T 1343/19 (Low frequency glatiramer acetate therapy/YEDA) 10-09-2020

1. The appeals comply with Articles 106 to 108 and

Rule 99 EPC and are admissible.

Respondent's request for transmission of the oral proceedings via phone or equivalent means to those unable to travel

2. The oral proceedings in the current case were scheduled to take place in the physical presence of the parties and the public, having regard to general travel restrictions including obligations to self-isolate being absent and not to be expected around the date of the oral proceedings.

When the board decided on the respondent's request for video or audio transmission of the oral proceedings, it was not foreseen that, where oral proceedings took place in the physical presence of the parties, persons, be it persons accompanying one of the parties or members of the public, could attend other than in person, for example, by electronic means, regardless of whether transmission by such means was officially or "privately" organised (see the communication of the Boards of Appeal dated 29 July 2020, published on the web section of the Boards of Appeal). The board did not consider it appropriate, nor necessary, to deviate from the publicly announced measures for the conduct of oral proceedings before the boards in this case.

When taking the decision about the respondent's request, the board also considered that the parties would be duly represented by professional representatives at the oral proceedings and that if a representative attending the oral proceedings considered it necessary to seek information or instructions from a person unable to attend, they could always request, during the oral proceedings, a short break for such purposes.

3. Therefore, the respondent's request was rejected.

Introduction

4. The invention concerns a low frequency dosage regimen of GA for treating patients suffering from RRMS, a particular form of MS. MS is a chronic disease of the central nervous system, and patients require treatment on a long-term basis. Patients suffering from RRMS, one of the five main forms of MS, experience sporadic exacerbations or relapses, as well as periods of remission.

5. GA, a mixture of polypeptides, is also referred to in the art as Copolymer 1 or Copaxone**(®). Before the priority date of the patent in suit, GA 20 mg QD was the recommended dosage regimen of GA for the treatment of patients with RRMS. GA is self-administered by SC injection.

Main (sole) request - claim 1

6. The set of claims of this request is identical to the set of claims of the main request in the proceedings before the opposition division. The opposition division held that this request met the requirements of the EPC (see section VI. above).

Claim construction

7. The claim is drafted as a second medical use claim pursuant to Article 54(5) EPC and is directed to a

GA 40 mg TIW dosage regimen administered by SC injection for treating a patient suffering from RRMS or who has experienced a first clinical episode and is at high risk of developing clinically definite MS, with the pharmaceutical composition further comprising mannitol.

8. Thus, one embodiment of claim 1 is the use of a

GA 40 mg TIW dosage regimen for treating a patient suffering from RRMS in which the pharmaceutical composition further comprises mannitol. This is the embodiment considered in this decision.

9. In view of paragraph [0016] of the patent and in line with the decision under appeal (see points 3.1 and 4.1) and the respondent's arguments on appeal, the board considers that the term "treating" in claim 1 is to be understood to mean "alleviating a symptom" of RRMS but not to mean "curative treatment". The claimed therapeutic effect is thus the alleviation of a symptom of RRMS in a patient suffering from RRMS.

10. The board agrees with the respondent that the person skilled in the art can be taken as being a team comprising at least a physician involved in the diagnosis and treatment of patients suffering from or suspected to be suffering from MS and a statistician with experience in planning and interpreting clinical trials.

11. The board also agrees with the respondent that the skilled person would have understood the claim to relate to a continuous treatment because RRMS is a chronic condition demanding continuous therapy.

Inventive step (Article 56 EPC)

Purpose of the claimed invention and possible starting points for the assessment of inventive step

12. The opposition division held that the conventional GA 20 mg QD dosage regimen as described in

documents D19/D19a represented the closest prior art, while the GA 40 mg QOD dosage regimen disclosed in document D1 was considered not to be a "realistic" starting point for the assessment of inventive step.

13. The appellants maintained that the GA 40 mg QOD dosage regimen disclosed in document D1 was, in accordance with the relevant case law of the boards of appeal, a "possible" starting point for the assessment of inventive step in accordance with the problem and solution approach.

14. The first question in this case is thus whether the disclosure of the GA 40 mg QOD dosage regimen in document D1 is a possible starting point or, in the words of the opposition division, a "realistic"

starting point for the assessment of inventive step pursuant to the problem and solution approach.

15. In accordance with the established case law of the boards, the closest prior art for assessing inventive step is normally a prior art disclosing subject-matter conceived for the same purpose or having the same objective as the claimed invention and having the most relevant technical features in common, i.e. requiring the minimum of structural modifications (see also Case Law of the Boards of Appeal of the European Patent Office, "CLBA", 9th edition 2019, section I.D.3.1).

16. Thus, the primary consideration for the selection of the closest prior art is that it has the same purpose or objective as the claimed invention. A disclosure can be considered a "realistic" or "possible" starting point (hereinafter "possible") if it aims at the same purpose or objective as the claimed invention.

17. The purpose or objective of a purpose-limited product claim under Article 54(5) EPC is, generally, the therapeutic indication recited in the claim. In the case at hand, this is the treatment of RRMS, i.e. alleviating a symptom of it (see points 7. and 9. above). This is the purpose of the claimed invention.

18. In the decision under appeal, the opposition division held that the patent explicitly taught that the GA 40 mg TIW dosage regime "maintains efficacy and increases tolerability" with respect to the conventional GA 20 mg QD dosage regimen. The opposition division further noted that the patent provided a protocol for a clinical trial but no results. However, in view of "reports concerning reduced side effects from 20 mg GA at reduced administration frequency in the prior art (D2-D5, D55, D59)", the reduction of side effects from the TIW administration in the patent could, according to the opposition division, "not be qualified as prima facie implausible". Accordingly, the "optimization of the tolerability of treatment" was taken into account for the determination of the closest prior art.

The opposition division noted that the GA 40 mg QD dosage regimen exemplified in document D1 was found in later studies to be accompanied by increased adverse reactions (i.e. it was less tolerable) while not having an improved efficacy.

It was on the basis of these considerations that the opposition division concluded that the GA 40 mg QOD dosage regimen described in document D1 was not a "realistic" starting point for the development of a dosage regimen aimed at optimising tolerance of treatment (see decision under appeal, points 6.1

to 6.3).

19. It is evident from the preceding point that the opposition division based the selection of the closest prior art on the effect stated in the patent as being achieved in the light of the starting point described in the patent, the GA 20 mg QD dosage regimen.

20. However, as stated above in point 16., the purpose to be used for selecting the possible starting point is that of the claimed invention. While the description is sometimes resorted to for determining the purpose of claimed compounds, this is not necessary when the purpose is stated in the claim, as in the case of purpose-limited product claims under Article 54(5) EPC.

21. Hence, in the current circumstances, the purpose to be used for selecting the closest prior art, as established by the case law of the boards in the context of the problem and solution approach, is the one stated in the claim.

22. Turning to the question of which prior art disclosures fulfil the criterion of having the same purpose as the claimed invention, i.e. which are for use in the treatment of RRMS, the board agrees with the appellants that these are any GA dosage regimens disclosed in the prior art for use in the treatment of RRMS. Any of these can be considered to represent a possible starting point for the assessment of inventive step (see point 16. above).

23. While the GA 20 mg QD dosage regimen was the recommended dosage regimen before the effective date of the patent in suit, various other GA dosage regimens using higher doses or lower frequencies had been proposed or tested in the prior art, as described in the following points.

24. Thus, in document D1, the safety and efficacy of a

GA 40 mg QD dosage regimen in RRMS patients was compared to that of a GA 20 mg QD dosage regimen (see Example 1). Based on the data after 9 months, it is concluded that "The increased efficacy observed with 40 mg/day GA in reducing MRI-measured disease activity and relapse rate indicates that it is well tolerated and can improve the treatment of RRMS patients. The improvement in efficacy, however, is not accompanied by a corresponding increase of adverse reactions which would be expected upon doubling of the administered dose" (see page 19, last paragraph).

Document D1 also discloses the use of the higher dose,

40 mg, at a lower frequency, every other day, i.e. a

GA 40 mg QOD dosage regimen, for alleviating a symptom in a patient suffering from RRMS wherein GA is administered to the patients by subcutaneous injection in a composition which also comprises mannitol (see page 8, lines 1 to 13, and claims 1 to 4).

25. In documents D2, D3, D4 and D5, the GA 20 mg QD dosage regimen was compared with a dosage regimen using the same dose at a lower frequency, a GA 20 mg QOD dosage regimen, in RRMS patients. Despite the limitations of these open-label studies (in documents D2 and D3) or "rater-blinded" studies (in documents D3 and D4), of which the authors are aware (see document D2, abstract), the authors conclude that the studies suggest that the two compared dosage regimens are equally effective in RRMS (see the abstracts of documents D2, D3, D4 and D5).

26. Documents D19 (abstract) and D19a (slides), collectively referred to as document D19, provide results from the FORTE clinical trial, a phase III, randomised, double-blind study with RRMS patients comparing the GA 20 mg QD dosage regimen with a dosage regimen using a higher dose at the same frequency, the GA 40 mg QD dosage regimen. The authors note that the GA 40 mg QD dosage regimen has a "[g]ood safety and tolerability profile" and that "no unexpected adverse effect with the higher dose" was observed (see slide 26). Only marginally differences in "Serious Adverse Events", namely 4.3% for GA 20 mg versus 4.2% for

GA 40 mg, and "Injection Site Reactions", namely 55.6% for GA 20 mg versus 58% for GA 40 mg, were reported (see slide 25). The authors conclude that in RRMS patients, both dosage regimens were "safe and well tolerated, and were equally effective in reducing

clinical relapses and MRI activity" (see document D19, abstract).

27. A further, secondary, criterion in establishing the closest prior art for the assessment of inventive step among the possible starting points is the similarity of the most relevant technical features between the selected prior art and the claimed invention (see point 15. above).

28. As set out in points 23. to 26. above, various GA dosage regimens had been disclosed in the prior art for use in the treatment of RRMS. The GA 40 mg QOD dosage regimen disclosed in document D1, advanced by the appellants as representing the closest prior art, uses the same dose as the claimed dosage regimen. Like the claimed dosage regimen, it uses less than daily administration, i.e. a reduced frequency of administration. It thus represents a starting point which shares the same purpose as the claimed invention and also has technical features - in terms of dose and frequency of administration - most similar to the claimed dosage regimen. Other dosage regimens disclosed in the prior art addressing the same purpose, including the GA 20 mg QD dosage regimen disclosed in

document D19 and advanced by the respondent as closest prior art, have technical features which are less similar to those of the claimed invention.

29. While there is no disclosure in document D1 that the GA 40 mg QOD dosage regimen had actually been tested, the board has not seen evidence that the skilled person would have had concerns that this regimen would not have been suitable for the treatment of RRMS.

On the contrary, the efficacy of low frequency administration of GA in patients suffering from RRMS had been established in the art before the priority date of the patent in suit (see documents D2 to D5 and point 25. above). Indeed, the respondent held that "the evidence of some level of continued efficacy when attempting 20 QOD and expectation of improved tolerability when decreasing frequency (see D2 and D3)" would have belonged to the "general knowledge of GA" of the skilled person when reading the patent in suit. Of course, the skilled person's common general knowledge would have been the same when reading the patent in suit and when reading document D1 at the day before the effective date of the claimed invention (see also CLBA, section I.D.3.1).

30. The board concludes from the above that document D1 and its disclosure of the GA 40 mg QOD dosage regimen is a possible starting point for the assessment of inventive step in accordance with the problem and solution approach, and is in fact the closest prior art.

31. The respondent's main line of argument in support of choosing a different starting point for the assessment of inventive step may be summarised as follows. The "purpose" of the invention was, according to the patent, to improve the tolerability of GA compared to the GA 20 mg QD dosage regimen. Since the objective "purpose and effect" of the disclosure of document D1 was to increase the dose of GA to improve efficacy, it failed the initial test of being directed to the same purpose as the invention.

32. This line of argument fails because the purpose of the claimed invention is the treatment of RRMS (see point 17. above), and the GA 40 mg QOD dosage regimen disclosed in document D1 is used for this purpose (see point 24. above).

33. In a further line of argument, the respondent held that the "untested" GA 40 mg QOD dosage regimen of

document D1 failed the test of being a possible starting point in the light of the subsequently published "failure" of document D1's exemplified

GA 40 mg QD dosage regimen.

34. The board agrees with the respondent that the skilled person's view on the day before the effective date of the claimed invention (see also above, point 29.) is relevant for determining the disclosure content of the prior art for evaluating inventive step. With respect to the GA 40 mg QD dosage regimen, it was known on that date that "]t]he 40mg dose did not demonstrate increased efficacy in reducing relapse rate; however, the higher dose maintained the favorable safety and tolerability profile of COPAXONE**(®) 20mg" (see

document D8, page 1, first paragraph).

35. The clinical trial data relating to the

GA 40 mg QD dosage regimen available before the effective date of the claimed invention (see point 34. above) thus merely showed that it failed to meet the primary end point of "improved efficacy". This was contrary to what the initial results reported in document D1 suggested. The GA 40 mg QD dosage regimen did, however, have similar efficacy to the GA 20 mg QD dosage regimen and the same favourable safety and tolerability profile (see also document D19 and point 24. above).

36. The board can therefore see no reason why this knowledge about the GA 40 mg QD dosage regimen would have deterred the skilled person from considering the

GA 40 mg QOD dosage regimen as a possible starting

point for finding a dosage regimen effective in the treatment of RRMS.

37. In a yet further line of argument, the respondent submitted that real-world circumstances had to be taken into account for choosing the proper starting point for the problem and solution approach and that these real-world circumstances were that GA 20 mg QD remained "the optimal treatment dose" of GA at the priority date.

38. This line of argument is not found persuasive either. The "optimal dose" of GA was, in fact, unknown at the priority date, and there was considerable interest in alternate dosing regimens of GA in RRMS in the field. The skilled person would have been aware of this (see document D4, abstract, lines 1 to 4; document D5, abstract, lines 3 to 5; and points 24. to 26. above).

39. Finally, again with respect to the respondent's position that the GA 20 mg QD dosage regimen disclosed in document D19 was the closest prior art, the board observes that while it may seem convenient to assess inventive step according to a single problem and solution approach starting from one disclosure, there is no reason to limit the assessment to one starting point. Pursuant to Article 56 EPC, the claimed invention must not be obvious to the person skilled in the art having regard to any prior art, subject to Article 56, second sentence, EPC. Accordingly, the claimed subject-matter lacks an inventive step if it is found to be obvious as a result of one of these approaches. In the case at issue, the claimed subject-matter is found to lack an inventive step when starting from the GA 40 mg QOD dosage regimen disclosed in document D1 (see point 60. below). Hence, there is no need to consider other starting points, such as the GA 20 mg QD dosage regimen, before concluding that an inventive step is lacking.

Difference and its effect(s)

40. The parties were in agreement that the sole difference between the claimed subject-matter and the GA 40 mg QOD dosage regimen disclosed in document D1 was the lower frequency of administration, namely three times a week versus every other day. In practice, this difference amounts to one injection less of GA every two weeks.

41. As regards the effect(s) linked to this difference, the respondent did not dispute that there was no evidence on file comparing the two dosage regimens directly with regard to any effect.

42. The respondent pointed to post-published evidence in the form of the GLACIER clinical trial (see

documents D28, D29 and D30) comparing the claimed regimen with the approved GA 20 mg QD dosage regimen. They argued that the improvement of the claimed regimen over this regimen, as demonstrated by the clinical trial, should be taken into account for the formulation of the objective technical problem to honour the achievement of the inventors.

43. Leaving aside the question whether post-published evidence can be used as the only evidence for proving an effect of the claimed subject-matter with regard to the prior art used as the starting point for the assessment of inventive step according to the problem and solution approach, it is the established case law of the boards in the context of the problem and solution approach that the only effects taken into account for the formulation of the problem are those demonstrated to be caused by features by which the claimed invention and the prior art, which is used as the starting point in accordance with the problem and solution approach, differ (see also CLBA, section I.D.2). Hence, since the current analysis starts with the dosage regimen of GA 40 mg QOD, evidence comparing the claimed dosage regimen with regimens other than this dosage regimen is not relevant.

44. The effect of improving the tolerability of the treatment is an effect envisaged in the patent - yet with regard to the GA 20 mg QD dosing regimen. This effect cannot be acknowledged with regard to the prior art dosage regimen taken as the starting point for the assessment of inventive step here in the absence of any evidence to that effect.

45. As pointed out by the appellants, the claimed dosage regimen and the GA 40 mg QOD dosage regimen can be considered to be materially identical (see

document D73, page 397, lines 7 to 17; and

document D84, paragraph 33).

Objective technical problem to be solved

46. Therefore, based on the GA 40 mg QOD dosage regimen as a starting point and the effects of the differing features as defined in point 40. above, the board agrees with the appellants that the objective technical problem to be solved by the claimed subject-matter is the provision of an alternative GA dosage regimen for administration to RRMS patients.

Obviousness of the claimed solution

47. It was commonly known that RRMS is a chronic disease which requires long-term therapy (see also point 11. above) and that patient compliance is one of the most challenging issues in treating patients with chronic diseases (see document D38, a review article, abstract, lines 1 to 3). Indeed, it is evident from

document D39 (see page 1, first paragraph) that long-term adherence to disease-modifying therapy - the benefit of which is not immediately apparent in terms of perceived improvement of health state - was known to be a challenge for patients with MS.

48. It was also well known in the art that SC injection of GA is uncomfortable (see document D34, page 121, last paragraph), challenging for long-term patient compliance (see document D4, abstract, lines 1 to 4) and associated with injection-related adverse events such as ISRs (see document D19, slide 25).

49. It was also generally known that reducing the number of injections may have a more pronounced effect on compliance than, for example, reducing the number of pills a patient needs to take (see document D38, page 188, left-hand column, last two lines of the first paragraph).

50. In the board's view, it is an evident consequence of lowering the frequency of injections that the frequency of injection-associated adverse events such as ISRs and the patient's discomfort caused by having to inject the drug will be lowered as well (see also document D34, page 121, last paragraph).

51. In the board's judgement, the skilled person, when faced with the objective technical problem formulated above, would thus have been motivated to modify the

GA 40 mg QOD dosage regimen by reducing the frequency of administration in the expectation of improving patient compliance and discomfort.

52. The board considers that the skilled person would have been familiar with other medicines available for the treatment of RRMS at the priority date and their dosage regimens and would have taken these dosage regimens into account, especially those with a reduced frequency of administration, for solving the problem.

53. Thus, one such dosage regimen the person skilled in the field of RRMS would have been familiar with is the dosage regimen for SC administration of interferon beta-1a (Rebif**(®)) to RRMS patients, namely three times per week, preferably on the same three days each week (see document D45, page 2; and document D50, abstract).

54. In the board's opinion, the skilled person would have realised that such an administration scheme was simple and easy to adhere to and thus likely to increase patient compliance also for this reason.

55. The skilled person would also have had reasons to expect that a GA 40 mg TIW regimen was efficacious because, first, the weekly amount of GA administered would only have been slightly reduced in comparison to a 40 mg QOD regimen. Second, the skilled person would have been aware that the 20 mg QOD dosage regimen - having an even lower cumulative weekly dose - was efficacious (see point 29. above).

56. The respondent's criticism that the documents relied upon by the appellants as evidence that the skilled person would have been motivated to change the frequency of administration from QOD to TIW were extremely general and unrelated to GA is not tenable. With the exception of document D38, a review article relating to the impact of dose frequency on compliance and health outcomes, all the other documents relied on by the appellants relate to the treatment of MS or RRMS with GA or other disease-modifying therapies, such as Rebif**(®).

57. With respect to the alleged absence of a "pointer" to the TIW dosage regimen, the board notes that the skilled person would have been aiming at providing an alternative GA dosage regimen for administration to RRMS patients. In these circumstances, any suitable dosage regimen would have been an equally obvious solution to the problem and, therefore, choosing one of these would have been obvious, too. Nevertheless, in the case at hand, the board considers that the skilled person would have indeed had good reasons to select the TIW regimen (see point 54. above).

58. The respondent's line of argument that no connection between frequency of administration and patient compliance could be made based on documents D51 and D66 is also not persuasive. In document D66, four different dosage regimens involving four different drugs were compared with regard to injection frequency and number of missed injections (see page 573, left-hand column, second full paragraph). In the board's view, no conclusions can be drawn from this comparison for altering the frequency of administration of the same drug and patient compliance. Similar considerations apply to document D51, which compared discontinuation rates for four different drugs and not discontinuation rates for the same drug administered with different frequencies (see Figure 1).

59. The respondent's argument as to an element of surprise in the claimed regimen over the GA 20 mg QD dosing regimen cannot succeed as it runs counter the problem and solution approach as set out above. The closest prior art is the GA 40 mg QOD dosage regimen, and no technical effect achieved over it had been demonstrated (see points 41. to 44. above).

60. The board concludes that the skilled person faced with the objective technical problem of providing an alternative GA dosage regimen for administration to RRMS patients would have replaced the QOD administration scheme of the GA 40 mg QOD dosage regimen with a TIW administration scheme and would thus have arrived in an obvious manner at an embodiment of claim 1.

Conclusion

61. The main (sole) claim request in the appeal proceedings does not meet the requirements of Article 56 EPC. Accordingly, the patent cannot be maintained in amended form on the basis of this request and, in the absence of another, allowable claim request, the patent has to be revoked.