T 0652/12 (Treatment for systemic onset juvenile idiopathic arthritis/CHUGAI) 08-12-2016

The invention

1. The invention concerns an antagonist monoclonal antibody against human IL-6 receptor for use in the treatment of systemic onset type juvenile rheumatoid arthritis of childhood.

2. Juvenile rheumatoid arthritis of childhood is also known in the art as juvenile idiopathic arthritis (JIA). "JIA is the most common rheumatic disease of childhood [...]. It is a heterogeneous inflammatory disorder that is classified in different subtypes based on the clinical characteristics in the first 6 months of disease. Three principal types of onset are recognised (oligoarthritis, polyarthritis and systemic arthritis)" (see document D25, page 92, paragraph 1). The systemic onset sub-type of the disease (sJIA) is a chronic arthritis developing in children of less than 16 years of age (ibid. and the application, page 5, lines 4 to 12) that is characterised by a systemic onset, consisting in high-spiking fever, rheumatoid rash, hepatosplenomegaly and/or serositis (see document D1, page 472, paragraph 1).

Main (sole) request

Claim 1

3. Claim 1 is for an antagonist monoclonal antibody against human IL-6 receptor for use in the treatment of sJIA. The sJIA is further defined as a disease that cannot be controlled with any of nonsteroidal anti-inflammatory drugs, long term bolus steroids and immunosuppressants.

4. At oral proceedings the appellant explained that these latter features served to emphasize that the claimed invention represented the first truly effective therapy for sJIA. The board is therefore of the view that the skilled person would construe the claim as directed to an antagonist monoclonal antibody against human IL-6 receptor for use in the treatment of sJIA.

Inventive step - Article 56 EPC

Closest prior art

5. Document D25 discloses the use of etanercept, a fusion protein of a portion of a human soluble TNFalpha receptor and the Fc portion of a human antibody constant region, which acts by blocking the interaction between TNFalpha and beta with their cell surface TNF receptors, for the treatment of JIA (see document D25, page 96, left column, section 2). The document provides a summary of the results of a clinical trail of etanercept on particular patients with polyarticular JIA (ibid.) and inter alia concludes that it (etanercept) represents an "important addition to [available] treatments for JIA, [...] offering a promising alternative for patients who had persistently active arthritis despite treatment with methotrexate" (Id., page 97, final paragraph).

6. According to document D25 "[...] methotrexate has become the therapeutic agent of choice for children with JIA who fail to respond adequately to NSAIDs. A number of studies have shown that methotrexate is an effective and well tolerated medication for the treatment of patients with JIA, with 60 to 70% of patients experiencing a significant clinical benefit with the standard dose regimen of 10 to 15 mg/m**(2)/week. Furthermore, preliminary evidence has been provided that methotrexate may significantly alter the natural history of JIA" (see page 93, right column).

7. Thus, since sJIA patients fall within the overarching group of JIA patients, it is apparent that sJIA patients had been treated according to the above mentioned regimen.

8. The treatment of sJIA patients with methotrexate disclosed in document D25 is therefore regarded as the closest prior art for the presently claimed subject-matter.

The technical problem and its solution

9. The difference between the closest prior art, represented by document D25 and the claimed subject-matter lies in the molecule used and the focus on sJIA as the specific sub-type of JIA to be treated.

10. The claim further specifies that the sJIA, is such that its "symptoms cannot be controlled with nonsteroidal anti-inflammatory drugs, long term bolus steroids and immunosuppressants". These features reflect the information provided in "Working Example 1" concerning a 5-year-old male sJIA patient who, prior to therapy according to the invention, had been treated with aspirin, oral bolus administration of prednisolone, methyl-prednisolone pulse therapy and plasmapheresis, and furthermore the combined use of cyclosporin A. These features of the claim reflect the fact that at the effective date of the application, the existing pharmaceutical therapies did not provide a fully effective means of controlling the symptoms of the disease.

11. In view of these differences, the objective technical problem can be formulated as the provision of an effective agent for the treatment of sJIA.

12. As is generally the case where a therapeutic application is claimed, attaining the claimed therapeutic effect is a functional technical feature of the claims (see Case Law of the Boards of Appeal of the European Patent Office, 8th edition, II.C.6.2).

Obviousness

13. The skilled person starting from the treatment of sJIA with methotrexate as disclosed in document D25 (representing the closest prior art) and seeking to solve the problem formulated above would have encountered in the same document, a section headed "Future directions" (see page 97) where, in relation to future therapies for sJIA, the following is disclosed: "[...] a vast body of evidence points to prominent IL-6 production as playing a major role in systemic-onset JIA, therefore suggesting that anti-IL-6 therapies may be effective in this disease. The available experimental approaches to the specific neutralisation of IL-6, including a humanised anti-IL-6 receptor antibody and receptor antagonists, are under evaluation in preclinical and clinical settings."

14. Since anti-IL-6 therapy with humanised anti-IL-6 receptor antibody is explicitly mentioned as a potential treatment for sJIA patients, the board considers that the above cited passage provided the skilled person with a direct incentive to consider treating sJIA patients with humanised anti-IL-6 receptor antibody as suggested.

15. The appellant has argued that the skilled person would not have reasonably expected that sJIA could be treated with an antagonist monoclonal antibody against human IL-6 receptor as claimed. A main line of argument in this regard was based on the disclosure in document D14 that the treatment of a 16-year-old female with a 12 year history of severe sJIA, with infliximab (cA2), a chimeric mAb directed against human TNFalpha, did not modify the severity of the arthritis. In the appellant's view, the failure of infliximab to treat sJIA would have adversely affected the skilled person's expectations that therapies based in anti-IL-6 activity would be effective. Although document D14 reported that the sJIA patient treated with infliximab showed a "rapid decrease" in IL-6 levels" with maintenance of the response thereafter, neutralisation of IL-6 did not result in an improvement of sJIA.

16. The results disclosed in document D14 show that, in a single patient, down-regulation of IL-6 by means of an antibody directed to TNFalpha was able to control some of the symptoms of sJIA but did not result in any improvement of joint pain or tenderness. The authors could not explain why the sJIA patient did not respond as well to the therapy as adult rheumatoid arthritis (RA) patients, stating "the reason for this difference is not known, and while any conclusions drawn from a single case must be considered tentative, the data may indicate that TNFalpha is a less important inflammatory mediator in the articular disease of systemic JCA than it is in adult RA. Alternatively, the explanation may lie in matters relating to the dose or scheduling of the cA2. It is noteworthy that even the systemic disease features were controlled for only about 10 days, despite treatment with a relatively high dose of cA2. The patient was catabolic, as evidenced by the significant weight loss she had experienced over the preceding 3 months, and it is possible that the administered cA2 was rapidly degraded as a result of her catabolic state" (see page 592, final two paragraphs).

17. The board cannot agree with appellant's evaluation of the disclosure of document D14. In the board's view, the skilled person reading both the passage in document D25 concerning the potential of anti-IL6 therapies for treating sJIA and taking into account the disclosure of document D14 cited above, would not have been persuaded that anti-TNFalpha therapy was definitively incapable of improving joint pain or tenderness associated with sJIA. The skilled person would have noted that document D14 itself stated that the results reported were regarded as tentative since the study only involved a single patient and because the particular circumstances of that patient might have explained the observed results.

Furthermore, the skilled person would have evaluated the disclosure of document D14 in the context of the disclosure of document D25. The authors of document D25 were aware of and acknowledged the results reported in document D14 (see document D25, page 97, left column, final full paragraph) and nevertheless remained optimistic about the potential of anti IL-6 therapies for treatment specifically of sJIA. Indeed they noted that clinical evaluation of anti-IL-6 therapies, including of a humanised anti-IL-6 receptor antibody, were already under way (see Point 13 above). While the authors of document D25 had a demonstrated interest in the involvement of IL6 in sJIA (see for instance document D16), there is no evidence available to the board that supports the appellant's assertion that the authors of document D25 only mention IL-6 based therapy of sJIA because of personal bias. On weighing the evidence before it, the board concludes that the skilled person, having evaluated both the disclosure of document D14 and the disclosures of those documents leading to the hypothesis that sJIA is an IL-6 mediated disease (see page 96, left column, second paragraph), would have considered that the expectation that therapy of sJIA based on neutralising IL-6 might succeed was reasonable.

18. In another line of argument, the appellant suggested that starting from document D25 as closest prior art and seeking to solve the above formulated technical problem, the skilled person would have been led to etanercept as a solution, this being the entire point of document D25.

19. The board recognises that document D25 is primarily concerned with giving an account of the potential of etanercept for the treatment of JIA. However, the question of whether etanercept, which is not an IL-6 binding antibody, provides an alternative solution to the technical problem is not an issue in considerations of obviousness of the claimed subject-matter. Moreover, the fact that, in an article whose main topic is the efficacy of etanercept in the treatment of JIA, the authors highlighted the potential of anti-IL-6 therapies specifically for sJIA, would in the board's view, have had significant positive impact on the skilled person's expectations with regard to the likely success of such therapies.

20. Similarly, the appellant's arguments relating to the fact that the prior art recognised IL-6 as one of several cytokines elevated in systemic onset JIA patients, but that no cytokine or its elevation had been identified as causing the disease, is not seen by the board as significantly weakening the expectation of success of the skilled person contemplating the claimed anti-IL-6 therapy for sJIA. There is no evidence available to the board that supports the idea that the skilled person needed to know the definitive cause of sJIA before considering potential therapies. Indeed the evidence from document D25 shows that various therapies were under consideration (see point 13.13. , above). Furthermore, the fact that more than one potential solution to the technical problem was available to the skilled person at the relevant date of the application need not necessarily reduce their expectation of success for any particular one of those solutions, especially if, as here, that expectation was based on concrete facts and evidence.

21. The appellant considered that conclusions reached in decision T 385/07 on the issue of expectation of success, should apply equally to the case at hand. At issue in that decision was the question of whether or not the anti-tumour activity of a drug against a certain cancer type established in a clinical trial was predictive of its anti-tumour activity in another cancer type (see Reasons, point 16). The present board cannot see that such considerations apply to the present case where the question to be answered does not concern the extrapolation of the therapeutic activity from one disease type to another, albeit related disease type. On the contrary none of the appellant's arguments succeeds in establishing that there were reasons for the skilled person not to take the pointer in document D25 seriously.

22. In view of the above considerations, the board concludes that the subject-matter of claim 1 lacks inventive step with regard to the disclosure of document D25.