose of the new RPBA to "front-load" the proceedings in the sense that all means of attack and defence had to be presented at the beginning of the appeal. The late filing was also detrimental to procedural efficiency because otherwise the appeal could be brought to an end for want of any allowable claim requests. As the objections against claims 4 and 5 had already been present in both the notice of opposition and the statement of grounds of appeal, there could be no "exceptional circumstances" justifying the late filing (citing decision T 172/17).

21. The board concluded that although the deletion of dependent claims 4 and 5 constitutes an amendment to the appeal within the meaning of Article 13(2) RPBA 2020 (see above), it did not change the factual and legal framework of the appeal. This distinguishes the case from decision T 172/17, in which auxiliary requests 1 to 3, which were not admitted, contained an amendment to independent claim 1 through the insertion of the subject-matter of former dependent claims.

22. In the case in hand, the deletion of dependent claims 4 and 5 does not affect the objections relating to added subject-matter, sufficiency of disclosure and inventive step for the other claims, all of which had been addressed in the statement of grounds of appeal, the reply and the board's communication under Article 15(1) RPBA 2020. The appellant was therefore not disadvantaged by the admittance of the request. This distinguishes the case from, for example, those underlying decisions T 2222/15 (Reasons 29 and 30), T 1569/17 (Reasons 4.3.4) and T 317/20 (Reasons 28 to 44), where the deletion of claims would have substantially shifted the case, thereby giving rise to new issues to be decided upon.

23. Moreover, the board could not agree with the appellant that the "convergent approach" of the RPBA 2020 (see "Table setting out the amendments to the RPBA and explanatory remarks" accompanying the RPBA 2020), which arguably aims at "front-loading" the appeal proceedings, creates a blanket ban on deleting dependent claims at a later stage of the appeal proceedings. In this respect, the board interprets the wording "shall, in principle," in Article 13(2) RPBA 2020 such that it leaves the board at least some discretion in its assessment of the alleged exceptional circumstances. Sensibly applying this discretion appears to be particularly important in technical fields with patents containing a large number of dependent claims. Generally prohibiting the deletion of dependent claims in reaction to the development of the appeal proceedings would require a huge number of auxiliary requests to be filed at an early stage, i.e. as early as with the statement of grounds of appeal or the reply, covering all combinations and permutations of possible fall-back positions. This would not be in the interest of procedural economy and cannot be deemed to be in line with the "convergent approach" and the aim and purpose of the RPBA 2020.

24. The board concludes that deleting dependent claims 4 and 5 enhances procedural economy as doing so clearly overcomes existing objections without giving rise to any new issues. In the board's opinion these are cogent reasons justifying exceptional circumstances as per Article 13(2) RPBA 2020 (see also T 1857/19, Reasons 1.1, penultimate paragraph).

25. As it deemed the request admissible under the stringent requirements of Article 13(2) RPBA 2020, the board considered it unnecessary to further decide whether the less stringent requirements of Article 13(1) RPBA 2020 were fulfilled.

26. Auxiliary request 6 was admitted into the appeal proceedings.

Amendments (Article 100(c) EPC) - claim 1

27. Page 33, lines 7 to 11 of the application as filed discloses: "In a specific embodiment the polypeptide comprising an Fc variant of a wildtype human Fc polypeptide comprises a triple mutation: an amino acid substitution at position Pro329, a L234A and a L235A mutation (P329/LALA). In a further specific embodiment the above mentioned polypeptides comprise a human IgG1 region."

28. The skilled person will read these two sentences together to mean that the latter embodiment comprises an Fc variant of a human IgG1 region with the specified mutations. As concerns the nature of the polypeptide, the skilled person is instructed on page 2, lines 1 to 3 that one aspect of the invention is that "the polypeptide is an antibody or an Fc fusion protein". The skilled person would read this passage as applying in general to all polypeptides carrying Fc variants and mutations disclosed in the application.

29. As concerns the mutation at position Pro329, there is a clear pointer to glycine, which is disclosed as the preferred mutation throughout the application, for example on page 7, lines 5 to 12, which concludes: "[...] a glycine residue appears to be unexpectedly superior over other amino acid substitutions, like alanine, for example, at position 329 in destroying the proline sandwich in the Fc/Fcgamma receptor interface." On page 31, lines 3 to 5, the P329G mutation is clearly singled out: "In another embodiment Pro329 is substituted with an amino acid which is either smaller or larger then proline. In still another embodiment the substituted amino acid is Gly, Ala or Arg. In a further aspect of the invention Pro329 of the Fc polypeptide is substituted with glycine." Furthermore, in the experimental section, the following is underlined on page 82: "P329G, P329A, SPLE and LALA mutations have been introduced ... Thus, the combination of P329G with either LALA of SPLE mutations is much more effective than the P329G mutation or the double mutations LALA or SPLE alone."

30. The application thus discloses a polypeptide which is an "antibody or an Fc fusion protein" comprising an Fc variant of a wild-type human IgG1 Fc region and the P329/LALA mutations of which P329G, L234A, L235A (PGLALA) is the preferred embodiment.

31. In conclusion, the board finds that the subject-matter of claim 1 does not extend beyond the content of the application as filed (Article 100(c) EPC).

Sufficiency of disclosure (Article 100(b) EPC)

Fc fusion protein - claim 1

32. Fc regions are commonly known and are described in the patent (see e.g. paragraph [0016]). Producing fusion proteins by genetic engineering is also part of the common general knowledge (see e.g. review in document D15, paragraph bridging pages 59 and 60). The appellant did not assert any serious doubts that the skilled person was able to obtain Fc fusion proteins as detailed in claim 1.

Technical effect achievable "over whole range claimed" - claims 2 and 3

33. The antibodies carrying the PGLALA mutations tested in the patent show the effects as mentioned in the claims, i.e. "ADCC ... reduced to 0-20%" and "reduced or ablated affinity for an Fc receptor responsible for an effector function" (see Examples 2, 4 and 5). The appellant has not provided any evidence that these effects are restricted to the particular antibodies used in the examples and the board sees no reason to assume this to be the case. Moreover, the respondent has provided evidence that the effect can also be achieved for antibodies directed to other targets (see e.g. document D20). Therefore, for want of any serious doubts, it can be accepted that the patent enables the skilled person to obtain antibodies or Fc fusion proteins having the functional features as required by claims 2 and 3, without undue burden.

Medical use - claims 5 and 6

34. Claim 5 is formulated in the form of a first medical use ("for use as a medicament") according to Article 54(4) EPC ("for use in a method referred to in Article 53(c)"). In view of the above finding with regard to the sufficient disclosure of the antibody and Fc fusion protein as such, it remains to be analysed whether those compounds are suitable for use as a medicament.

35. The patent shows that the PGLALA mutations can be introduced into known therapeutic antibodies having a human IgG1 Fc region and that an antibody of this kind provides relevant medical effects such as reduced Fc receptor affinity and reduced effector function, known to be useful in several therapeutic contexts (see e.g. paragraphs [0020] and [0021]). It is plausible that this finding also extends to Fc fusion proteins in which the Fc part is fused to a therapeutically effective protein (see e.g. paragraphs [0116] and [0117] of the patent) and that the mutated antibodies or Fc fusion proteins can be used as a medicament in said known therapies without the mutations in the Fc region impairing the therapeutic effect.

The appellant has contested that the examples in the patent show that the mutated antibodies bind to their (antigen) targets and are therapeutically effective. The appellant, however, has not provided any evidence to that effect.

It is common general knowledge that the Fc region and the antigen-binding region of an antibody can be modified independently of each other (see the "Background" section of the patent). This is further supported by later-published data, e.g. document D30, which reports on ongoing clinical trials of PGLALA-mutated therapeutic antibodies (page 458, left-hand column, second-to-last paragraph) and shows retained binding to the antigens (paragraph bridging pages 5 and 6).

Therefore, the only remaining question is whether claim 5 should be restricted to these particular therapies.

36. The case law of the boards of appeal concerning the question of sufficiency of disclosure of a first medical use is not very extensive and generally relates to the situation where, unlike in the case in hand, the substance or composition is part of the state of the art (in accordance with Article 54(5) EPC 1973 corresponding to Article 54(4) EPC 2000). However, for the question of whether the "medical use" aspect of the claim is sufficiently disclosed, this distinction is irrelevant as the skill required to use a known substance or composition in medicine is the same as that required for a substance or composition provided by the patent for the first time.

37. In decision G 5/83, Reasons 15, the Enlarged Board of Appeal stated: "Thus the inventor of a 'first medical indication' can obtain purpose-limited product protection for a known substance or composition, without having to restrict himself to the substance or composition when in a form technically adapted to a specified therapeutic purpose. The appropriate protection for him is, therefore, in its broadest form, a purpose-limited product claim. No problem arises over its susceptibility of industrial application, within the meaning of Article 57 EPC." The board interprets this statement to mean that the Enlarged Board, although not commenting explicitly on Article 83 EPC, also saw no general issue of sufficiency of disclosure for a broad first medical use claim and did not see the need for the inventor to "restrict himself ... to a specified therapeutic purpose".

38. Before decision G 5/83, decision T 128/82 had followed the same line of thinking: "If an inventor is granted absolute protection in respect of a new chemical compound for use in therapy, the principle of equal treatment would require that an inventor who for the first time makes a known compound available for therapy should be correspondingly rewarded for his service with a purpose-limited substance claim under Article 54(5) EPC to cover the whole field of therapy" (see Reasons 10). With regard to Article 84 EPC, the decision stated: "The mere fact that there are not instructions concerning all and any possible specific therapeutic applications does not justify limiting the scope to the therapeutic application actually mentioned. This would not be in accord with the general practice of the European Patent Office concerning therapeutically active compounds" (see Reasons 12). Thus, although Article 83 EPC is not mentioned, this decision does not require a limitation to a specific therapeutic use either.

39. In decision T 604/04, sufficiency of disclosure of a claim to a monoclonal antibody "for use in therapy or diagnosis", i.e. a first medical use, was denied because "the mere disclosure of a monoclonal antibody against the polypeptides of Figure 4 or 5 without identifying a diseased state caused by the 'misfunctioning' of these polypeptides is not sufficient to acknowledge a use in therapy for the monoclonal antibody" (see Reasons 25). The case in hand, however, is different from the situation underlying decision T 604/04 because the patent discloses that established therapeutic antibodies and Fc fusion proteins can be modified as claimed in order to reduce the effector function without affecting the therapeutic effect. Common general knowledge about antibodies and Fc fusion proteins and their therapeutic function(s) thus provides the basis for acknowledging a use in therapy.

40. This board cannot derive any requirement from the EPC whereby a patent would have to show that a compound is suitable for each and every disease in order for a first medical use to be sufficiently disclosed. Instead, it is sufficient to show that the compound is suitable for at least one particular medical use, as is the case in the patent at issue (see point 34. above).

41. Claim 6 defines the disease in functional terms ("wherein it is favourable that an effector function of the antibody or Fc fusion protein is strongly reduced"). The patent discusses the physiological background in which the effector function plays a role (see paragraphs [0020] and [0021]). The wording "in a method for treating a disease ... wherein it is favorable that an effector function ... is strongly reduced" in the claim presupposes an existing (or future) treatment with an antibody or an Fc fusion protein. To put the invention into practice, it is therefore not necessary to identify a new compound or treatment, but only to establish whether there is a need for reduced effector functions in a known treatment. The appellant has not argued that the latter aspect would be an undue burden. The skilled person is therefore able to identify the appropriate diseases without undue burden.

42. Thus, the invention to which the claims relate is sufficiently disclosed in the patent.

Inventive step (Article 100(a) EPC and Article 56 EPC)

Suitable starting point

43. The parties did not agree on a suitable starting point for an inventive step analysis. The board, however, considers this irrelevant when the subject-matter claimed is not obvious from the state of the art proposed by the opponent (i.e. document D13 or document D10), as in the case in hand (see below).

44. Document D13 discloses the anti-CD20 antibody #497, which carries the P329G mutation in its Fc region. The mutation shows effects on Fc receptor binding and C1q binding compared with the same antibody with a wild-type Fc region as analysed by a high-throughput assay (see Figure 41, #497). The data in document D13 show the following effects on binding: FcgammaRI unchanged (1.03-fold), C1q increased (4.72-fold), all other Fc receptors (FcgammaRIIA, FcgammaRIIB, FcgammaRIIC, FcgammaRIIIA, FcRn) reduced.

Difference, effect(s) and objective technical problem

45. It is undisputed that the subject-matter of claim 1 differs from antibody #497 disclosed in document D13 on account of the presence of the L234A and L235A mutations in the Fc region.

46. The effect resulting from this difference, as far as established in the patent, is reduced FcgammaRI binding to "nearly undetectable levels" of the PGLALA triple mutation variant compared with the P329G variant (see Figure 1b and paragraph [0320]).

47. The patent shows that several other characteristics are substantially the same when the PGLALA variant is compared with P329G but are reduced in the PGLALA variant when compared with an antibody having the wild-type Fc region. These effects are:

1) binding to FcgammaRIIA (see Figure 1c)

2) binding to FcgammaRIIIA (see Figure 1e)

3) cytolytic activity (see Figure 3a)

4) ADCC activity (see Figure 4a)

5) CDC activity (see Figure 5a)

48. The binding of the PGLALA variant to FcgammaRIIB is reduced compared with wild-type, but no comparison with the P329G variant is carried out (see Figure 1d). The binding of the PGLALA variant to C1q is not analysed (see Figure 2) but it is considered "very likely [that] also the triple mutations comprising the aforementioned single mutations, strongly reduces the above mentioned functions of C1q" (see paragraph [0325]).

49. The objective technical problem can therefore be formulated as providing antibodies/Fc fusion proteins that show reduced binding to FcgammaRIIA and FcgammaRIIIA, reduced cytolytic activity, ADCC activity and CDC activity as compared with wild-type, and reduced binding to FcgammaRI to "nearly undetectable levels".

Obviousness

50. The skilled person would take document D12 or D14 into account when aiming to solve the above problem because both are concerned with reducing binding to Fcgamma receptors. Both documents report reduced FcgammaRII receptor binding for antibodies with the LALA double mutation in the Fc region (see document D12, Abstract and document D14, Abstract). Document D12 further implies reduced FcgammaRI binding on the basis of competition experiments but does not directly measure it. Document D14 reports reduced FcgammaRI and C1q binding for antibodies carrying the LALA mutations (see document D14, Abstract).

51. The question to be answered is therefore whether it was obvious for the skilled person to combine the P329G mutation and the LALA double mutation in the Fc region of an antibody or Fc fusion protein in order to achieve strongly reduced FcgammaRI binding (to "nearly undetectable levels"), while maintaining reduced binding to FcgammaRIIA and FcgammaRIIIA and reduced cytolytic, ADCC and CDC activity.

52. It is undisputed that the high-throughput binding experiments in document D13 provide only low-confidence data. This is evident from the large error margins and diverging results when assays were performed in duplicate (see e.g. #329, #350, #502). Cytolytic activity, ADCC activity and CDC activity were not directly assayed in document D13 but can be inferred indirectly from the binding of the respective receptors, e.g. C1q binding for CDC, FcgammaRIIIA binding for ADCC. The skilled person therefore would have considered the data in document D13 on Fc receptor binding to be only a first indication of the effects achieved by the P329G mutation which required further experimental confirmation.

53. Document D13 contains no indication to combine mutations in order to achieve greater reduction of binding to particular receptors. Some of the reported examples of combinations of mutations even result in interfering effects, i.e. a combination may cancel out the effects observed for the single mutations (see e.g. #43, #44, #46).

54. The appellant argued during oral proceedings that the double mutations in document D13, which showed a partially cancelling effect, could not be compared with the PGLALA triple mutant as the double mutations reported in document D13 were more closely spaced in the amino acid sequence and thus more likely to interfere with each other.

The board does not agree because the distance in the primary sequence does not necessarily reflect the spatial distance between residues in a folded molecule, such as an antibody. D13 would thus suggest to the skilled person that cancellation of effects was in principle possible.

55. Moreover, documents D12 and D14 do not contain any indication that the LALA mutations could be combined with other mutations in order to achieve a further-silenced Fc region.

56. Even if the skilled person had considered combining the P329G mutation disclosed in document D13 with the LALA mutations disclosed in documents D12 and D14, there would have been no reasonable expectation of success that FcgammaRI binding could be reduced to "nearly undetectable levels" because the P329G mutation showed no effects on FcgammaRI binding while the LALA mutations showed reduced FcgammaRI binding but still at detectable levels. A further reduction of FcgammaRI binding owing to the combination of the three mutations to "nearly undetectable levels" was thus unexpected and not obvious.

57. A reduction in C1q binding and CDC activity as compared with wild-type could not be expected from the combination either, since D13 reported an approximately fourfold increase in C1q binding for the P329G variant, suggesting an increased CDC (see document D13, paragraph [0007], "Fc/C1q binding mediates complement dependent cytotoxicity (CDC)", and the patent, paragraph [0019], "Fc binding to C1q mediates a process called complement dependent cytotoxicity (CDC)"). Although document D14 reports decreased C1q binding for the LALA variant, the skilled person could not reasonably expect this reduction to be maintained and not cancelled out when combining LALA with P329G.

58. In conclusion, the state of the art does not contain any indication or prompt to add further mutations to the P329G mutation disclosed in document D13 in order to further reduce FcgammaRI binding, nor did the skilled person have a reasonable expectation of success in combining the three mutations. Starting from the disclosure of antibody #497 in document D13, the skilled person would not have arrived at the subject-matter of claim 1 in an obvious manner.

59. The assessment of inventive step does not change when starting from document D10 because antibody 909 reported in D10, which carries the P329G mutation, is completely uncharacterised, i.e. neither receptor binding nor ADCC nor CDC were tested. In comparison with the subject-matter of claim 1, the same difference, effect and objective technical problem as for document D13 are established (see points 45. to 49. above). As there is no binding data for the P329G mutant, the skilled person starting from the disclosure of document D10 had even less of an expectation of success of arriving at a variant with strongly reduced FcgammaRI binding and reduced binding to the other Fc receptors, as well as reduced ADCC and CDC.

60. The appellant asserted an additional inventive step objection in the event that the respondent considered claim 1 to mean that, apart from the PGLALA mutations, "any other number of amino acid changes" could be present in addition to PGLALA, implying that claim 1 would encompass Fc variants that have little resemblance to the native human IgG1 Fc sequence.

61. However, the respondent agreed that that interpretation would be far-fetched and endorsed the opposition division's interpretation that "although the variants may have additional mutations in comparison with the wild-type Fc region, these variants must still be human IgG1 Fc regions, and thus, also have the properties of human IgG1 Fc regions" (see decision, sheet 10; statement of grounds of appeal, page 36, sixth paragraph; reply to the appeal, page 18, point 5.3.3).

62. As the parties seem to agree that the very broad interpretation is incorrect, there is no need to address the appellant's additional inventive step objection.

63. The subject-matter of claim 1 is inventive. As claims 2 to 6 are dependent on claim 1, their subject-matter is inventive as well.