T 1389/13 (YKL-40 monoclonal antibodies/BIO-Y) 10-07-2018

1. The appeals of both appellants are admissible. Each of them complies with the requirements pursuant to Articles 106 to 108 and Rule 99 EPC.

2. Admissibility of the opponent's (appellant II's) appeal had been contested by appellant I based on the argument that no statement of grounds of appeal pursuant to Article 108, third sentence, EPC had been filed by the opponent, and the statement of grounds of appeal in question had been filed by a different legal person.

3. Notice of appeal dated 13 June 2013 was duly filed by the opponent Bayer Pharma Aktiengesellschaft and the appeal fee was duly paid. The notice of appeal comprises, in addition to the details required pursuant to Rule 99(1) EPC, the party's internal reference number.

4. The statement of grounds of appeal that was subsequently received was signed by the same representative who had signed the notice of appeal and the notice of opposition. The appeal case number, the number of the patent in suit, the name of the (then sole) patent proprietor and the internal reference number mentioned in the document corresponded to the indications provided in the notice of appeal. Explicit reference was made to the "appeal of opponent filed on 13 June 2013".

5. The fact that "Bayer Schering Pharma AG", the opponent's former name, as proven by the documentary evidence, was indicated on the second page of the statement of grounds of appeal as the legal person on behalf of which the document was submitted, points to the fact that it was indeed on behalf of the opponent and not on behalf of a third party.

6. Also, considering that there is no indication on file that a legal person called "Bayer Schering Pharma AG" existed at the point in time when the statement of grounds was filed, the mentioning of "Bayer Schering Pharma AG" in the statement of grounds of appeal is an obvious error and it is evident that it should read "Bayer Pharma AG" (or "Bayer Pharma Aktiengesellschaft").

7. Thus, the board has no doubt that the statement of grounds of appeal in question was indeed filed on behalf of the opponent, i.e. the party referred to as appellant II in these appeal proceedings.

8. Furthermore, there is no doubt, and this has not been contested, that the four-month time limit under Article 108, third sentence, EPC has been met.

9. Accordingly, appellant II has duly submitted a statement of grounds of appeal, and its appeal is thus admissible.

10. Appellant II was duly summoned but did not attend the oral proceedings, in accordance with its announcement to the board on 20 June 2018. The oral proceedings took place as scheduled in accordance with Article 116(1) EPC, first half-sentence, and Rule 115(2) EPC. Appellant II was treated as relying on their written case in accordance with Article 15(3) RPBA.

Main request - claim 1

Sufficiency of disclosure (Article 100(b) EPC)

11. The invention defined in the claim is an antibody, antigen binding fragment or recombinant protein thereof, which is specific for human YKL-40 and which is "capable of inhibiting growth of a cell upon binding to an epitope on YKL-40, wherein the cell is an YKL-40 expressing cancer cell" (emphasis added by the board).

12. Both examples 1 and 2 relate according to their title to the inhibition of cancer cell growth by anti-human YKL-40 monoclonal antibodies, the former in vitro and the latter in vivo.

13. The in vitro experiments of example 1 relate to various YKL-40 expressing cancer cell lines which are treated with various antibodies specific for human YKL-40. The results of the experiments are determined by the so-called MTT assay - which is described in paragraphs [0202] and [0203] - and are summarised in paragraphs [0204] to [0206] and Figures 1 and 2. The paragraphs in the description read in particular:

"[0202] MTT-assay (allows to distinguish between living and dead cells in the culture) was performed according to Mossmann T. J Immunol Methods 65:55-63, 1983.

[0203] 40 myl MTT was added to each well (2 mg/ml stock solution) and the plates were incubated for 1 hour at 37°C in a normoxic incubator. Afterwards the media was discarded and 100 myl DMSO added to each well. Plates were shaken for 10 sec and the OD (optical density) values were read at 570 nm (with the background correction on 690 nm). Results are given as an avarage [sic] of OD in 6 wells +/- standard devition [sic].

[0204] As it can been seen from Figure 1 monoclonal antibodies (MAb) 116F9 and 201 F9 have a repressive effect on growth of U87 glioblastoma cells reflected by a reduced number of cells in treated wells (with antibody) compared to control wells (without antibody named "Kontrol" in Figure 1 and "Negative" in Figure 2) after 72 hours of treatment independently of the presence FCS in the culture media. Monoclonal Ab 115F9 and polyclonal Ab R667 (not shown) did not inhibit the growth of tested cancer cells. MAb116F9 was further tested in cultures of two human osteosarcoma cell lines MG63 and U2OS and one human malignant melanoma cell line SK-MEL-28.

[0205] The results shown in Figure 2 demonstrate that MAb 116F9 has a growth repressive effect in both osteosarcoma cells, but not in melanoma SK-MEL-28 cells. The two tested osteosarcoma cell lines are characterized by a high expression level of YKL-40, whereas SK-MEL-28 cells line has a very low expression level, if any.

[0206] These results demonstrate that monoclonal antibodies against YKL-40 (MAb 116F9 and 201 F9) have the growth repressive effect in YKL-40 expressing cancer cells. The effect may be due to inhibition of cell growth and survival or induction of apoptosis, or due to both." (emphasis added by the board)

14. The board emphasises that paragraph [0206] of the description explicitly states that the results obtained with the MTT assay demonstrate a growth repressive effect on cancer cells, which effect may be due to inhibition of cell growth and survival or induction of apoptosis, or due to both.

15. The board thus concludes on the basis of evidence from the patent itself, that the MTT assay disclosed in the patent in suit is, as such, not suitable to distinguish at least between cancer cell growth repressive effects due to the inhibition of the growth of cells (as required for the invention defined in claim 1) or due to induction of apoptosis, i.e. the induction of cell death.

16. Appellant I argued that in the context of cell biology in general and the patent in particular, the skilled person considered the terms "inhibiting cell growth" (as used in the claim) and "having growth repressive effect" (as used in example 1) as interchangeable.

17. In support of its argument, appellant I referred in particular to the title of examples 1 and 2 of the patent in suit in which it was explicitly stated that these were related to the "inhibition of cancer cell growth" (see point 12 above). They further referred to the first sentence in paragraph [0204] of the patent (see point 13 above), which stated that the "repressive effect on growth" of cancer cells of an antibody in the patent was "reflected by a reduced number of cells in treated wells (with antibody) compared to control wells". Since the term "growth of a cell" referred to an increase in the number of cells in a population and "inhibiting growth of a cell" meant reduced numbers of cells as compared to the start, the paragraph [0204] reflected the general understanding by the skilled person of the equivalence of the terminologies.

18. Appellant I furthermore submitted that, in view of the general understanding of the equivalence of the meaning of the terms "inhibiting cell growth" and "having growth repressive effect", the last sentence of paragraph [0206] of the patent may be ambiguous and unclear. Whereas "apoptosis" was different from "inhibition of growth", i.e. both terms did not describe the same situation, they were however not mutually excluding each other, i.e. inhibition of growth could be due to apoptosis and apoptosis could lead to an inhibition of growth. However, given the general understanding of the skilled person and the remainder of the teaching in the patent, the passage would not have incited the skilled person upon reading the patent with a mind willing to understand to draw an artificial distinction between the terms "inhibiting cell growth" and "having growth repressive effect". The MTT assay was therefore perfectly suitable for identifying the compounds as defined by the functional feature in the claim.

19. The board notes, however, that a number of passages throughout the description of the patent in suit emphasise and distinguish different possible biological activities of the compounds of the invention, including the inhibition of growth of cells (which is the functional feature comprised in the claim), induction of apoptosis of cells, and a "growth repressive effect".

Indeed, paragraph [0001] reads:

"The present invention relates to monoclonal anti-human YKL-40 antibodies, which are capable to inhibit the growth and/or inducing apoptosis of cells, in particular cancer cells, pharmaceutical compositions comprising said antibodies and uses said antibodies and/or pharmaceutical compositions for treatment of a disease wherein inhibition of cell growth, cell differentiation, remodelling of extracellular matrix, metastasis and/or induction of cell death due to apoptosis is a prerequisite for successful curing." (emphasis added by the board);

paragraph [0113] reads:

"According to the invention antibodies 115F9, 116F9 and 201F9 are capable of binding to an epitope as defined above and thereby inhibiting the function of YKL-40 in connection with cell growth and survival by inhibiting at least one biological activity of YKL-40 protein described herein." (emphasis added by the board); and

paragraph [0114] reads, under the heading "Functionally active antibody":

"Thus, the present invention relates to an antibody, an antigen binding fragment, or recombinant protein thereof, which is capable of recognising an epitope [...] said antibody, antigen binding fragment or recombinant protein being capable of modulating at least one biological activity of human YKL-40 or an YKL-40 functional homolog, or a functional fragment thereof said activity being associated with i) cell growth ii) cell survival, iii) cell differentiation iv) extracellular matrix remodeling, v) development of liver fibrosis, vi) development of tissue fibrosis, vii) development of organ fibrosis, viii) development of angiogenesis, ix) development of rheumatoid arthritis, x) development of inflammation, and/or xi) development of metastasis." (emphasis added by the board)

20. Thus, on the basis of the patent, the board cannot concur with appellant I that the general understanding of the meaning of the terms "inhibiting cell growth" and "having growth repressive effect" was that they were equivalent and that this would be derivable from the patent. The board also cannot concur that a distinction between the meaning of the terms "inhibiting cell growth" and "having growth repressive effect" is artificial.

21. Therefore, the board is not persuaded by appellant I's arguments that the MTT assay is suitable for identifying the compounds as defined by the functional feature in the claim.

22. Appellant I has further argued that the patent in suit discloses besides the MTT assay, another method for measuring the growth of cancer cells, namely the in vivo method described in example 2 of the patent relying on the visual measurement of the tumour size in the experimental mice treated with antibodies of the invention.

23. However, the board considers, and the contrary has not been argued by appellant I, that this method suffers from the same drawback as the MTT assay, as here a growth repressive effect on the numbers of cells is determined in a way - size of the tumour - which fails to distinguish between inhibition of the growth of cells and the induction of apoptosis.

24. Finally, the board notes that appellant I has not argued that the skilled person was aware of any method which was capable of distinguishing between inhibition of the growth of cells and induction of apoptosis either.

25. Accordingly, the board concludes that the patent in suit does not provide the skilled person with suitable methods for obtaining the compounds of the claim, i.e. such compounds which are capable of inhibiting growth of a cell. The patent therefore does not disclose the invention in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art (Article 100(b) EPC).

First to sixth auxiliary requests - claim 1

Sufficiency of disclosure (Article 83 EPC)

26. Claim 1 of each of these requests, like claim 1 of the main request, requires the claimed compounds to be "capable of inhibiting growth of a cell upon binding to an epitope on YKL-40".

27. Appellant I concurred with the board that if the patent was found to not sufficiently disclose the invention as defined in claim 1 of the main request, then this applied mutatis mutandis to the invention defined in these claims.

7th auxiliary request - admission into the proceedings

28. Claim 1 is identical to claim 1 as granted but for the insertion of the wording "wherein the inhibition of growth is measured by MTT assay" at the end of the claim.

29. Pursuant to Article 13(1) RPBA, an amendment to a party's case after it has filed its grounds of appeal or reply may be admitted and considered at the board's discretion.

30. The request was filed during the oral proceedings after the board had announced its opinion that, in relation to the invention as defined in claim 1 of the main request and of the first to sixth auxiliary requests, the patent lacked sufficiency of disclosure.

31. Appellant I argued that this negative opinion had come as a complete surprise because the board had not issued a communication informing the parties of its preliminary opinion in the written proceedings. Moreover, the insertion of the specific assay used to measure the inhibition of growth in claim 1 remedied the lack of sufficiency of disclosure of the invention as defined in claim 1 of the main request. The set of claims of this request should therefore be admitted into the proceedings.

32. The board notes that the line of argument that the MTT assay was not suitable to determine whether any of the compounds referred to in the claims was capable of inhibiting growth upon binding to an epitope on YKL-40 had been on file since appellant II had submitted it with its statement of grounds of appeal in relation to the amended version of the patent considered allowable by the opposition division. The line of argument had again been presented in relation to appellant I's main request and auxiliary requests then on file in the reply of appellant II to the appeal of appellant I (see section VI). Appellant I, being aware of this line of argument, could thus have anticipated that one of the possible outcomes of the appeal was that the issue would be decided in the negative for them and they therefore could have reacted to it, even without a preliminary opinion of the board in the written proceedings.

33. Furthermore, the board considers it not prima facie apparent how the amendment in claim 1 consisting solely of the insertion of the very method for the measurement of a particular parameter in a claim, here inhibition of growth of a cell, which was earlier held by the board to fail to distinguish this parameter from another parameter, here induction of apoptosis, can remedy the lack of sufficiency of disclosure found in relation to the invention defined in claim 1 of the main request.

34. Accordingly, the board, exercising its discretion under Article 13(1) RPBA, decided not to admit the request into the appeal proceedings.

8th auxiliary request - claim 1 - Article 123(3) EPC

35. Appellant I filed this request with the reply to the statement of grounds of appeal of appellant II and it was renumbered as the 8th auxiliary request during the oral proceedings (see section XI).

36. Compared with claim 1 of the patent as granted the claim no longer requires that the "antibody, antigen binding fragment or recombinant protein thereof" is "capable of inhibiting the growth of a cell upon binding to an epitope on YKL-40". Instead, the "antibody, antigen binding fragment or recombinant protein thereof" as now claimed is specified to be "capable of specifically recognizing and binding to an epitope comprising residues 210-220 of SEQ ID NO: 1".

37. Appellant I argued that paragraph [0214] of the patent stated that the antibody 201F9 - which recognises the epitope now referred to in the claim, "an epitope comprising residues 210-220 of SEQ ID NO: 1" - inhibited the biological activity of YKL-40 which therefore lead to the inhibition of the growth of cancer cells. It was beyond doubt that the antibody 201F9 was capable of inhibiting growth of cancer cells.

38. Appellant I alleged that, generally, any antibody binding to the same epitope as another antibody necessarily had the same functionality as that antibody. Therefore, any antibody binding to the epitope to which the antibody 201F9 binds will necessarily have the same biological activity as the antibody 201F9 to inhibit the growth of cancer cells, and this was in fact so regarding all compounds referred to claim 1 since they were all "capable of specifically recognizing and binding to an epitope comprising residues 210-220 of SEQ ID NO: 1".

39. The board is not convinced by appellant I's allegation that the compounds referred to in claim 1 - "antibody, antigen binding fragment or recombinant protein thereof" - and defined to be "capable of specifically recognising and binding" to a particular epitope all necessarily exhibit the same functionalities as a reference compound, here the antibody 201F9 which also binds to this epitope. By way of example, the board refers to the substantial variability in the size and nature of the compounds subsumed under the terms "the antibody, antigen binding fragment or recombinant protein thereof" in claim 1 which leads, already from the simple point of view of steric hindrance, to a variety of different impacts on the interaction of ligand partners and their consequential functionalities, thereby rendering it not conceivable to the board that claim 1 after amendment encompasses compounds having mandatorily at least the property referred to in claim 1 as granted by way of a functional feature, i.e. those being "capable of inhibiting growth of a cell upon binding to an epitope on YKL-40". In other words, the board is not convinced that the claim does not extend the protection conferred vis-à-vis the claims as granted.

40. In the absence of relevant provisions in the EPC, the case law of the boards of appeal, in the context of the principle concerning the allocation of the burden of proof, has established that each party bears the burden of proof for the facts it alleges (Case Law of the Boards of Appeal, 8th edition 2016, hereafter "CLBA", III.G.5). This principle also applies within the context of the requirements of Article 123(3) EPC (see e.g. decision T 2285/09 of 20 January 2011).

41. In view of the above considerations, the board accordingly concludes that in relation to claim 1 the requirements of Article 123(3) EPC are not met.

9th auxiliary request - admission into the proceedings

42. Compared with claim 1 of the 8th auxiliary request, claim 1 of the 9th auxiliary request was not directed to products which were an "antibody, antigen binding fragment or recombinant protein thereof", but to products which were antibodies (see section XIV).

43. The auxiliary request was filed during oral proceedings in response to the finding of the board that claim 1 of the 8th auxiliary request did not comply with the requirements of Article 123(3) EPC. Appellant I argued that, because the claims were now restricted to antibodies, the board's concerns under Article 123(3) EPC could no longer apply.

44. The board notes that the findings on claim 1 of the 8th auxiliary request were neither related nor restricted to particular classes of compounds covered by the claims (see points 26 to 28). Therefore, the reasoning applies to the present claim 1 and is thus considered as not complying with the requirements of Article 123(3) EPC.

45. Hence, the submitted 9th auxiliary request was not clearly allowable.

46. The board, exercising its discretion under Article 13(1) RPBA, therefore decided to not admit the request into the appeal proceedings.

Request on apportionment of costs (Article 104 EPC and Article 16 RPBA)

47. Pursuant to Article 104(1) EPC, each party to the opposition proceedings bears the costs it has incurred, unless, for reasons of equity, a different apportionment of costs is ordered. Article 16 RPBA specifies that the board may order a different apportionment of costs upon request and gives examples of situations in which a different apportionment may be justified.

48. Generally, the boards of appeal have stated that ordering a different apportionment of costs is justified if the conduct of a party or parties is not in keeping with the care required and thus is disadvantageous for the other party or parties (see CLBA, IV.C.6.2).

49. In the context of its request for a different apportionment of costs, appellant I submitted two main lines of argument.

50. In the first line, appellant I submitted that appellant II should have announced their intention not to attend the oral proceedings earlier. Appellant I considers that, had there been an earlier notification by appellant II of its non-attendance, they would then have had an opportunity to obtain the opinion of the board on their pending claim requests at some point before the oral proceedings, noting that no written communication setting out the board's preliminary opinion had been issued up to then. As a consequence, then, the oral proceedings could have been cancelled or the attendance of appellant I at the oral proceedings could have been avoided. Either option would have saved costs for appellant I, it being a small company.

51. In the second line of argument appellant I pointed to deficiencies in the procedure on the part of the EPO which allegedly put them at a disadvantage: i) the delay in forwarding appellant II's letter announcing its non-attendance at the oral proceedings to appellant I, with the consequence that appellant I had even less time to react; and ii) the fact that the board had not issued a written preliminary opinion, which prevented appellant I from reacting before the oral proceedings took place, so as to possibly avoid them, and from finding out, before the oral proceedings, the crucial issue in relation to sufficiency of disclosure.

52. The board notes that the latter line of argument on the perceived misconduct on the part of the EPO (the board dealing with the case) has no bearing on the board's decision about a different apportionment of costs under Article 104 EPC since the EPO is not a party to the proceedings, nor is it conceivable that the delay in forwarding the communication or the non-issuance of a written preliminary opinion can be ascribed to appellant II. Hence, these submissions need not be dealt with.

53. In view of the circumstances of the present case, the question to be answered to decide about a different apportionment of costs is thus whether or not the oral proceedings, or at least the attendance of appellant I at these oral proceedings, could have been avoided, had appellant II announced earlier about their intention not to attend the oral proceedings earlier (see point 50).

54. Both appellant I and II had requested oral proceedings. Therefore, oral proceedings were scheduled and the parties were summoned by the board. The board notes that even if appellant II's information that they did not intend to appear at the oral proceedings was considered to be the equivalent to a withdrawal of appellant II's request for oral proceedings, appellant I's request for oral proceedings was still pending. Accordingly, in all circumstances, the oral proceedings had to be held.

55. Thus, the board concludes that the perceived misconduct on the part of appellant II, i.e. that they should have filed the notification of its non-attendance at the oral proceedings earlier, was not the cause for appellant I attending the oral proceedings. Accordingly, the board comes to the conclusion that appellant II's conduct was not disadvantageous for appellant I.

56. In view of the above considerations the board decided to reject appellant I's request for a different apportionment of costs.