T 1439/09 (Sclerostin/UCB PHARMA) 16-04-2013

Reasons for the decision

1. Procedural requests

Late filed grounds of opposition

1.1 The appellant submitted that the opposition division erred in the exercise of its discretion when it decided not to admit the late filed grounds of opposition of Article 100(a) EPC in combination with Article 57 EPC, and of Article 100(c) EPC into the proceedings. Referring to Rule 81(1) EPC, it was of the opinion that the rule's language obliged the opposition division to admit new grounds of opposition in any case if they prejudiced the maintenance of the European patent.

1.2 The wording of Rule 81(1) EPC, "Grounds for opposition ... may be examined by the opposition division ..." makes it clear that the opposition division has the discretionary power to admit grounds for opposition which were originally not invoked.

1.3 If the way in which the department of first instance has exercised its discretion on a procedural matter is challenged in an appeal, it is not the function of the board of appeal to review all the facts and circumstances of the case as if it were in the place of the department of first instance, and to decide whether or not it would have exercised such discretion in the same way as the department of first instance. A board of appeal should only overrule the way in which a department of first instance has exercised its discretion if the board concludes it has done so according to the wrong principles, or without taking into account the right principles, or in an unreasonable way (cf. Case law of the Board's of Appeal, 6th edition, VII.E.6.6, and decision cited therein).

1.4 The opposition division held that both grounds were not prima facie relevant, decided not to admit them, and gave an, albeit short, reasoning in its decision.

1.5 Thus, the board comes to the conclusion that the opposition division applied its discretionary power correctly and sees no reason to overturn its decision.

Third party observations

1.6 Anonymous, unsigned third party observations were filed during the appeal proceedings.

1.7 In decision T 146/09, this board, in a different composition, held that the identification of a third party in the context of third party submissions in opposition proceedings was particularly important in order to allow the competent organ of the EPO to verify whether the observations were indeed filed by a third party rather than by a party to the proceedings. Otherwise, a party might be tempted to submit late observations and/or documents by means of anonymous third party observations in order to avoid negative procedural consequences such as apportionment of costs. Moreover, unsigned submissions by a party to the proceedings were deemed not to have been filed if, after a communication according to Rule 50(3) EPC has been sent out by the EPO, they are not signed in due time. Since unsigned anonymous third party observations did not allow the EPO to send out such an invitation, they necessarily remained unsigned. As a consequence, they were deemed not to have been filed.

1.8 In the present case, the board sees no need to depart from this line of reasoning. Therefore, the anonymous observations filed under Article 115 EPC are deemed not to have been filed and are disregarded by the board.

New objection of lack of novelty over a divisional application

1.9 Claim 20 encompasses monoclonal antibodies binding to the protein encoded by any of the recited Seq IDs with a Ka of greater than or equal to 10**(8) M**(-1)but not to the protein Dan or the protein Gremlin.

1.10 The appellant submitted that the priority document of the case under appeal did not disclose this subject matter. Thus, the relevant date for the assessment of novelty was the filing date of the patent application.

The appellant further submitted that the divisional European patent application, EP No. 06011535, arising from the patent under appeal, disclosed antibodies falling within the scope of claim 20. In addition, the antibodies according to the divisional application were disclosed in the common priority document. Under these circumstances, claim 20 lacked novelty according to Article 54(3) EPC over its own divisional application.

1.11 The appellant submitted, that the legal issues arising from this objection were not complicated and that admitting the novelty objection at this stage of the proceedings would not lead to a significant delay of the procedures.

1.12 The board is of the opinion that a sound assessment of the question whether a divisional patent application could anticipate subject matter of its own parental patent application requires a substantial amount of legal analysis which would unavoidably lead to an adjournment of the proceedings. In view of the late filing, i.e. less than two months before oral proceedings were held, in accordance with Article 13(3) RPBA, the board decides not to admit the late filed objection under Article 54(3) EPC into the proceedings.

Late filed documents

1.13 Document D65 and the corresponding priority document D70 were filed in response to the proprietor's response to the grounds of appeal. As a consequence thereto, the respondent filed amended claim requests. Under these circumstances, the board decides to admit documents D65 and D70 into the proceedings.

1.14 Document D86 filed by the respondent is identical with document D100 filed by the appellant. Since both parties and the board considered this document relevant, it was admitted.

1.15 Documents D90 and D101 to D103 were filed by the respondent and the appellant, respectively, in response to the board's communication. Both parties agreed to their introduction and the board decided to admit them.

Admissibility of the Main request

1.16 In point 4 of its communication attached to the summons to oral proceedings, the board had indicated that a decision on the admissibility of documents D65 and D70 would be taken at the oral proceedings. It had also indicated that it would most likely admit further submissions filed in direct response to the admission of the late filed documents.

The main request filed at the oral proceedings contains amendments which are a direct response to the admission of documents D65 and D70 into the proceedings. Under these circumstances the board decides to admit the main request.

Articles 123(2), 123(3) and 84 EPC

2. In view of the board's decision on the admissibility of Article 100(c) EPC as a ground of opposition (cf. points 1.1. to 1.5 above) and the fact that amended claim 20 is the result of the incorporation of the features of dependent claims 22 and 28 as granted into independent claim 20 as granted, in accordance with the cross references stated therein, the amendments in claim 20 are not open to an objection under Article 123(2) EPC (cf. e.g. decision T 367/96 of 3 December 1997).

3. The appellant did not raise any objections under Articles 123(2), 123(3), and 84 EPC, and the board sees no need to do this on its own motion.

Article 83 EPC

4. The parties have not disputed, and the post published documents (e.g. D33, D38, D42, D48, D86) confirm, that the protein Sclerostin, identified in the patent under appeal by a positional cloning approach, plays a role in inhibiting bone growth and therefore represents a plausible target for controlling bone growth. There was also agreement that the skilled person could readily produce antibodies against Sclerostin. An objection under Article 83 EPC was only raised against claim 25.

5. Claim 25 refers to the use of an antibody according to claim 20 for the manufacture of a medicament for increasing bone mineralization.

6. The appellant submitted that the patent erroneously taught a direct interaction between Sclerostin and BMPs, and erroneously taught that the disruption of this interaction by antibodies affected bone mineralisation. The skilled person following this teaching could not obtain any medically useful antibodies, because the interactions described in Example 5 were artefacts. Moreover, the patent did neither disclose a single antibody affecting bone mineralisation nor identify regions of Sclerostin important to its physiological function. Therefore, as far as claim 25 was concerned, the skilled person was not in a position to readily identify antibodies suitable for medical use.

7. The language of claim 25 does not require the inhibition of a particular interaction. Thus, although there was a controversial discussion about the exact mode of action of Sclerostin, the answer to the question of sufficiency of disclosure does not depend on its outcome, as long as the skilled person could readily perform tests to establish whether an antibody had an effect on bone mineralisation.

8. The board will therefore first establish whether such assays were readily available.

9. In relation to medical uses, the patent teaches methods for determining whether a selected molecule is capable of increasing bone mineral content, comprising the "steps of (a) mixing a selected molecule with TGF-beta binding protein and a selected member of the TGF-beta family of proteins, (b) determining whether the selected molecule stimulates signalling by the TGF-beta family of proteins, or inhibits the binding of the TGF-beta binding protein to the TGF-beta family of proteins" (cf. paragraphs [0030, 0139]. While methods for assaying a direct interaction between Sclerostin and BMPs are disclosed in more detail in Example 5, the patent does not further specify how the skilled person would analyse signalling by TGF-beta family proteins.

10. The appellant, in the context of its attack on inventive step, submitted that tissue culture tests would have been obvious to perform in various established systems in order to assess the role of candidate molecules in bone formation (cf. document D51, point 7, and Annex EW6). Known test systems included osteoblast cell lines such as MC3T3-E1 or ROS 17/2.8, primary osteoblast-enriched cell cultures (e.g. rat calvaria cells), or cartilage-derived primary chondroblasts/chondrocytes from chicken or rat. Alternatively, organ cultures from chicken sterna or rat calvaria could be established. Common markers of bone mineralization included osteocalcin or alkaline phosphatase. Animal studies could then be used to validate any observed effects.

11. Such assay systems have also been used to establish the role of BMPs in bone morphogenesis, i.e. to assay BMP mediated signalling (cf. e.g. Ruppert et al., 1996, attached to D59), and the board has no doubts that the skilled person could have used them not only for assaying the role of a candidate protein in the inhibition of bone mineralization, but also for assaying the effects of potential inhibitors of the inhibitor of bone formation. The appellant arrived at the same conclusion in point 5 of annex EW6, attached to declaration D51.

12. Evidence that alkaline phosphatase and mineralization assays based on Mouse MC3T3 cells, BMP2, Sclerostin and anti-Sclerostin antibodies yield useful results is disclosed in post published document D58. This document discloses affinity selected anti-Sclerostin antibody fragments which were assayed for an effect on the inhibition of alkaline phosphatase activity by Sclerostin (Example 4). While most of the antibody fragments were ineffective, some showed variable degrees of reversal of the effect of Sclerostin. The best antibody inhibited the activity of Sclerostin by about 75 to 85%, albeit at an antibody concentration deemed too high. As further shown in Example 7, mineralization assays based on Mouse MC3T3 cells, Sclerostin and BMP-2 yield measurable effects of anti-Sclerostin antibodies on calcium deposition (Figure 2).

13. As mentioned above, the parties discussed the mode of action of Sclerostin and the ensuing consequences for the identification of neutralizing antibodies extensively and controversially. Apart from the patent itself, some post published documents such as e.g. document D33 disclosed an effect of Sclerostin on BMP signalling (cf. Fig. 4) while others disclosed an important mode of action of Sclerostin via Wnt signalling (documents D40 to D42).

14. To clarify this point, both parties submitted document D86, disclosing an important extracellular interaction between Sclerostin and the Wnt protein, and an intracellular interaction between Sclerostin and BMP7.

15. In the board's view, detailed knowledge of the actual mode of action of Sclerostin might be useful for further optimizing screening procedures for the finding of therapeutically useful antibodies (cf. Example 2 of D48, and by Example 6 of D58). However, as long as the skilled person could identify at least some therapeutically useful antibodies on the basis of known in vitro assays (cf. points 12 and 13 above), even though this might have involved a serious effort, this additional detailed knowledge was not essential for performing the claimed invention without undue burden.

16. The appellant has further argued that even if the skilled person would have identified antibodies affecting the expression of e.g. alkaline phosphatase in osteoblasts, such antibodies were far from being clinically useful.

17. The patent system takes account of the intrinsic difficulties and the boards of appeal have accepted that for a sufficient disclosure of a therapeutic application, it is not always necessary that results of applying the claimed composition in clinical trials, or at least to animals are reported. Yet, this does not mean that a simple verbal statement in a patent specification that compound X may be used to treat disease Y is enough to ensure sufficiency of disclosure in relation to a claim to a pharmaceutical. It is required that the patent provides some information in the form of, for example, experimental tests, to the avail that the claimed compound has a direct effect on a metabolic mechanism specifically involved in the disease, this mechanism being either known from the prior art or demonstrated in the patent per se. Showing a pharmaceutical effect in vitro may be sufficient if for the skilled person this observed effect directly and unambiguously reflects such a therapeutic application (T 241/95, OJ EPO 2001, 103, point 4.1.2 of the reasons, see also T 158/96 of 28 October 1998, point 3.5.2 of the reasons) or, as decision T 158/96 also put it, if there is a "clear and accepted established relationship" between the shown physiological activities and the disease (cf. point 9 of decision T 609/02).

18. In the present case, the patent clearly and undisputedly discloses a new protein, Sclerostin, and establishes it as a target for medical intervention in diseases of low bone density. Sclerostin is disclosed as an inhibitor of bone growth, and the patent teaches a way of identifying neutralizing antibodies of potential medical use by reference to functional assays. Asking for further proof of medical usefulness goes beyond the standards for assessing sufficiency of disclosure as set out by e.g. decision T 609/02 of 27 April 2004. Therefore the appellant's argument must fail.

19. In summary, the facts on file do not support the appellant's argument that the identification of neutralizing antibodies represented an undue burden.

As the skilled person was in a position to identify a neutralizing antibody readily and without undue burden, the board decides that the invention according to claim 25 is sufficiently disclosed (Article 83 EPC).

Article 54(3) EPC

20. The appellant raised a novelty objection against claim 20 in view of document D65.

21. Claim 20 refers to monoclonal antibodies binding to the proteins encoded by any of the recited SEQ IDs (cf. item XIV above) with a Ka of greater than or equal to 10**(8) M**(-1)but do not bind the protein Dan or the protein Gremlin. Subject matter defined in this way is not disclosed in the priority document of the patent under appeal, and thus, the relevant date for establishing novelty is the date of filing.

22. Document D65 constitutes prior art under Article 54(3) EPC, claiming priority from i.a. US provisional application 60/151700 (document D70). The filing date of this priority application is 31 August 1999 i.e. after the priority date but before the filing date of the patent under appeal.

23. Document D65 and its priority document D70 disclose a gene encoding a protein termed PRO7476. The encoded protein is completely identical with Sclerostin as defined by SEQ ID 2 in the patent under appeal. The nucleic acid sequence encoding PRO7476 differs from all the nucleic acid sequences recited in claim 1 of the patent under appeal. The protein of Seq ID 2 was disclosed in the priority application, and all other protein sequences recited in claim 19 differ from that of PRO7476. Hence claims 1 and 19 are not affected by the disclosure of document D65.

24. Document D65 and its priority document furthermore disclose antibodies specifically binding to PRO7476 (D65, claim 2; D70, claim 34) and provide a general teaching how to raise poly- and monoclonal antibodies (D65, pages 71 to 76; D70, pages 49 to 58).

25. Referring to [0116] of the patent under appeal, where antibodies specifically binding were defined as antibodies specifically binding with the protein of SEQ ID 2 but not with i.a. Dan or Gremlin, the appellant argued that monoclonal antibodies specifically binding with PRO7476 fell within the scope of claim 20. The limitation of the claim to monoclonal antibodies with a Ka of greater than or equal to 10**(8) M**(-1)could not help in overcoming this objection because, as shown by documents D101 to D103, the average Ka of monoclonal antibodies was 10**(8) M**(-1)and the majority of the monoclonal antibodies raised would be expected to have a Ka greater than this value.

26. According to the evidence on file, common Ka values of antibodies range from 5x10**(4) to 10**(11) M**(-1)(D90), 10**(5) to 10**(12) M**(-1)(D101), 10**(7) to 10**(10) M**(-1)(D102), and 10**(8) to 10**(12) M**(-1)(D103). Thus, a reference to an antibody specifically binding with a particular protein encompasses antibodies with affinity constants ranging from clearly below 10**(8) M**(-1)up to 10**(12) M**(-1).

Claim 20 is limited to antibodies binding to Sclerostin with a Ka of greater than or equal to 10**(8) M**(-1), hence to a subgroup of all those antibodies that the skilled person following the teaching of document D65 would obtain. Such a subgroup is however neither explicitly nor implicitly disclosed in document D65.

27. Thus, the board decides that the subject matter of claim 20 is novel.

Article 56 EPC

28. Document D3 represents the closest prior art. It discloses a genetic locus on human chromosome 17 linked to Van Buchem disease, a disease characterized by increased bone formation. The authors identified a candidate region of <1 cM between two specific markers, and noted that a number of genes had already been assigned to this chromosomal region. They concluded that detailed physical mapping of the known genes in relation to the candidate locus should help in reducing the number of candidate genes. It was also noted that the clinical symptoms of Van Buchem disease resembled those of sclerosteosis. Based on the mode of inheritance in Van Buchem patients, the authors speculated that the disease causing mutation led to a loss of function of the unknown gene, and that antisense treatment might become a form of therapy for diseases linked to low bone density.

29. In light of this disclosure, the technical problem underlying the present invention can be seen in the provision of a target for therapy of diseases linked to low bone density.

30. For the solution of this problem, the patent proposes the isolated nucleic acid molecules of claim 1 and the proteins of claim 19.

31. As shown in example 1, the gene identified as encoding Sclerostin comprises a non-sense mutation unique to sclerosteosis patients which plausibly explains the observed phenotype. The board is therefore satisfied that the above mentioned problem has indeed been solved.

32. It remains to be established if the claimed solution involves an inventive step.

33. The appellant submitted that the skilled person, starting from document D3, would have arrived at the claimed solution on the basis of in silico analyses and without inventive skills. Prompted by document D3, the skilled person would have probed databases for clones in the candidate region of D3, would have entered the clones in a gene prediction program, would have found a limited number of genes, most of which were not of interest, and would finally have arrived at a candidate gene with some homology with a bone related protein. This candidate gene, which encodes Sclerostin, was the obvious solution to the technical problem mentioned above.

34. The board has no doubts that the skilled person, at the date of filing had the necessary skills to perform in silico analyses on the basis of the available genomic and other databases. The board does however not agree that the skilled person would have arrived at the claimed solution in an obvious way.

35. As it turned out later, the 0.7 cM region mentioned in document D3 encompasses about 3.4 megabases (page 10 of respondent's letter of 15 April 2010) most of which (about 85%) had not been sequenced at the filing date. It is not apparent why the skilled person would have a priori limited its analysis to only those regions between the genetic markers which had already been sequenced and would have further reduced the number of candidate genes on the basis of often hypothetical functional annotations (note in this context that PRO7476 of document D65 was identified in a search for growth factor homologs; cf. also the contradicting expert declarations D51, D68, and D61).

36. Moreover, even if the skilled person would have limited its strategy to analysing the publicly available data bases as suggested by the appellant, and would have arrived at a most promising gene sequence displaying some homology with the protein Dan, the obvious next step for further analysis of this candidate gene would have been to look for mutations in the gene in Van Buchem patients in order to explain the observed phenotype. The skilled person could however not have confirmed a role of the candidate gene in Van Buchem disease because the gene is not mutated in those patients. (cf. document D22, showing that the mutation underlying Van Buchem disease is located in a regulatory region considerably upstream of the gene, which had not yet been sequenced at the date of filing).

37. The appellant further submitted that the skilled person could have looked for mutations in the candidate gene in sclerosteosis patients.

38. This approach is based on hindsight because, although a locus had been mapped in Van Buchem patients, document D3 (page 398, left column, 2nd paragraph) merely suggested that the localization of the Van Buchem disease gene would allow the testing of the hypothesis that dominant endosteal hyperosteosis and/or sclerosteosis were allelic to Van Buchem disease. In other words, the idea that the genetic alteration underlying both diseases affected the same gene was speculative.

39. The appellant further submitted that the skilled person could have tested the candidate gene for an effect on bone formation on the basis of readily available in vitro assays. There is however no evidence that only one of the candidate genes in this region of the genome would have shown an effect in one or more of the known assays for bone formation.

40. In summary, the skilled person, following the in silico approach suggested by the appellant, would have had to take multiple decisions along the way to arrive at the claimed solution. This included decisions concerning the inclusion or exclusion of non-annotated sequences, a pre-selection of likely candidates genes on the basis of functional annotations, a narrowing down of the preselected genes on the basis of sequence homologies, a selection from multiple options for verifying the link to the observed phenotype (analysis of the gene in patients with Van Buchem disease, in patients with sclerosteosis or (one or several) in vitro assays for bone formation). At each point, the skilled person would have to take the right decision to arrive at the claimed solution in an obvious way. This is only possible with hindsight.

41. According to the established case law, the question to be asked in respect of inventive step is not whether the skilled could have arrived at the claimed solution but whether it would have arrived at the solution with a reasonable expectation of success.

42. The board concludes that the skilled person, starting from document D3 and using its general knowledge would not have arrived at the claimed solution in an obvious way.

Therefore, the board decides that the subject matter of claims 1 to 41 of the main request meets the requirements of Article 56 EPC.