T 0553/08 (BR43x2 receptor/ZYMOGENETICS) 19-11-2009

Reasons for the Decision

Main request filed during oral proceedings

Claims 1 to 6

1. Claims 1 to 6 of this request correspond to the claims of the request accepted by the opposition division with the omission of the medical condition "renal neoplasms" in claim 1. In accordance with the principle of prohibition of reformatio in peius, a claim request which would consist exclusively of claims 1 to 6 accepted by the opposition division could not be challenged on appeal as the respondents (opponents) did not file any appeal. In contrast, the present situation is that claims 1 to 6 (with the deletion of an embodiment in claim 1) are part of a new request comprising 32 claims. Like all new requests, this request is to be considered as a whole, which means that in the framework of the appeal, claims 1 to 6 would also be open to question. However, the respondents did not object to any of these claims during opposition proceedings (see point 16 of the decision under appeal) and they also did not bring forward any arguments on appeal as to why they would not comply with the requirements of the EPC. The board will not reconsider their allowability of its own motion in the absence of any factual basis for doing so.

Article 123(2)(3) EPC

Claims 17 and 27

2. Claims 17 and 27 relate to the use of either BR43x2 (SEQ ID NO:2), its extracellular domain (SEQ ID NO: 4) or of antibodies against SEQ ID NO: 2 or SEQ ID NO: 4, for the manufacture of a medicament against, in particular, membranous nephropathy, IgA nephropathy, Berger's Disease, IgM nephropathy, Goodpasture's Disease, post-infectious glomerulonephritis, mesangioproliferative disease, minimal-change nephrotic syndrome or secondary glomerulonephritis or vasculitis associated with lupus. These specific medical conditions which are disclosed in the passage bridging pages 55 and 56 of the application as filed (Article 123(2) EPC) are not mentioned in the granted claims. However, as submitted by the appellant, they are specific subsets of the medical conditions of glomerulonephritis or vasculitis which were recited in granted claim 20. For this reason, there is no extension of the scope of the claims. The requirements of Article 123(2)(3) EPC are fulfilled.

Article 54 EPC; novelty

Claims 7 to 32

3. The decision of the opposition division to reject the granted claims for reasons of lack of novelty was taken in relation to subject-matter which is no longer claimed. In the board's judgment, none of the prior art documents on file discloses the BR43x2 polypeptide/anti-BR43x2 antibodies nor, a fortiori, their uses for the manufacture of medicaments against specific diseases (claims 7 to 31). In the same manner, no prior art document discloses the use of antibodies against the tumour necrosis factor receptor (TNFR) TAC1 (SEQ ID NO: 6) for the manufacture of a medicament against asthma, bronchitis or emphysema (claim 32). The requirements of Article 54 EPC are fulfilled.

Articles 56 and 83 EPC; inventive step, sufficiency of disclosure

Product claims 7 to 16

4. These claims relate in particular to the BR43x2 polypeptide/DNA encoding it/pharmaceutical composition comprising anti-BR43x2 antibodies. The BR43x2 DNA was isolated in the course of a study of receptors of the tumour necrosis factor (TNF) ztnf4. Two known tumour necrosis factor receptors TACI and BCMA were found to have the same property as BR43x2, namely that of binding ztnf4.

5. Documents (1) or (9) may be taken as closest prior art, document (9) being the scientific publication corresponding to the patent document (1). In what follows, reference will be made to document (1). In this document, TACI is characterized by its sequence (SEQ ID NO: 2). It is described on page 18 as a cell surface protein comprising a C-terminal cytoplasmic end, a membrane spanning segment and an N-terminal extracellular domain with two cysteine-rich regions. Because of its structural features, it is acknowledged on page 19 as a member of the TNFR super family. Document (1), eg page 18 and Example, also teaches that after the cross-linking of its N-terminal end with its ligand, TACI binds at its C-terminal end with the N-terminal end of the CAML protein, which binding, in turn, induces activation of the Ca**(+)-dependent transcription factor NF-KB. This factor is known to play an important role in the activation of lymphocytes (document (1), page 2, lines 28 to 30). Therapeutic uses are envisaged for TACI/anti-TACI antibodies/TACI ligand based on the link presumed to exist between TACI activation by ligand and B cells activation. It is suggested from pages 56 to 58, that TACI agonists such as TACI ligand could be administered for treatment of a subject in whom immune stimulation, in particular of B cells, is desired; alternatively, that suppression of TACI activity may be useful for treating undesirable immune responses such as autoimmune and inflammatory diseases including vasculitis, glomerulonephritis, systemic lupus erythromatosus (SLE) and rheumatoid arthritis (page 58, first full paragraph). The TACI ligand is, however, not identified and no data are provided which could render plausible any of the hypothesized uses.

6. Starting from the closest prior art, the problem to be solved may be defined as providing another member of the TNFR family.

7. The solution proposed is the BR43x2 polypeptide and the polynucleotide encoding it.

8. The patent in suit describes the isolation of BR43x2 DNA via the ability of the BR43x2 polypeptide - resulting from the transcription and translation of that DNA - to bind to the TNF ztnf4 (example 1). Furthermore, the sequence of BR43x2 is shown to be about 100% identical to that of the TNFR TACI in the region between amino acid 69 and amino acid 292. In fact, the difference between the two resides in that, in the TACI region 1 to 68, BR43x2 lacks amino acids 21 to 47, ie. the first cysteine-rich region of TAC1 has been replaced by a tryptophan residue.

9. Thus, the patent in suit provides evidence that BR43x2 functions as a receptor by binding a TNF and that it shares significant homology to a member of the TNFR family. Accordingly, it is concluded that BR43x2 is itself a member of this family and, therefore, a bona fide solution to the above mentioned problem.

10. This point is indeed confirmed in post-published document (33) where BR43x2 - under the name of "ShortTACI"- is defined on page 7220, right-hand column, as "an alternative spliced form of TACI containing a single CRD" (CRD: cysteine-rich region).

11. The prior art does not in any way suggest that a shorter version of TACI could act as a TNFR; in fact the existence of such a polypeptide is not even hinted at. If, for the sake of argument, one would consider it likely, then it remains quite unexpected that, although retaining the ability to bind ztnf4, the shorter TACI version has not retained the most conserved of the TACI two cysteine-rich regions but rather the least conserved one. For this reason, the subject-matter of product claims 1 to 7 is inventive (Article 56 EPC).

12. The skilled person would have no difficulty in reproducing the claimed polypeptide on the basis of its sequence or of that of the DNA encoding it. Preparing antibodies or a pharmaceutical composition is well within the ability of the skilled person. The requirements of Article 83 EPC are also fulfilled.

Articles 56 and 83 EPC; inventive step, sufficiency of disclosure

Use claims 17 to 31

13. It has just been established that product claims 7 to 16 fulfil the requirements for patentability. This implies that the patentability of a generic use of the claimed molecules would not need to be investigated. Yet, while being use claims in relation to BR43x2/portion thereof/ anti-BR43x2 antibodies, claims 17 to 31 have a distinctly different content from that of a "straightforward" generic use claim. Indeed, their subject-matter is rather the "therapeutic link" which may exist between the above mentioned molecules and specific medical conditions. For this reason, the patentability of the uses needs be assessed on its own. In accordance with the case law (T 1329/05 of 28 June 2005), a subject-matter may be regarded as a contribution to the art, ie. as an invention susceptible of being patented, if it solves the problem it is intended to solve and this should be made at least plausible by the disclosure in the patent in suit. Post-published evidence may in the proper circumstances also be taken into consideration.

14. The technical content of the patent in suit which is relevant to claiming medical uses for BR43x2/ portion thereof/anti-BR43x2 antibodies is as follows:

a)- BR43x2 is able to bind ztnf4 (Example 1);

b)- Overexpression of ztnf4 induces increases in B cells and Ig levels and is associated with the appearance of symptoms characteristic of eg. systemic lupus erythematosus, glomerulonephritis and autoimmune diseases (Examples 9 and 12, in vivo data, Example 3, in vitro data);

c)- By binding to ztnf4, TACI-Fg or -Ig inhibits its engagement with its cellular receptor and consequently, induces a decrease in B cells and Ig levels (Example 11, in vitro data, Examples 13 and 14, in vivo data).

15. In the board's judgment, this overall teaching makes it plausible that BR43x2 - which binds to ztnf4 - may be effective against medical conditions involving an increase in B cells and/or Ig levels. Here, it must be noted that the relevant data in the patent in suit regarding point c) were obtained with TACI rather than with BR43x2. However, inasmuch as, as already mentioned, both of them bind ztnf4 and this binding is responsible for ztnf4 inhibition, the board is prepared to accept the plausibility of BR43x2 being suitable for treating the specific diseases mentioned in the claims insofar as they are associated with high levels of B cells or immunoglobulins.

16. Plausibility is confirmed in post-published documents or by experimental data on file. Thus, document (50), page 19, discloses that delivery of TACI-Ig to mouse models of asthma inhibits binding of ztnf4 (identified as BLys) to its cellular receptor and results in B cell depletion and therefore, in a decrease of IgE production. The equivalent teaching is found in document (51). Documents (49) and (57) confirm that delivery of TACI-Ig to SLE patients induces a reduction in B cells and Ig levels. Prior art document (38), passage bridging pages 995 and 996, discloses that mice which overexpress ztnf4 have elevated levels of B cells, IgM, IgG and IgE and develop symptoms characteristic of SLE such as glomerulonephritis and proteinuria. As for document (48), it teaches that delivery of TACI-Ig to patients suffering from rheumatoid arthritis results in a decrease in IgM and in mature B cells.

17. There is, thus, no doubt as regards the patent specification providing a contribution to the problem of treating the diseases mentioned.

18. For the skilled person, it would have been fully unexpected that a tumour necrosis factor receptor derived from TACI could be put to the claimed uses even taking into account the closest prior art document (1). Indeed, as mentioned above, document (1) is wholly silent as to which ligand will bind TACI and whereas it mentions therapeutic uses, it is on the basis of mere assumptions. In the board's judgment, without the knowledge established in the patent in suit that the TACI ligand is ztnf4 and that the effect of ztnf4 is to increase levels of B cells and immunoglobulins, these assumptions are devoid of substance and, thus, unlikely to affect inventive step. There is no other document on file which, when combined with document (1), would render the claimed subject-matter obvious. Thus, the specific uses of the inventive BR43x2 polypeptide are themselves inventive.

19. For the same reasons, sufficiency of disclosure is achieved for the claimed uses above the obvious sufficiency of disclosure of manufacturing a medicament comprising a reproducible compound (BR43x2,...), that is, it is achieved in relation to the treatment of the specifically mentioned diseases.

20. Claims 17 to 31 fulfil the requirements of the EPC.

Use claim 32

21. The reasoning developed under Articles 56 and 83 EPC in relation to the use of BR43x2/anti-BR43x2 antibodies for the manufacture of a medicament for the treatment of specific diseases applies all the more to the use of anti-TACI (SEQ ID NO: 6) antibodies for the manufacture of a medicament against asthma, bronchitis or emphysema because, as already mentioned above, the experiments relevant in this context were performed with TACI itself. Post-published document (50) provides confirmation of the fact that asthma is linked to an increase in IgE levels which can be treated with TACI-Ig. The claim fulfils the requirements of the EPC.