T 2168/17 (Combination therapy 2/GENENTECH) 20-04-2021

1. The appeal complies with Articles 106 to 108 and

Rule 99 EPC and is admissible.

Main request and auxiliary request 1

Inventive step (Article 56 EPC) - claim 1

Closest prior art and objective technical problem

2. A combination of a CD20-binding antibody (such as rituximab) and a BLyS antagonist for use in a method of alleviating a B cell regulated autoimmune disorder (e.g. systemic lupus erythematosus (SLE)) is claimed (see sections I and IV).

3. Both parties agreed that the disclosure in document E18 represented the closest prior art. The board sees no reason to deviate from this.

4. Document E18 discloses the treatment of B cell regulated autoimmune diseases (e.g. systemic lupus erythematosus (SLE) and rheumatoid arthritis) with rituximab (a CD20-binding antibody). In a section entitled "Rituximab for SLE", document E18 further discloses that administering rituximab reduces the levels of peripheral B cells in SLE patients (see page 1487, right-hand column, second-to-last paragraph: "rituximab often resulted in significant depletion in the levels of peripheral B cells"; and page 1488, left-hand column, lines 1 to 3: "After treatment, the levels of B lymphocytes were depleted in the peripheral blood for at least 3-16 months"). Moreover, with regard to rheumatoid arthritis patients, document E18 discloses that following rituximab treatment "[a]ll patients had significant depletion of peripheral B cells" (see page 1488, right-hand column, last paragraph).

5. Document E18 accordingly teaches that depletion of B cells is relevant to treating autoimmune diseases such as SLE and rheumatoid arthritis, and that this can be achieved, at least partially, by administering rituximab.

6. The claimed subject-matter differs from the therapy disclosed in document E18 in that the CD20-binding antibody (rituximab) is used in combination with a BLyS antagonist (such as a BR3 immunoadhesin or an anti-BLyS antibody) for treating autoimmune diseases.

7. Example 4 of the patent demonstrates improved B cell depletion for the combination referred to in the claim as compared with a CD20-binding antibody (rituximab) or a BLyS antagonist (BR3-Fc) alone. In particular Figures 29 to 31 show the reduction of B220+ splenocytes and of CD21 and CD23 positive subpopulations, representing MZ and T2/FO cells, in response to the combination treatment. During oral proceedings the parties agreed that B220 was a marker for "all B cells". The board thus concludes that improved B cell depletion is achieved at least in the spleen as manifested by the reduced numbers and types of B cells. Improved B cell depletion will translate into improved treatment of B cell regulated autoimmune disorders.

8. The objective technical problem can thus be formulated, as it was by the parties, as providing an improved method for alleviating B cell regulated autoimmune disorders.

Obviousness

9. Document E18 discloses that upon treatment with rituximab in SLE patients levels of autoantibodies to native DNA and complement were not affected (page 1487, right-hand column, second-to-last paragraph). It further states that: "rituximab as a single agent may not be adequate for the treatment of diseases resulting from the production of pathogenic autoantibodies, since it is likely that the dominant cellular source of disease-associated autoantibodies, especially IgG antibodies, are [sic] plasma cells that do not bear CD20 (Figure 2)." (see page 1489, right-hand column, last paragraph). Document E18 therefore teaches that the B cell depletion achieved by rituximab treatment was not sufficient to treat diseases resulting from the production of pathogenic autoantibodies.

10. It is proposed in document E18 that "the optimal treatment of diseases that have autoantibody mediated pathology may require a regimen that also affects plasma cells" (page 1489, right-hand column, last paragraph) and that "the long-term goal of therapy should be to eliminate all components of the disease-associated autoimmune process, including the offending autoreactive B cells, plasma cells, and memory cells" (page 1490, left-hand column, first paragraph).

11. Document E18 offers a potential solution to this problem by suggesting that "the efficacy of rituximab treatments for patients with autoimmune diseases may be improved by the addition of second agents" and that "it may be desirable to utilize agents that block the recently discovered BLyS/BAFF/zTNF4 system (for review, see ref. 47), to interfere with these potent survival signals directed toward membrane-associated receptors on peripheral B cells" (page 1490, right-hand column, middle paragraph). It was commonly known that BLyS played an important role in the survival of B cells (see background section of the patent, page 2, paragraph [0005]: "BLyS (also known as BAFF, TALL-1, THANK, TNFSF13B, or zTNF4) is a member of the TNF1 ligand superfamily that is essential for B cell survival and maturation" and "signaling through BR3 mediates the B cell survival functions of BLyS"). Document E18 accordingly further teaches that a solution to the ineffective treatment of autoimmune diseases with rituximab might be to combine it with a BLyS blocking agent to interfere with the survival signals on peripheral B cells.

12. Accordingly and in summary, document E18 discloses that (i) B cell depletion with rituximab was not sufficient for treating diseases resulting from the production of pathogenic autoantibodies, such as SLE, that (ii) further B cell types, including plasma cells, should be depleted and that (iii) the BLyS system of survival signals was a potential target for achieving this.

13. Document E1 discloses specific solutions for blocking the BLyS system by stating, for example, that "BR3 receptor immunoadhesins ... preferably block or reduce the respective receptor binding or activation by TALL-1 [BLyS] ligand" and "anti-TALL-1 [BLyS] antibodies ... are capable of blocking or reducing binding of the respective ligands to the ... BR3 receptors" (page 10, line 39 to page 11, line 8).

14. The skilled person aiming at improving the treatment of B cell regulated autoimmune disorders would thus have consulted document E1, which inter alia relates to BR3 and its ligand BLyS ("also referred to as TALL-1, BAFF or THANK", see document E1, page 1, line 22). The "Effects of BR3-Fc Polypeptides in in vivo lupus model" are tested in Example 7 (see pages 130 and 131). Figures 11A to 11D show that the treatment resulted in reduced proteinurea levels (a symptom of lupus), enhanced survival and fewer anti-dsDNA antibodies than in control-treated mice. The last sentence on page 131 summarises that "[t]hese data suggest that BR3-Fc treatment blocked production of auto-antibodies by B cells in the lupus mice and enhanced survival by blocking TALL-1 function in vivo." This confirms the proposed solution in document E18, i.e. that blocking the BLyS (TALL-1) system was effective in treating autoimmune diseases.

15. The respondent argued that the skilled person seeking a solution to the objective technical problem, would dismiss the disclosure in document E1 in view of the teaching in documents E8 and E9, which taught away from the solution proposed in document E18. Document E8 raised questions as to the relevance of anti-DNA antibodies (see page 827, left-hand column, second-to-last paragraph: "In SLE, anti-DNA antibodies are not related closely to clinical improvement, but the pathogenicity of these antibodies is uncertain.") and plasma cells (see page 827, right-hand column, second paragraph: "our understanding of human B-lymphocyte and plasma cell kinetics is rudimentary"). Document E9 disclosed that the "role of BAFF [BLyS] in the generation and survival of memory cells is also currently unexplored", that "BAFF [BLyS] dependence [of plasma cells] needs to be established" (see document E9, page 242, second paragraph) and that "several observations call into question the involvement of BAFF [BLyS] in the GC reaction" (see page 244, second paragraph).

16. The board does not agree. Document E8 also states that "longer-term remission in autoimmune disease may only be achievable if B-lymphocyte depletion is combined with some form of plasma cell depletion strategy". It then concludes that "[a]t present, no safe and effective anti-plasma cell agents are available, but increased understanding of the survival signals required by plasma cells may lead to new therapeutic avenues" (page 828, left-hand column, last paragraph). The skilled person thus learned from document E8 that targeting the survival signals required by plasma cells as proposed in document E18 and exemplified in document E1 was an avenue worth pursuing.

17. Document E9 is a scientific review article which identifies certain knowledge gaps about BLyS (BAFF). The board notes, however, that document E9 concludes on a rather confident note by stating that "[t]he biochemical and genetic dissection of the BAFF [BLyS] system has yielded a clear and relatively unambiguous picture of an obligate survival signal for both maturing and fully differentiated B cells" (page 253, last paragraph). The board is hence satisfied that document E9 teaches that BLyS is required for B cells to survive, which is in line with the teaching of documents E18 and E1.

18. The board further notes that document E1 was published after documents E8 and E9, meaning that the skilled person would consider document E1 to independently disclose information of which the authors of documents E8 and E9 might not have been aware when drafting the review articles. The board therefore sees no merit in the argument that the skilled person would dismiss combining the disclosure of document E18 with the teaching in document E1.

19. The respondent further argued that the suggested interference "with these potent survival signals directed toward membrane-associated receptors on peripheral B cells" (in this case by using agents which block the BLyS/BAFF/zTNF4 system) in document E18 (page 1490, right-hand column, second paragraph) was only one alternative available to the skilled person for improving the efficacy of rituximab treatment, and that choosing this particular alternative was not obvious to the skilled person.

20. The board does not agree, because all the listed alternatives are disclosed as being equally valid (see document E18, page 1490, right-hand column, second paragraph: "...addition of second agents, such as conventional chemotherapeutic drugs. Alternatively, it is likely that future studies will also evaluate co-treatments with specific biologic agents to interfere with T cell helper signals, such as ... As an alternative approach it may be desirable to utilize agents that block the recently discovered BLyS/BAFF/zTNF4 system") and there was no reason for the skilled person to reject any one of them. Selecting one of the suggested alternatives for improving the efficacy of rituximab, and thus one of several obvious courses of action, cannot involve an inventive step.

21. The question remains whether the skilled person, having regard to the combined teachings of documents E18 and E1, would reasonably have expected an improved therapy as a result of improved depletion of B cells by combining rituximab with a BLyS antagonist (e.g. BR3-Fc) and not just the same level of depletion as with rituximab alone.

22. In Figure 2, document E18 discloses cells which do not express CD20 ("CD20-neg"; see figure legend: "CD20 is expressed only at intermediate stages and not on plasma cells"). On page 1489, right-hand column, last paragraph, the authors find it "likely that the dominant cellular source of disease-associated autoantibodies, especially IgG antibodies, are plasma cells that do not bear CD20 (Figure 2)" and that "plasma cells may still continue to produce disease-causing autoantibodies". Since document E18 goes on to state that "optimal treatment of diseases that have autoantibody-mediated pathology may require a regimen that also affects plasma cells", the board concludes that the suggestion in document E18 to use an "agent that blocks BLyS/BAFF/zTNF4" (page 1490, right-hand column, second paragraph) in combination with the CD20-binding antibody rituximab was aimed at addressing non-CD20 cells, e.g. plasma cells, "the major source of antibodies in the body" (see sentence bridging pages 1485 and 1486). Furthermore, Example 7 of document E1 demonstrates that anti-DNA autoantibodies and proteinurea - a hallmark of SLE - are reduced after BR3-Fc administration, thus confirming that "BR3-Fc treatment blocked production of auto-antibodies by B cells in the lupus mice and enhanced survival by blocking TALL-1 function in vivo" (see last sentence on page 131).

23. In view of the above-mentioned disclosures, the board concludes that the skilled person was aware that targeting BLyS with a soluble BR3-Fc immunoadhesin could result in the depletion of autoantibody-producing cells lacking CD20, including plasma cells (see also points 13. and 14. above).

24. The skilled person therefore had a reasonable expectation that the combined use of a CD20-binding antibody and a BLyS antagonist (such as a BR3-Fc immunoadhesin) would result in the depletion of additional (non-CD20) B cell types, such as plasma cells. It was therefore obvious to the skilled person to combine rituximab with a BLyS antagonist for an improved method for alleviating B cell regulated autoimmune disorders.

25. In view of the above considerations, the claimed subject-matter does not involve an inventive step.

Auxiliary request 2

Inventive step (Article 56 EPC) - claim 1

26. The claimed subject-matter differs from that of claim 1 of the main request in that it is specified that "the BLyS antagonist is an anti-BLyS antibody". The respondent has not argued that this feature alters the technical effect resulting from the difference between the claimed subject-matter and the rituximab therapy disclosed in document E18. In the context of sufficiency of disclosure, the respondent has further argued that "there is a clear expectation from the patent disclosure that an anti-BLyS antibody that blocks BR3 interaction with a BLyS polypeptide can be used to provide the same antagonist effect [as a BR3 immunoadhesin]" (see reply to the statement of grounds of appeal, page 14). The objective technical problem is therefore not different from that outlined above for the main request and auxiliary request 1 (see point 8. above).

27. The question which has to be answered is thus whether the skilled person, when starting from the rituximab therapy disclosed in document E18 representing the closest prior art and further consulting document E1, would have used an anti-BLyS antibody to block the BLyS system. Document E1 discloses that "TALL-1 [BLyS] antagonists and APRIL antagonists contemplated for use further include anti-TALL-1 [BLyS] antibodies... capable of blocking or reducing binding of the respective ligand to the TACIs or BR3 receptors" (see page 11, lines 5 to 8). In the opinion of the board, the skilled person would therefore have considered an anti-BLyS antibody as an obvious alternative to the BR3-Fc immunoadhesin tested in Example 7 of document E1. It would further have been evident to the skilled person in view of the teaching in document E1 that the interaction between BLyS and BR3 could be blocked in both directions, i.e. by "anti-TALL-1 [BLyS] antibodies ... capable of blocking or reducing binding of the respective ligand [BLyS]" or by "an antagonist (such as a BR3 immunoadhesin) which blocks or neutralizes activity of TALL-1 [BLyS]" (see page 11, lines 7 to 8 and lines 19 to 20).

28. The skilled person would therefore have considered combining a CD20-binding antibody with an anti-BLyS antibody capable of blocking or reducing binding of the respective ligand to the TACIs or BR3 receptors to alleviate B cell regulated autoimmune disorders as one of several obvious solutions available to improve the prior-art method. The claimed subject-matter thus lacks an inventive step.

Auxiliary request 3

Admittance (Article 12(4) RPBA 2007)

29. The appellant challenged the admittance of auxiliary request 3 into the appeal proceedings. The board decided to consider the request but in view of the negative decision on inventive step (see below) sees no need to provide reasons for this decision.

Inventive step (Article 56 EPC)

30. The subject-matter of claim 1 differs from that of claim 1 of the main request in that "the BLyS antagonist is an anti-BLyS antibody and wherein the anti-BLyS antibody partially or fully blocks BR3 interaction with a BLyS polypeptide". As no further effect is linked to this additional feature, the objective technical problem is identical to that outlined above for the main request (see point 8. above).

31. According to page 15, lines 19 to 21 of document E1, "[t]he terms 'BR3', 'BR3 polypeptide' or 'BR3 receptor' when used herein encompass 'native sequence BR3 polypeptides'". Also, in view of the disclosure on page 11, lines 5 to 8 (see point 27. above), document E1 thus teaches that the disclosed anti-BLyS antibodies are capable of blocking the binding of BLyS to BR3.

32. The claimed subject-matter therefore lacks an inventive step for the same reasons as set out in point 28.

Auxiliary requests 4 and 5

Inventive step (Article 56 EPC)

33. Claim 1 of auxiliary request 4 is identical to claim 1 of auxiliary request 2, and claim 1 of auxiliary request 5 is identical to claim 1 of auxiliary request 3 (see section IV).

34. The subject-matter of these claims thus lacks an inventive step for the same reasons as outlined above for auxiliary requests 2 and 3 (see points 26. to 32. above).

Auxiliary requests 6 to 11

Inventive step (Article 56 EPC) - claim 1

35. The respondent has not further argued to the effect that the claimed subject-matter of these requests involves an inventive step, in particular in view of a combination of the disclosures in documents E18 and E1. Moreover, the board notes that the specific disease systemic lupus erythematosus (SLE) now referred to in the claim is also disclosed in document E1 (Example 7 and claims). The addition of this feature hence fails to result in subject-matter involving an inventive step.

36. Thus this claimed subject-matter equally lacks an inventive step.