T 0304/17 (Antibody that binds IL-17A/F and inhibits induction of IL-8 and IL-6/GENENTECH) 10-01-2020

Reasons for the Decision

1. The appeal complies with Articles 106 to 108 and Rule 99 EPC and is therefore admissible.

Interventions (Article 105 EPC)

Intervention of Eli Lilly and Company

2. Notice of intervention was filed on behalf of Eli Lilly and Company on 4 April 2018 in a written reasoned statement in accordance with Rule 89(2) EPC and Rule 76 EPC. The opposition fee was paid on the same date.

3. Pursuant to Rule 89(1) EPC, notice of intervention is to be filed within three months of the date on which proceedings referred to in Article 105 EPC are instituted, i.e. either when proceedings for infringement of the same patent have been instituted against the assumed infringer (Article 105(1)(a) EPC), or when, following a request of the patent proprietor to cease alleged infringement, the assumed infringer has instituted proceedings for a ruling that he is not infringing the patent (Article 105(1)(b) EPC).

4. There was no dispute that the appellant's counterclaim for infringement was made on 5 January 2018 (see also document D97) and that the three-month time limit under Rule 89(1) EPC was met when calculated on this basis (see also Rule 131(1) and (4) EPC).

5. However, the appellant argued that Eli Lilly and Company had had standing to intervene at an earlier point in time, such that the three-month time limit had already expired by 4 April 2018. This point is of relevance because it is established case law that the two alternative means for intervention under Article 105(1) EPC are mutually exclusive in the sense that once an opportunity has existed for the third party to intervene under one alternative, subsequent fulfilment of the requirements under the second alternative does not provide any further opportunity to intervene (see also decision T 296/93, OJ EPO 1995, 627, point 2.6 of the Reasons, and decision T 18/98, point 2.2 of the Reasons).

6. The appellant's objection was based on the argument that Article 105(1)(b) EPC did not specify a particular chronology of events and that, accordingly, the three-month time limit was triggered once the two conditions - the patent proprietor's request to cease infringement and the institution of proceedings by the assumed infringer for a ruling of non-infringement - were fulfilled.

7. However, the board does not agree with this understanding of Article 105(1)(b) EPC. The principles set out in Articles 31 and 32 of the Vienna Convention on the Law of Treaties (VC) are taken into account when interpreting EPC provisions (see also decision G 5/83, OJ EPO 1985, 64, points 1 to 6 of the Reasons). Pursuant to Article 31(1) VC, a treaty is to be interpreted in good faith in accordance with the ordinary meaning to be given to the terms of the treaty in their context and in the light of its object and purpose.

8. It follows from the clear wording of Article 105(1)(b) EPC that the provision is based on a specific sequence of events ("following a request of the proprietor of the patent ..., the third party has instituted proceedings ..."; emphasis added by the board).

9. The Travaux Préparatoires confirm that this sequence of events had intentionally been chosen by the legislator (see document D117; for the legislative history of Article 105 EPC 1973 see http://webserv.epo.org/projects/babylon/tpepc73.nsf/0/A58D54B45320BD46C125742700477DCC/$File/Art105eTPEPC1973.pdf; in this context, see in particular BR/144/71, point 78; M/PR/I, points 417 to 419; M/19, point 14; and M/21, point 8; for the role of the Travaux Préparatoires in the context of interpreting EPC provisions, see Article 32 VC).

10. The result of a literal interpretation is also in line with a systematic interpretation, because in both alternative scenarios ? Article 105(1)(a) and (b) EPC ? it is the formal institution of proceedings (at a court or another competent national authority) which triggers the time limit. These are events which can be unambiguously established with legal certainty, since they are official dates (see also decision T 296/93 above, point 2.5 of the Reasons) and thus set "a clear demarcation line" (see also decision T 18/98, point 2.2 of the Reasons). It is important that the start of the time limit can be established with legal certainty, because this triggers a time limit, the purpose of which is to enable a third party to acquire the status of an opponent after expiry of the opposition period. Accordingly, the date should be unambiguously identifiable for the parties involved and for the EPO.

11. The decisions relied upon by the appellant in this context do not support its case since none of the underlying situations was comparable to the present one; rather, they were concerned with different issues. Decision T 392/97 addressed the question of whether certain letters qualified as a request to cease infringement within the meaning of Article 105(1)(b) EPC, and decision T 1713/11 addressed the question of whether the institution of a specific criminal action under Austrian law constituted the institution of proceedings under Article 105(1)(a) EPC.

12. In the absence of an earlier standing to intervene, in the present case the event triggering the three-month time limit under Rule 89(1) EPC was the filing of the appellant's counterclaim for infringement of the patent in suit. Given the uncontested date of 5 January 2018 for the counterclaim, the intervention of 4 April 2018 occurred in due time and the requirements under Article 105(1)(a) EPC were thus met.

13. In its second line of argument, the appellant had argued that its counterclaim for infringement of the patent in suit did not qualify as an event triggering the three-month time limit.

14. In contrast to the appellant's opinion, however, the board does not consider it relevant that the counterclaim for infringement did not initiate new proceedings and was to be dealt with in existing proceedings. Whether or not separate proceedings take place is a consequence of the relevant national law. It was not contested that the appellant was not obliged to launch a counterclaim for infringement and whether a counterclaim was made had therefore been up to the appellant. Nor was it in dispute that in the UK a counterclaim is treated in the same way as a free-standing claim and that, if proceedings for a declaration of non-infringement are discontinued, the counterclaim for infringement can continue.

15. Irrespective of the fact that the underlying situation of decision T 1713/11 is not comparable to the present one (see point 11), the board sees no conflict with the section referred to by the appellant. In point 2.3 of the Reasons of decision T 1713/11, the board in that case described the two alternative scenarios pursuant to Article 105(1) EPC and noted that, under Article 105(1)(a) EPC, the patent proprietor had to take the first step. The "step" referred to was the institution of proceedings for infringement which, as further noted in that decision, did not require court proceedings but it did "require the patentee to take the first step".

16. It is of no relevance that, at the moment of the appellant's (counter)claim for infringement, proceedings for a declaration of non-infringement were already pending, because those could not have triggered the time limit for filing notice of intervention in the absence of a preceding request by the appellant to cease alleged infringement (see also decision T 228/03, point 2.3 of the Reasons).

17. Lastly, decision T 188/97, referred to by the appellant, relates to a situation in which seizure proceedings containing an injunctive order were brought by the patent proprietor, followed by court proceedings brought by the patent proprietor for infringement. This is not comparable to the present situation, where proceedings for a declaration of non-infringement brought by the assumed infringer were followed by a counterclaim for infringement brought by the patent proprietor.

Intervention of Eli Lilly Nederland B.V.

18. The intervention of Eli Lilly Nederland B.V. complies with the requirements pursuant to Article 105(1)(a) EPC and Rule 89 EPC. This was also not contested by the appellant. Notice of intervention was filed on 21 November 2019 in a written reasoned statement in accordance with Rule 89(2) EPC and Rule 76 EPC. The opposition fee was also duly paid. The three-month time limit pursuant to Rule 89(1) EPC was met in view of the infringement proceedings which were instituted by the appellant against Eli Lilly Nederland B.V. on 11 September 2019 before the Regional Court of Düsseldorf.

19. The interventions by intervener I and intervener II were therefore admissible. Thus, the interveners had the status of opponents, in accordance with Article 105(2) EPC, and were designated opponent 06 (intervener Eli Lilly and Company) and opponent 07 (intervener Eli Lilly Nederland B.V.), or respondent VI and VII, respectively.

Main request

Amendments (Article 123(2) EPC) - claim 1

20. In the decision under appeal, the opposition division held that the subject-matter of the claim failed to meet the requirements of Article 123(2) EPC, inter alia because there was no clear and unambiguous disclosure that the way to test the antagonistic activity of an antibody binding IL-17A/F was to measure the inhibition of the activity of the IL-17A/F heterodimeric complex to induce production of IL-8 and IL-6 (see point 3.7.2 of the decision under appeal).

21. It is not disputed by the appellant that the application does not contain an explicit disclosure of the feature "which inhibits the activity of the IL-17A/F heterodimeric complex to induce production of IL-8 and IL-6" in the context of an antibody which specifically binds to an isolated IL-17A/F heterodimeric complex. Instead, the appellant developed several lines of argument in support of a direct and unambiguous disclosure in the application as a whole.

22. According to the established case law of the boards of appeal, amendments are only permitted within the limits of what a skilled person would derive directly and unambiguously, using common general knowledge, and seen objectively and relative to the date of filing, from the whole of the application as filed. It is not permitted for the skilled person to be presented with new technical information after the amendment (see decision G 2/10, OJ EPO 2012, 376, points 4.3 and 4.5.1 of the Reasons; see also Case Law of the Boards of

Appeal of the European Patent Office, 2019, 9th edition, II.E.1.1 and II.E.1.3.1).

23. It was common ground that for the purpose of this case the person skilled in the art is a scientist or team of scientists specialised in the fields of microbiology, immunology and treatment of immune-related and/or inflammatory diseases, aware of the IL-17 family of cytokines and experienced in testing their functions. The board has no reason to see this differently.

24. In its main line of argument, the appellant relied on page 5, lines 18 to 19; page 6, lines 2 to 3; page 69, line 12 to page 71, line 36; page 72, lines 33 to 35; and Example 1B of the application. The appellant's argument is based on the contention that the passage on page 72, lines 33 to 35, is the only one in the application where antibody assays are explicitly discussed, and that induction of IL-8 and IL-6 production in Example 1B is the only activity given as an example and hence the characteristic and "indicative" activity of the IL-17A/F heterodimer. From this they concluded that the "indicative" activity of the antagonistic anti-IL-17A/F antibody is the inhibition of the induction of IL-8 and IL-6 production (see section XV).

25. The board is not persuaded by the appellant's main line of argument for the following reasons.

25.1 In Example 1B on page 113, lines 14 to 18, under the heading "Cell-based Assays - IL-17A/F Induces the production of IL-8 and IL-6", the application discloses that fractions of purified recombinantly produced IL-17A/F were incubated with TK-10 cells and conditioned media collected and analysed by ELISA for the production of IL-8 and IL-6. Furthermore, "[d]ose response curves comparing IL-8 and IL-6 induction by IL-17A/F, IL-17 and IL-17F" (emphasis added by the board) were determined (see page 113, lines 29 to 30 and Figure 5). However, while Example 1B discloses the induction of IL-8 and IL-6, this activity is not explicitly disclosed on page 113 as the "indicative" activity of the IL-17A/F heterodimer, nor as an activity that should be inhibited, let alone by an antibody.

25.2 Moreover, in the board's judgement, the skilled person reading Example 1B would not understand that induction of IL-8 and IL-6 is the "indicative" activity of the IL-17A/F heterodimer. On the contrary, it is apparent from the example, in particular from Figure 5 and its legend on page 17 and from the discussion of the example on page 115, lines 10 to 20, that the IL-17A/F heterodimer's ability to induce IL-8 and IL-6 production was compared with that of the IL-17 homodimers, IL-17 and IL-17F, which were well known to possess that ability (see page 3, lines 14 to 15; page 4, lines 36 to 37; page 115, line 11). Thus, the ability to induce IL-8 and IL-6 production does not distinguish the IL-17A/F heterodimer from the IL-17 homodimers. At best, the heterodimer is more potent than the homodimers as regards the induction of IL-8 but not that of IL-6.

25.3 Secondly, contrary to the appellant's contention, the passage on page 72 of the application is not the sole section in the application where antibody assays are explicitly discussed. The skilled person reading the application as a whole would have noted that the application explicitly emphasises other activities to be inhibited by antibodies binding to IL-17A/F and also that it provides the appropriate assays for screening for such antibodies.

25.4 Thus, claim 53 as filed in combination with claim 34 as filed discloses "the proliferation of T-lymphocytes in a mammal" and "decreasing infiltration of inflammatory cells into a tissue of a mammal" as functions to be inhibited by an antibody, while inhibition of the induction of IL-8 and IL-6 production is not recited in any of the claims as filed.

25.5 Furthermore, on page 94, lines 28 to 35, under the heading "Screening for Anti-IL-17A/F Antibodies [...] With the Desired Properties", the application teaches that "[t]he growth inhibitory effects of an anti-IL-17A/F antibody [...] of the invention may be assessed by methods known in the art, e.g., using cells which express an IL-17A/F polypeptide either endogenously or following transfection with the IL-17A/F gene. For example, appropriate tumor cell lines and IL-17A/F-transfected cells may treated with an anti-IL-17A/F monoclonal antibody [...] of the invention at various concentrations for a few days (e.g., 2-7) days and stained with crystal violet or MTT or analyzed by some other colorimetric assay. Another method of measuring proliferation would be by comparing **(3)H-thymidine uptake by the cells treated in the presence or absence an [sic] anti-IL-17A/F antibody [...]". On the next page, the application teaches that "[p]referably, the anti-IL-17A/F antibody [...] will inhibit cell proliferation of an IL-17A/F-expressing tumour cell in vitro or in vivo" and that "[t]o select for an anti-IL-17A/F antibody [...] which induces cell death, loss of membrane integrity as indicated by,

e.g., propidium iodide (PI), trypan blue or 7AAD uptake may be assessed relative to control".

25.6 The application as filed thus informs the skilled person which functions are inhibited by antagonistic antibodies and which assays can be used to screen for such antibodies. These assays are familiar to the skilled person (see preceding point), and none of them involves testing the inhibition of IL-8 and IL-6 production.

25.7 The appellant has not advanced any argument why the skilled person would ignore this explicit teaching in the application as filed. In the board's judgement, the skilled person reading the application as a whole, when faced with the question of what activity should be used to assess whether an anti-IL-17A/F antibody is an inhibitory antibody, would turn to pages 94 and 95 of the application and not to Example 1B, as argued by the appellant.

26. In additional lines of argument, the appellant relied on a passage on page 33; on a passage on page 75; and on passages on pages 115 and 117 as proving a link between an inhibitory antibody and blocking the production of IL-8 and IL-6. None of the appellant's further lines of argument was found persuasive by the board, for the reasons set out below.

27. Page 33, lines 21 to 28, of the application lists several biological activities of IL-17A/F as follows: "[o]ne preferred biological activity includes inducing activation of [hardly legible, presumably NFkappaB] and stimulation of the production of the proinflammatory chemokines IL-8 and IL-6. Another preferred biological activity includes stimulation of peripheral blood mononuclear cells or CD4**(+) cells. Another preferred biological activity includes stimulation of the proliferation of T-lymphocytes. Another preferred biological activity includes, for example, the release of TNF-alpha from THP1 cells. Another activity includes an enhancement of matrix synthesis in articular cartilage. Alternatively, another activity includes promoting breakdown of articular cartilage matrix as well as inhibiting matrix synthesis. Another preferred biological activity includes modulating the level of the interleukin-17 signalling pathway during mild to severe stages of inflammatory bowel disease or during stroke."

28. It is apparent from the preceding point that page 33, lines 21 to 28, refers to several activities for the IL-17A/F heterodimer, including the induction of IL-8 and IL-6, which however is not highlighted as particularly preferred. Moreover, on page 33, this activity is disclosed in combination with another activity, presumably NFkappaB. Even if it is accepted that the example provides a pointer to the induction of IL-8 and IL-6, there is no basis for isolating the induction of IL-8 and IL-6 from this other activity. Moreover, the application as filed does not expressly state that any of these activities in particular should be inhibited by an antibody. There is thus no basis for selecting the induction of IL-6 and IL-8 as the particular function to which an IL-17A/F inhibitory antibody should be directed. Accordingly, the appellant's argument based on page 33 fails.

29. The passage on page 75, lines 8 to 10, reads as follows: "[a]lternatively, compounds, e.g., antibodies, which bind to stimulating IL-17A/F polypeptides and block the stimulating effect of these molecules produce a net inhibitory effect and can be used to suppress the T cell mediated immune response by inhibiting T cell proliferation/activation and/or lymphokine secretion."

30. While the passage mentions blocking antibodies, it relates to the inhibition of lymphokine secretion generally and not to IL-8 and IL-6 specifically and hence does not disclose an antibody which inhibits the activity of the IL-17A/F heterodimeric complex to induce production of IL-8 and IL-6.

31. The passage on page 115, lines 7 to 9, reads: "Thus, specific antibodies which bind selectively to the novel heterodimeric complex of IL-17A/F have been identified which may serve to modulate the activity of this novel cytokine".

32. The passage which follows it, on page 115, lines 10 to 20, reads: "IL-17A/F was analyzed for ability to stimulate a proinflammatory response using the TK-10 human kidney cell line (Figure 5). This cell line responds to both IL-17 and IL-17F by production of IL-8. IL-17A/F also robustly induced IL-8 production in this cell line (Figure 5A). Interestingly, IL-17A/F was observed to have a unique potency that differs from that of either IL-17 or IL-17F. The difference in activity differs from IL-17 and IL-17F by roughly an order of magnitude in each case. The substantially greater activity of IL-17A/F than IL-17F in this assay suggests that IL-17A/F may comprise a critical component of the cytokine activity resulting from the IL-17F gene product. This unique potency may enable the molecule to possess distinct range of actions in vivo. IL-17A/F also induced production of IL-6 from this cell line (Figure 5B). Additionally, it is likely that IL-17A/F may possess additional characteristics not present in either IL-17 or IL-17F as a result of its novel heterodimeric composition that may alter the kinetics and utilization of receptor subunits in vivo, resulting in unique biological consequences".

33. These two passages relate to different experiments, and there is no link between the antibodies mentioned in the first paragraph and the assay mentioned in the second paragraph. Thus, the first passage on page 115 (see point 31) discusses antibodies which were identified by screening a phage library of synthetic Fab antibodies and which may serve to "modulate" the activity of the IL-17A/F heterodimer. The next passage, on page 115, lines 10 to 20 (see point 32), discusses the results of a different example, the cell-based assay, and while the potency of the IL-17A/F heterodimer to induce IL-8 and IL-6 is compared with that of the homodimers, the passage is silent on a possible inhibition of that activity, let alone by antibodies. Accordingly, these passages on page 115 fail to disclose an antibody which inhibits the activity of the IL-17A/F heterodimeric complex to induce production of IL-8 and IL-6.

34. On page 117, lines 4 to 6, Examples 1 and 2 are summarised as follows: "Thus, these studies provide and identify a novel immune stimulant (i.e. IL-17A/F) that can boost the immune system to respond to a particular antigen that may not have been immunologically active previously. As such, the newly identified immune stimulant has important clinical applications. Other known immune stimulants such as IL-12 have been identified." The application then summarises the data of a recent cancer vaccine trial in which patients were treated "with different doses of IL-12, an immune

stimulant capable of inducing the proliferation of T cells".

35. The paragraph concludes with the statement on page 117, lines 16 to 19, that "[l]ikewise, this novel IL-17A/F cytokine or agonists thereof, would therefore find practical utility as an immune stimulant. Whereas molecules which inhibit IL-17A/F activity (antagonists) would be expected to find practical utility when an inhibition of the immune response is desired, such as in autoimmune diseases."

36. In the next paragraph on page 117, lines 20 to 22, the application states that "[t]hus, antibodies to this new cytokine which either mimic (agonist antibodies) or inhibit (antagonist antibodies) the immunological activities of IL-17A/F would possess therapeutic qualities. Small molecules which act to inhibit the activity of this novel cytokine would also have potential therapeutic uses."

37. It is apparent from point 35 above that on page 117, lines 16 to 19, the application refers to molecules which inhibit activities of IL-17A/F, but not to antibodies as defined in claim 1. On page 117, lines 20 to 22, the application then defines the activities that should be inhibited by an antagonist antibody as the "immunological activities of IL-17A/F".

38. "Immunological activities" are defined on page 33, lines 29 to 30, of the application as follows: "An 'immunological' activity refers only to the ability to induce the production of an antibody against an antigenic epitope possessed by a native or naturally-occurring IL-17A/F polypeptide." While the definition

is confusing, it is clear that induction of IL-8 and IL-6 does not fall within it.

39. Even if it is accepted that the immunological activity is not as defined on page 33 of the application but that referred to in the preceding paragraph on page 117, IL-8 and IL-6 induction are still not mentioned on page 117. Indeed, page 117 mentions "proliferation of T cells", as in claim 53 as filed, and "immune stimulant", which is a different function from the induction of IL-8 and IL-6.

40. Therefore, in the board's view, the passage on page 117, lines 20 to 22, even when read in combination with the passage that precedes it, does not disclose an antibody which inhibits the activity of the IL-17A/F heterodimeric complex to induce production of IL-8 and IL-6.

41. From the above, the board concludes that the skilled person cannot derive from the application as filed as a whole, directly and unambiguously, using common general knowledge, and seen objectively and relative to the date of filing, that the activity of the IL-17A/F heterodimeric complex to induce production of IL-8 and IL-6 is an activity to be inhibited by an antibody. Therefore, the use of this activity to define a class of inhibitory antibodies does indeed provide the skilled person with new technical information that was not originally disclosed.

42. For this reason alone, claim 1 of the main request does not meet the requirements of Article 123(2) EPC.

Auxiliary requests 1 to 3

Amendments (Article 123(2) EPC) - claim 1

43. Claim 1 of each of the auxiliary requests specifies that the antibody "inhibits the activity of the IL-17A/F heterodimeric complex to induce production of IL-8 and IL-6" (see section IV). Therefore, claim 1 of these requests does not meet the requirements of Article 123(2) EPC for the same reasons as those given above for claim 1 of the main request.