T 0858/13 (Antagonistic anti-NGF antibodies for use in bone cancer pain treatment/RINAT NEUROSCIENCE, REGENTS OF THE UNIVERSITY OF MINNESOTA) 11-04-2017

Reasons for the Decision

1. The appellants' appeals are admissible.

Introduction to the invention

2. The present invention concerns the use of an antagonist of nerve growth factor (NGF) in the treatment of bone cancer pain.

3. NGF belongs to the neurotrophin protein family. Its members induce the development of neurons and are important for their survival and proper functioning. A binding of NGF to either the membrane-bound trkA tyrosine kinase receptor or the p75 receptor, the latter being structurally related to proteins of the tumour necrosis factor receptor family, causes an upregulation of neuropeptides in sensory neurons (see patent, paragraph [0002]).

4. Antagonists are agents that directly or indirectly result in decreased biological activity of molecules of interest, in the present case NGF (see paragraph [0014] of the patent).

Main request

Inventive step (Articles 100(a) and 56 EPC)

Closest prior art

5. For assessing whether or not a claimed invention meets the requirements of Article 56 EPC, the boards of appeal normally apply the "problem and solution" approach. This requires as its first step the identification of the closest prior art. This is generally a prior art document disclosing subject-matter conceived for the same purpose or aiming at the same objective as the claimed invention and having the most technical features in common, i.e. requiring the minimum of structural modifications (see Case Law of the Boards of Appeal, 8th edition 2016 (hereinafter "CLBA"), I.D.3.1).

6. Appellants I considered the disclosure of document A9, appellants II and III that of either A9 or A14, as the closest prior art for the subject-matter of claim 1.

7. Document A9 discloses the administration of at least one local anaesthetic as sympathetic nerve blocker in a first step, followed by the administration of at least one antagonist of NGF to nullify its stimulatory activity on neurons in the treatment of sympathetic nerve-mediated chronic pain in human patients (see column 5, lines 8 to 23; column 11, line 62, to column 12, line 11; column 15, lines 14 to 17). Disclosed states of chronic pain to be treated are inter alia associated with neoplastic diseases (see column 13, lines 3 to 10).

7.1 The document reports, in relation to the processes causing chronic pain, that the uptake of excess NGF at the local site of injury "begins the vicious, repetitious cycle of events causing the development and stage progression of chronic pain" (see column 11, lines 14 to 20). In this context, it teaches that NGF "is taken up by specific receptors in the axons of sympathetic fibers and sensory fibers and is transported up the fiber in retrograde fashion to the neural cell body" (see column 10, lines 34 to 37) and that the "excess production of nerve growth factor then stimulates the neuron cell body into a hyperactive state; and the continued excess production of nerve growth factor will cause a repeated and increasing stimulation effect and hyperactivity of both sympathetic neurons and somatic sensory neurons" (see column 10, lines 62 to 68). Lastly, the document reports that NGF's stimulation of neurons "will continue indefinitely until the nerve growth factor itself is removed or nullified by an antagonist" (see column 11, lines 8 to 13).

7.2 Document A9 discloses four categories of NGF antagonists. Firstly, it mentions vinca alkaloids, for example vincristine, which "prevent the retrograde axonal uptake of nerve growth factor along the nerve fiber in-vivo" (see column 22, lines 60 to 66, column 24, line 29); secondly, colchicine that acts by inter alia inhibiting superoxidation and cell growth (column 22, line 66, to column 23, line 3; column 25, lines 12 to 18); thirdly, polyclonal and monoclonal anti-NGF antibodies that neutralise the activity of NGF (see column 23, lines 3 to 8; column 26, lines 12 to 31); and fourthly, guanethidine, reserpine and 6-hydroxydopamine, which function as inactivators of sympathetic neurotransmitters (see column 23, lines 8 to 13; column 25, lines 49 to 55).

7.3 Furthermore, the document reports on four clinical studies involving human patients suffering from various chronic pains. "Case History 1" and "Case History 2" disclose two patients affected by a severe pain originating from multiple myeloma located either in the "lower lumbar spine and sacrum" (see column 27, lines 32 to 39) or "in all his bones" (see column 28, lines 19 and 20). It was common ground between the parties that these disclosures meant that both patients suffered from a chronic bone cancer pain. The patients are treated by administering vincristine after having first received local anaesthetics to block their sympathetic nerves. After the treatment, the patients are reported to be either "essentially pain free" after nine months or "relatively pain free" one week later (see column 27, line 53, to column 28, line 27).

8. Document A14 discloses that NGF is involved in sensitisation in a variety of chronic pain states. It reports that NGF is strongly expressed in vitro in the murine osteolytic sarcoma cell line 2472, which expression continues in vivo in mice that had received intramedullary injection of these cells into the femur.

Furthermore, the document reports that in these mice calcitonin gene-related peptide (CGRP)-immunoreactive nerve fibres are surrounded by cancer cells in tumour-bearing mouse femora. It states that the majority of these fibres are sensitive to NGF and therefore suggests that NGF "may at least in part be responsible for the sensitization of a subpopulation of primary afferent fibers in bone cancer pain" (see abstract). However, document A14 does not disclose an actual treatment of bone cancer pain.

9. Hence, only document A9 relates to the same purpose as that underlying the claimed invention, i.e. a treatment of bone cancer pain. Accordingly, the board concludes, in accordance with the criteria established by the case law (see point 5 above), that the administration of a local anaesthetic followed by the administration of vincristine in the treatment of chronic bone cancer pain disclosed in "Case History 1" and "Case History 2" in document A9 represents the closest prior art.

Technical problem and solution

10. Appellants I submitted that the subject-matter of claim 1 differed from the closest prior art treatment disclosed in document A9 in using an antagonistic anti-NGF antibody instead of vincristine. This antibody specifically targeted NGF without harming sensory neurons, which were certainly damaged by vincristine's neurotoxic activity. Furthermore, it was submitted that the patent demonstrated that the pain-relieving efficacy of an anti-NGF antibody in the claimed therapeutic application was increased compared to that achieved with morphine, a further notable improvement over the findings in document A9.

11. The patent discloses in examples 2 and 3 that an anti-NGF antibody has a superior efficacy compared to morphine in alleviating pain in a mouse model of bone cancer (see paragraphs [0188], [0201], [0209], [0224]) and that the anti-NGF antibody does not cause significant adverse side-effects under these conditions (see e.g. paragraph [0226]). However, the patent does not disclose a comparison of the efficacy or the potential toxicity of vincristine and an anti-NGF antibody in the same model system.

12. Accordingly, the patent does not disclose results which can be compared directly with the results in the closest prior art document A9, and this has actually not been argued by appellants I.

13. Accordingly, in view of these considerations the board is of the opinion that the results in the patent do not demonstrate a more potent effect or a reduced toxicity of the anti-NGF antibody over vincristine in the treatment of bone cancer pain and that therefore no case for improved effects over the effects in the closest prior art has been established.

14. Thus, the objective technical problem to be solved is the provision of an alternative means in the treatment of bone cancer pain.

15. The board is satisfied that the subject-matter of claim 1 solves this technical problem in view of the demonstrated efficacy of the antagonistic anti-NGF antibody in the claimed therapeutic application in the patent (see point 11 above).

Obviousness

16. It has to be assessed whether or not the skilled person, starting from the administration of a sympathetic nerve blocker followed by the administration of vincristine in the treatment of bone cancer pain as disclosed in document A9 and faced with the technical problem defined above, would arrive in an obvious manner at the use of an antagonistic anti-NGF antibody as an alternative to vincristine.

17. Document A9 teaches that: "Blockade of the sympathetic nerve tract alone using local anesthetics is by necessity short-term if effective and is efficacious only in early distrophies. Investigative research by other has shown that NGF blockade percutaneously can also be efficacious, but the method requires long-term, repeated applications. The present invention maintains that sympathetic blockade coupled with NGF antagonism by any effective means act together to produce far more efficacious and longer lasting relief from chronic pain" (see column 11, lines 35 to 44, emphasis added). Accordingly, the document discloses as a generic concept the central role of NGF antagonists in achieving long-term effects in the treatment of chronic pain. In this context bone cancer pain and vincristine's function as an NGF antagonist are explicitly disclosed (see points 7 and 7.3 above).

18. The skilled person seeking for alternative means in the treatment of bone cancer pain would in the same document have encountered Section C, headed "Administering An Antagonist Of Nerve Growth Factor To The Living Subject Whereby The Administered Antagonist Substantially Nullifies The Neuron Stimulation Effect Caused By Such Nerve Growth Factor As Is Present" (see column 22, lines 34 to 39), where, in relation to NGF antagonists, the following is disclosed: "A third category is represented by the known polyclonal or monoclonal anti-nerve growth factor antibodies conventionally known and described in the literature which are recognized as being able to neutralize nerve growth factor molecules directly upon reactive contact" (see column 23, lines 3 to 8).

19. Since anti-NGF antibodies that neutralise NGF's stimulation of neural cells are explicitly mentioned in document A9 as NGF antagonists in the treatment of chronic pain, the board considers that the above-cited passages provided the skilled person with a direct incentive to contemplate their use in the treatment of patients suffering from bone cancer pain as an alternative to vincristine in the treatment.

20. Appellants I argued that the skilled person reading in particular the clinal study "Case History 1" in document A9 and taking common general knowledge into account would have had doubts that vincristine's reported effect in reducing chronic bone cancer pain was in fact mediated by an antagonism of NGF. This was so because the agent was known for its cytotoxic effects on neurons (see document A48, page 1419, column 1, third paragraph) and tumour cells (see document A9, column 4, lines 9 to 16). Both of these effects of vincristine were rather long-lasting, which seemed to match with the patient's reported pain-free state nine months after concluding the treatment.

In contrast thereto had any potential antagonising effect of vincristine on NGF to be relatively short in view of the reported administration for only four days (see Case History 1) and its known short half-life of about 20 hours (see document A48, page 1418, column 1, last paragraph). It followed from this that the skilled person would have had doubts that NGF itself was even a suitable target in treating bone cancer pain, in particular since results with other NGF antagonists were lacking in document A9.

20.1 The board notes that it is common ground between the parties that the skilled person reading document A9 is aware of vincristine's multiple effects in vivo, i.e. its cytotoxicity on neurons and cancer cells, and that it reduces chronic pain, including bone cancer pain (see column 4, lines 5-6 and 20-21, column 25, lines 9 to 11, and Case Histories 1 and 2).

20.2 Therefore, in the board's view, the skilled person has no reason to assume that vincristine's reported efficacy in reducing bone cancer pain in document A9 solely relies on only one of these effects, namely cytotoxicity. With regard to vincristine's relatively short biological half-life, the board notes that appellants I argued that the mechanisms underlying bone cancer pain and its transmission were unknown to the skilled person at the relevant date of the patent. In this situation, in the board's opinion, the skilled person would not have speculated whether short-term or long-term effects of vincristine were responsible for its reported reduction of bone cancer pain, since in the absence of any information both appear to be equally probable.

20.3 Furthermore, as set out in point 17 above, the central teaching of document A9 is directed to NGF as the target in chronic pain, and consequently NGF antagonism as the appropriate therapeutic approach. In line with this, document A9 reports that vinca alkaloids, e.g. vincristine, "function as blocking agents [of NGF, comment added by the board] and prevent the retrograde axonal uptake of nerve growth factor along the nerve fiber in-vivo" (see column 22, lines 63 to 66).

20.4 In view of these considerations the board is not convinced by appellants I's arguments.

21. In a further line of argument, appellants I submitted that bone cancer pain was a unique state of pain, since (i) analgesics that reduced inflammatory or neuropathic pain were often ineffective in its therapy and (ii) it induced a biochemical signature in neurons not seen in other pain states. Therefore, the skilled person reading document A9 would not have derived therefrom that NGF was a target at all in the treatment of bone cancer pain. The same applied to the prior art, since the documents cited suggested many potential target proteins, but not NGF. Furthermore, in view of the demonstrated clinical and biochemical uniqueness of bone cancer pain, the skilled person had no reasonable expectation that the anti-NGF antibody was therapeutically effective.

22. The board is not convinced by these arguments either, since, as set out in points 7.1 to 7.3 above, document A9 explicitly discloses that NGF is a central target in bone cancer pain and that vincristine as an NGF antagonist is effective in treating it. The involvement of NGF is also explicitly suggested in document A14 (see point 8 above). Moreover, the fact that some of the cited prior art documents do not mention NGF as a potential target in the claimed therapeutic application does not on its own constitute evidence that the skilled person would have disregarded it, least of all in the present case, where evidence and indications for NGF's involvement are available, while evidence or indications to the contrary are lacking.

23. In view of the above considerations, the board concludes that the subject-matter of claim 1 of the main request lacks an inventive step with regard to the disclosure of document A9 on its own and that this ground for opposition therefore prejudices the maintenance of the patent as granted (Articles 100(a) and 56 EPC).

Admission of auxiliary requests 1 and 2 into the proceedings (Article 13(1) RPBA)

24. The filing of the claims of auxiliary requests 1 and 2 by appellants I during the oral proceedings represented an amendment to appellants I's case within the meaning of Article 13(1) RPBA. The admission of these requests into the proceedings and their consideration were therefore at the board's discretion.

25. The claim requests were presented at the oral proceedings and thus at a very late stage in the appeal proceedings.

26. According to appellants I the requests were submitted specifically to address the board's finding under Article 56 EPC that the objective technical problem was the provision of an alternative and not of an improved treatment in bone cancer pain and were filed immediately once the board's opinion was known.

27. However, the board notes that the objection pursuant to Article 56 EPC, including the consideration that, having regard to the disclosure in document A9, the technical problem should be formulated in a less ambitious manner, namely as the provision of an alternative, had already been raised by opponent 01 in the first-instance proceedings (see contested decision, point 38 of the reasons) and has been retained by both appellants II and III in their statements of grounds of appeal (see page 6, third paragraph, of appellant II's letter dated 21 May 2013 and point 4.13 of appellant III's letter dated 24 May 2013, respectively). Appellants I must thus have already been aware of that objection when filing their statement of grounds of appeal or their reply to appellants II and III's statements of grounds of appeal. That the board might follow appellants II and III's approach was one of the two possible scenarios, but cannot be held to be unforeseeable. Also, no new objection was raised ex officio by the board and no new line of objection was raised by appellants II and III during the oral proceedings (see CLBA, IV.E.4.4.12). Therefore, in the present case, the board cannot conclude that an unexpected development of the case occurred that may have justified the late filing of auxiliary requests 1 and 2.

28. Furthermore, the claims filed as auxiliary requests 1 and 2 were amended in such a way as to include new features taken from the description. These amendments raised further issues, in particular objections as to clarity pursuant to Article 84 EPC as argued by appellant II, and were directed to subject-matter which had not been previously addressed in the appeal proceedings. This would have added further complexity to the case and led to a discussion of entirely new aspects for the first time at the oral proceedings before the board.

29. Based on the above considerations, the board decided not to admit auxiliary requests 1 and 2 into the proceedings pursuant to Article 13(1) RPBA.