Key points
- D1 is " D1: "The Prednisone-Sparing Effect of Anti-IL-5 Antibody (SB-240563)" details of Clinical Trial NCT00292877"
- " Document D1 describes a phase II clinical trial entitled "The prednisone-sparing effect of anti-IL-5 antibody (SB-240563)". The purpose of the clinical trial is "to determine if the treatment with anti-IL-5 antibody has a prednisone-sparing effect in patients with symptomatic eosinophilic bronchitis (with or without asthma)" (page 1, "Purpose"). '
- " Like the opposition division and the parties, the board considers the disclosure of this phase II clinical trial to constitute an appropriate starting point for assessing whether the claimed subject-matter involves an inventive step. Indeed, it concerns the treatment of patients with the same medical condition (i.e. steroid-dependent EB) using the same substance (i.e. a humanised antibody to IL-5) with the same objective (i.e. a reduction in prednisone administration)."
- " The therapeutic application defined in the claim differs from the disclosure in document D1 in that (i) an effective treatment is not inferable from the document since it does not disclose any results of the clinical trial and (ii) whereas the claim specifies a minimum level of prednisone-sparing effect - 90% - none is specified in the document."
- " t was undisputed that the patent discloses the results of the clinical trial as known from document D1, including a prednisone sparing effect as required by the claim."
- " In the board's view, the disclosure of a clinical trial with the same substance for the treatment of the same medical condition, and having the prednisone-sparing effect as the primary outcome measure of the clinical trial, there being no other distinguishing characteristics of the therapeutic application claimed than the efficacy, provides the skilled person with an expectation of success for the treatment (see also decision T 2506/12, Reasons 3.10 and decision T 239/16, Reasons 6.5). It was therefore obvious for the skilled person to conduct the treatment in document D1 with a reasonable expectation of success, unless the state of the art provided the skilled person with reasons for not pursuing the solution envisaged in the clinical trial or, in other words, unless the state of the art provided the skilled person with an expectation of failure (see also decision T 2506/12, Reasons 3.11 and decision T 239/16, Reasons 6.5, second paragraph)."
- Compare T0108/21: "the board finds that the announcement of the phase III trial in document D10 would have given the skilled person hope of success but not a reasonable expectation of it. A mere hope of success does not suffice as motivation to render the claimed subject-matter obvious. As a consequence, the subject-matter of claim 1 involves an inventive step starting from D10's disclosure of the successful phase II trial with an oral daily dose of 1.25 mg fingolimod." However, inventive step is always fact-specific.
- The Board reviews a number of other documents and then concludes: " In view of the above considerations, the skilled person had no reason to expect that the treatment described in document D1 would not succeed. The solution provided in the claim, specifying the level of reduction in prednisone to be 90%, is a consequence of pursuing the treatment described in document D1, for which the skilled person had a reasonable expectation that a prednisone reduction would be achieved without exacerbations. Therefore, the specific level of reduction of 90% recited in the claim does not play a role in the assessment of what the skilled person would do when faced with the problem formulated above, i.e. the provision of an effective treatment for prednisone-dependent EB with less side effects."
- Claim 1 is held to lack an inventive step.
Main request
Inventive step (Articles 56 and 100(a) EPC) - claim 1
Closest prior art
3. Claimed is a composition comprising a humanised antibody to human IL-5 for use in treating a human suffering from prednisone-dependent eosinophilic bronchitis (EB) (see section X.).
4. Document D1 describes a phase II clinical trial entitled "The prednisone-sparing effect of anti-IL-5 antibody (SB-240563)". The purpose of the clinical trial is "to determine if the treatment with anti-IL-5 antibody has a prednisone-sparing effect in patients with symptomatic eosinophilic bronchitis (with or without asthma)" (page 1, "Purpose"). The primary outcome measure is "the prednisone sparing effect of SB-240563 versus placebo as indicated by the absolute and percentage dose reduction possible without a clinical exacerbation[...]" (page 2, first paragraph). Regarding the condition eosinophilic bronchitis (EB), this document states: "Eosinophilic bronchitis, which is identified by quantitative sputum cell counts (eosinophils greater than 2%) is responsive to corticosteroid treatment. It occurs alone or in association with asthma or in some patients with chronic obstructive pulmonary disease (COPD)".
5. Like the opposition division and the parties, the board considers the disclosure of this phase II clinical trial to constitute an appropriate starting point for assessing whether the claimed subject-matter involves an inventive step. Indeed, it concerns the treatment of patients with the same medical condition (i.e. steroid-dependent EB) using the same substance (i.e. a humanised antibody to IL-5) with the same objective (i.e. a reduction in prednisone administration).
Objective technical problem
6. The therapeutic application defined in the claim differs from the disclosure in document D1 in that (i) an effective treatment is not inferable from the document since it does not disclose any results of the clinical trial and (ii) whereas the claim specifies a minimum level of prednisone-sparing effect - 90% - none is specified in the document. This was not disputed by the parties.
7. It was undisputed that the patent discloses the results of the clinical trial as known from document D1, including a prednisone sparing effect as required by the claim. The technical effect of the above differences is that an effective treatment of prednisone-dependent EB is provided allowing a 90% reduction of prednisone.
8. The objective technical problem may thus be formulated as the provision of an effective treatment of prednisone-dependent EB with reduced side effects.
Obviousness
9. The question of obviousness in the case at hand requires determining whether the state of the art provided the skilled person with a reasonable expectation that an anti-IL-5 antibody would be effective in the treatment of prednisone-dependent EB with less side effects.
10. The opposition division held that when starting from the disclosure in document D1, the skilled person had no reasonable expectation of solving the technical problem by providing a treatment with humanised antibody to IL-5. In their assessment of what the skilled person might have expected, the opposition division took into account documents other than document D1. However, the board holds that in this regard the disclosure in document D1 itself should also be considered.
11. In the board's view, the disclosure of a clinical trial with the same substance for the treatment of the same medical condition, and having the prednisone-sparing effect as the primary outcome measure of the clinical trial, there being no other distinguishing characteristics of the therapeutic application claimed than the efficacy, provides the skilled person with an expectation of success for the treatment (see also decision T 2506/12, Reasons 3.10 and decision T 239/16, Reasons 6.5). It was therefore obvious for the skilled person to conduct the treatment in document D1 with a reasonable expectation of success, unless the state of the art provided the skilled person with reasons for not pursuing the solution envisaged in the clinical trial or, in other words, unless the state of the art provided the skilled person with an expectation of failure (see also decision T 2506/12, Reasons 3.11 and decision T 239/16, Reasons 6.5, second paragraph).
12. For the sake of completeness, the board notes that, contrary to the respondent's assertion, in decision T 239/16 the board in its reasoning did not give any relevance to the phase of the clinical trial. Instead the decision states: "The board considers that the mere fact that an active agent selected from the group of bisphosphonates is being tested in a clinical study for the treatment of osteoporosis (as disclosed in document (55)) leads to an expectation of success, due to the fact that clinical studies are based on data obtained by pre-clinical testing both in vitro and in animals and require authority approval which takes ethical considerations into account." (see Reasons 6.5, second paragraph).
13. It therefore remains to be assessed whether the state of the art provided the skilled person with the expectation that the treatment would fail, as was argued by the respondent.
14. In a first line of argument, the respondent submitted that documents concerning hypereosinophilic syndrome (HES) or asthma treatment were not relevant to assess the skilled person's expectation of treating EB. The conclusions in these documents would not be applicable to EB, being characterised by elevated eosinophil sputum levels.
15. In a second line of argument, the respondent submitted that documents concerning asthma treatment, such as documents D6, D8, D13, D15, D16 and D27, in fact showed that there was a negative expectation regarding a successful treatment based on an antibody to IL-5. The disclosure in documents D13 and D27 was considered particularly relevant in this regard.
16. This line of argument does not seem to be pertinent to the claim at hand because it does not require that the patients suffer from asthma. Effects observed in asthma patients are not necessarily indicative of any effect in EB patients since the role of eosinophils in asthma is not fully elucidated (see, for example, document D6, page 1568, left-hand column, first sentence of last paragraph and document D27, left-hand column, second paragraph, first sentence)). To the contrary, EB is characterised by a level of sputum eosinophils of at least 2% as well as its responsiveness to corticosteroids (see patent application on page 8, lines 14 to 17).
17. The above notwithstanding, an analysis of the cited documents also does not seem to support the respondent's argument.
18. D6 discloses a study aimed at evaluating the safety, biological activity and pharmacokinetics of an antibody to IL-5 in the treatment of patients with severe persistent asthma. As part of the assessment of biological activity, circulating and sputum eosinophils levels were determined (abstract). The effect of the treatment on sputum eosinophil levels was not consistent. However, a decrease in sputum eosinophil levels was observed in three out of four patients with elevated sputum eosinophil levels (see page 1656, right-hand column, first full paragraph). The authors conclude that treatment with the antibody is safe. As concerns its therapeutic potential, they refer to the need for specifically designed efficacy trials (see abstract). As argued by the respondent, document D6 discloses that no improvement was observed in the treatment of severe asthma (see document D6, page 1658, first full paragraph). In this same paragraph, the authors indicate as possible reasons for this lack of efficacy that (i) the study was designed as a safety study and not powered to detect clinical efficacy and (ii) the dose and dosing frequency might have led to an insufficient reduction of eosinophils. Nevertheless, in this context they also state "[...] the pathogenesis of severe persistent asthma shows considerable heterogeneity. It has been suggested that within the severe asthma phenotype, distinction can be made between an eosinophil-driven subgroup and a neutrophil-driven subgroup [...] The patients included in this study were not selected for eosinophils in sputum or blood". In conclusion, according to the authors of document D6, the absence of positive results on efficacy could be explained by factors other than the target of the therapy, i.e. IL-5. Moreover, the eosinophil level is also advanced as a characteristic possibly relevant to the efficacy. The board can thus not derive from the disclosure in document D6 that an antibody to IL-5 would not be suitable for the treatment of EB.
19. Document D15 is concerned with allergic asthma. Treatment with an antibody to IL-5 resulted in a decrease in blood and sputum eosinophils. The role of eosinophils in the late asthmatic response is questioned because the treatment did not provide medical benefit upon allergen challenge (abstract and discussion, first full paragraph, line 4). Document D16 elaborates on the study reported in document D15. It concludes that there were "no significant changes in clinical measures of asthma" (see abstract, lines 16 to 28). This result is attributed to less of a reduction in airway eosinophil level than achieved with oral corticosteroids. The authors suggest larger studies to assess the efficacy at the level of patient subgroups differing in the level of airway obstruction or tissue eosinophilia (see page 201, left-hand column, third paragraph and paragraph bridging pages 201 and 202). From this disclosure, the board cannot derive an expectation that a treatment of EB, which is characterised by elevated eosinophil sputum levels, would not be successful.
20. Document D8 merely reviews studies such as those disclosed in documents D15 and D13 so that it does not add to the above conclusions on the assessment of the skilled person's expectation of success.
21. Document D13 concerns the treatment of asthma patients with persistent symptoms despite inhaled corticosteroid therapy. According to the authors of this article, no clinical benefit was demonstrated with treatment with an antibody to IL-5 despite significant reductions in blood and sputum levels (see abstract and page 1067, paragraph bridging the two columns). The authors note that the reason for different responses in tissue eosinophils with different diseases is not known, and they suggest further studies to determine whether the therapy would be useful in patient subgroups, namely those with persistent airway eosinophilia: "this study does not exclude that specific targeting of those with persistent eosinophilic disease might identify those likely to respond to anti-IL-5, although further studies would be required to clarify this point" (see page 1068, last paragraph and page 1069, last paragraph). Document D27 summarises studies on asthma Il-5 antibody therapies, including a review of the disclosure in document D13. It notes the results as discussed above but nevertheless concludes with the following outlook: "Anti-IL-5 has proven to be useful in managing hypereosinophilic syndrome (12, 13) and may also be shown to be beneficial in clinical trials in patients with asthma with airway eosinophilia associated with poor control, when corticosteroids are reduced. The results of these trials, which are underway, are eagerly awaited, because they have implications not only for the possible role of anti-IL-5 as a therapy for asthma but also in clarifying the role of airway eosinophils in its pathobiology." (see last paragraph).
22. Thus, documents D13 and D27 do not address the treatment of EB. Furthermore, concerning the treatment of asthma, they emphasise that the subgroup of patients with elevated levels of eosinophils may benefit from treatment.
23. In view of the above considerations, the skilled person had no reason to expect that the treatment described in document D1 would not succeed. The solution provided in the claim, specifying the level of reduction in prednisone to be 90%, is a consequence of pursuing the treatment described in document D1, for which the skilled person had a reasonable expectation that a prednisone reduction would be achieved without exacerbations. Therefore, the specific level of reduction of 90% recited in the claim does not play a role in the assessment of what the skilled person would do when faced with the problem formulated above, i.e. the provision of an effective treatment for prednisone-dependent EB with less side effects.
24. In view of the above considerations, the subject-matter of claim 1 is obvious to the skilled person and thus lacks an inventive step.
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