T 1927/22 (PCSK9 inhibitor for reducing Lp(a)/REGENERON) 06-12-2023

Admission of documents D115, D116, D148, D151 (former D148), D154 (former D153)

1. As none of these documents is relevant for the decision it was not necessary to decide on their admission.

Main Request (patent as granted)

Claim construction - claim 1

2. Claim 1 is in the format of a purpose-limited product claim under Article 54(5) EPC which reads: "Paragraphs 2 and 3 shall also not exclude the patentability of any substance or composition referred to in paragraph 4 for any specific use in a method referred to in Article 53(c), provided that such use is not comprised in the state of the art."

3. Opponent 1 argued that the claim was not a purpose-limited product claim under Article 54(5) EPC because "use in reducing lipoprotein(a) (Lp(a)) levels in a patient who exhibits a serum Lp(a) level above 30 mg/dL" was not limited to therapeutic uses, but included non-therapeutic uses. In support of this argument opponent 1 referred to the lack of a clear causal link between the reduction of Lp(a) and the risk of cardiovascular diseases.

4. Whether the claimed subject-matter is a purpose-limited product under Article 54(5) EPC can be determined by asking if the "specific use" defined in the claim also includes non-therapeutic uses.

5. In the present case the question arises whether reducing Lp(a) levels in a patient who exhibits a certain Lp(a) level falls completely under the exclusion of Article 53(c) EPC or whether it also includes uses which are not methods of treatment of the human body by therapy.

6. The board has seen no evidence that reducing Lp(a) levels in patients exhibiting a serum Lp(a) level above 30 mg/dL could represent a non-therapeutic intervention, e.g. for the purpose of performance enhancement, for cosmetic reasons or for life style improvement etc. The submissions of opponent 1 in this regard (see Annex A to its statement of grounds of appeal) relate instead to whether Lp(a) levels in patients are connected with cardiovascular diseases. However, these considerations are irrelevant for the question whether reducing lipoprotein(a) levels in a patient includes non-therapeutic purposes. The patent proprietor has provided ample evidence that elevated Lp(a) levels were generally considered a health risk at the relevant date of the patent (see review articles D11, D61, D63). Also in the documents cited as closest prior art by opponent 1, e.g. documents D22 and D110, the risk of elevated Lp(a) levels is recognised. It is established case law that "therapy" within the meaning of Article 53(c) EPC is not restricted to curing a disease, but also includes alleviating symptoms and reducing risk of occurrence of disease (see Case Law of the Boards of Appeal, 10th edition 2022, I.B.5.5.2). The board, in view of the common general knowledge in the art as reflected in the cited reviews, considers elevated Lp(a) levels a health risk (see abstracts of documents D11, D61 and D63) and that "reducing lipoprotein(a) (Lp(a)) levels in a patient exhibiting a serum Lp(a) level above 30 mg/dL" represents a treatment by therapy excluded by the provisions of Article 53(c) EPC.

7. Therefore, claim 1 of the main request is to be considered a purpose-limited product claim within the meaning of Article 54(5) EPC.

8. The board agrees with opponent 1 that the definition of a patient "who is diagnosed with or identified as being at risk of developing a cardiovascular disease or disorder prior to or at the time of administration of the composition, or who is diagnosed with or identified as being at risk of developing a thrombotic occlusive disease or disorder prior to or at the time of administration of the composition" does not require that these conditions are treated. Indeed, the claim defines the "use" only as "reducing Lp(a) levels" in such a patient. The claim does also not require the reduction of the risk of developing any of the diseases or disorders mentioned.

9. The definition of the patient group by the conditions from which the patient suffers is not limiting because

1) no concrete point in time at which the diagnosis/identification is made is specified ("prior to or at the time of administration", can be any time in the patient's life up-to and including the time of administration)

2) the type of diagnosis/identification is undefined

3) the degree of risk is undefined

4) the type of disorder is defined in such a way as to include a large percentage of the population (cardiovascular disease or disorder, thrombotic occlusive disease or disorder).

Novelty (Article 100(a) EPC and Article 54 EPC)

10. The patient group in the claim is further defined as "exhibiting a serum Lp(a) level above 30 mg/dL". According to the case law the definition of a new subgroup of patients can establish novelty of a second-medical use claim (see Case Law of the Boards of Appeal, 10th edition 2022, I.C.7.2.4 b)). Opponent 1 has not cited any prior art disclosing treatment of a patient having a serum Lp(a) level above 30 mg/dL with an anti-PCSK9 antibody.

11. In the present case, the Lp(a) level of at least 30 mg/dL is a clear and measurable physiological parameter which is functionally related to the pathological status of the patient (see point 6. above).

12. In the context of inventive step, opponent 1 argued that the threshold of 30 mg/dL was arbitrarily selected. The board agrees that there is a certain degree of arbitrariness in parameters for medical treatment. As it is put in the expert declaration D64:

"These types of thresholds are effectively guidelines, set by clinicians, to provide a simple framework for deciding when to give treatment and when not to treat. However, these thresholds are somewhat arbitrary, and based on a risk/benefit (and sometimes cost/benefit) analysis".

13. These considerations do not mean that the threshold is not meaningful and purposive in the sense of the established case law on novelty of further medical use claims conferred by the selection of a patient group. This is confirmed by the statement in document D64 that

"epidemiological studies provided a clear indication that risk of cardiovascular disease was elevated in patients with a plasma Lp(a) level above 30 mg/dL [...] giving a clear scientific rationale for Lp(a)-lowering therapy in such patients. Accordingly, 30 mg/dL is an appropriate threshold for defining the patients to be treated for Lp(a) lowering in the claims".

14. Thus, the choice of the patient group having Lp(a) levels of at least 30 mg/dL, as defined in the claim, is not arbitrary.

15. Reducing lipoprotein(a) (Lp(a)) levels by using anti-PCSK9 antibodies in a patient exhibiting a serum Lp(a) level above 30 mg/dL is not disclosed in the cited prior art, e.g. documents D3 or D23. In particular, none of these documents discloses a reduction of Lp(a) levels nor a patient group having Lp(a) levels of at least 30 mg/dL.

16. These features of claim 1 are also not disclosed in documents D115 and D116, the admission of which was contested by the patent proprietor. Even taking into account those documents, the board's finding on novelty would therefore not change.

17. In view of this, it is not necessary to determine whether reducing Lp(a) levels represents a new clinical situation, as suggested by opponent 1.

18. The subject-matter of claim 1 is novel (Article 54 EPC). The same applies to the subject-matter of dependent claims 2 to 12 which share all features of claim 1.

Admission of new arguments by the patent proprietor (12(4) RPBA)

19. Opponent 1 requested that the patent proprietor's arguments concerning Table 3B in the patent (see reply to the patent proprietor's statement of grounds of appeal, page 2, point 5) not be admitted into the proceedings. The patent proprietor had submitted a series of calculations based upon median percentage lowering over baseline Lp(a) levels and purported common general knowledge about Lp(a) for the first time in appeal. In opponent 1's view, these arguments were an amendment to the patent proprietor's case which was also complex in view of the necessary calculations.

20. The patent proprietor argued that the opposition division, during oral proceedings, had focused on the median values in Table 3B and, based on a wrong interpretation of these values, had come to the conclusion that the invention lacked sufficient disclosure. This had been surprising to the patent proprietor at the time and it had not had time to react appropriately during the oral proceedings. Therefore the respective arguments could only be filed with the statement of grounds of appeal.

21. The opposition division's preliminary opinion set out in its communication dated 5 July 2021 (see sheets 6 and 7), the minutes of the oral proceedings before the opposition division (see sheets 3 and 4) and the decision under appeal (see point 13.2.2) all corroborate the explanation provided by the patent proprietor.

22. According to Article 12(4) RPBA with regard to amendments to a party's case the board shall exercise its discretion in view of, inter alia, the complexity of the amendment, the suitability of the amendment to address the issues which led to the decision under appeal, and the need for procedural economy.

23. The board considers that the patent proprietor's new arguments are straight forward and are based on the common general knowledge of the skilled person for interpreting scientific data. Moreover, they address the issue of sufficiency of disclosure which led to the decision under appeal. They are also not detrimental to procedural economy because they do not introduce new facts, but only interpret the data in the patent. Finally, these arguments represent a timely reaction to the assessment made at the oral proceedings by the opposition division. The patent proprietor could not, at the oral hearing, be expected to respond with calculations and to explain in a substantiated way why the median value in a given group of Table 3B could not be indicative of the overall lowering of Lp(a) and why the opposition division's finding that the patent did not demonstrate Lp(a) lowering from baseline in non-statin-treated patients was wrong in fact. In view of these circumstances, the board admitted the arguments with regard to Table 3B into the appeal proceedings.

Disclosure of the invention(Article 100(b) EPC)

Therapeutic effect of reducing Lp(a) levels

24. In line with the claim construction by the board (see points 6. to 8. above), the objections brought forward by opponent 1 in relation to a missing link between Lp(a) levels and a preventive or therapeutic effect of CVD or TOD, play no role in the assessment of sufficiency of disclosure. The only effect that is a feature of the claim is the reduction of Lp(a) levels in a patient who exhibits a serum Lp(a) level above 30 mg/dL. No evidence was provided that this cannot be achieved.

Effect without statins

25. In its decision, the opposition division held that the invention to which claim 1 related was not disclosed in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art because "Table 3B show [sic] that without statins, Lp(a) levels increase compared to baseline, both in patients receiving placebo and in patients receiving the PCSK9 inhibitor" (see point 13.2.2). Since there was no working example in the patent showing a lowering effect of Lp(a) in patients who do not receive statins it was also not possible to rely on evidence published after the filing date.

26. However, the opposition division appears to have misinterpreted the data in Table 3B. This table reports data from patients with "Diet Only - No Atorvastatin Treatment", i.e. patients who are not treated with statins. It compares a group of 2 patients (N=2) treated with placebo (Pbo) with a group of 8 patients (N=8) treated with 150 mg mAb316P (anti-PCSK9 antibody). In the last four rows of the column relating to Lipoprotein(a) it shows the median and the minimum and maximum Lp(a) levels in mg/dL at baseline and at day 57 for both patient groups. It was common general knowledge that the median refers to the value in a group of values which has the same number of values above and below it. In the case of even numbers of values (here 2 and 8) the median is calculated as the average of the two middle values (i.e. the average of the 1st and 2nd value in the case of placebo and the average of the 4th and the 5th value in the case of mAb316P). The median is not to be confused with the mean or average of all values. The skilled person would understand that in the case of the patient group treated with antibody only, the median value and the values of the patients with the lowest (min) and the highest (max) values are provided, but that the values for the other six patients are not reported. It is also common general knowledge that an increase in the median does not necessarily equate to an increase in the average or mean of the values. The skilled person would thus realise that the slight increase in the median value does not mean that in the six patients not reported, there had necessarily also been an increase in the Lp(a) level between baseline and day 57.

27. A decrease in the compounded Lp(a) levels in the antibody treated group is provided in the table by the value "% change vs Pbo" which is -43.8%. This negative change is not outweighed by the positive % change in the placebo group (change for first patient: 58-47=11, i.e. 19%; change for second patient: 75-63=12, i.e. 37% change; median change: 28%). It is therefore apparent that the overall Lp(a) levels in the antibody only group must have decreased. The only possible explanation for this reduction that the skilled person could draw from the data in Table 3B is that at least some of the six (unreported) patients had a decrease in their Lp(a) levels that led to the reported overall decrease vs placebo. This is confirmed in the patent in paragraphs [0076] and [0081] which equally state that Lp(a) was lowered in patients "on diet alone" and also by the patent proprietor's expert in points 10 and 27 of document D64.

28. Based on the data in the patent alone the board considers it credible that a reduction of Lp(a) levels is also achieved in patients treated with an anti-PCSK9 antibody in the absence of statins. This is not contradicted by later published data in document D2 and associated document D2a (see table S10 and figure S8C).

29. The invention to which the claims relate is therefore sufficiently disclosed (Article 100(b) EPC).

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

Documents D110 or D22 as starting points

30. Document D110 has been chosen by the parties and the opposition division as representing the closest prior art for the subject-matter of claim 1.

31. Document D110 is a short article in a journal addressed to medical practitioners in which an expert in the field of cardiovascular diseases, Prof. K. Parhofer, replies to the question of a physician whether there exist "ways of reducing permanently elevated Lp(a)" (see document D110b, English translation of D110). Document D110 states that "[s]everal of the new lipid-lowering drugs in development (mipomersen, eprotirome, PCSK9-inhibitors, CETP inhibitors, etc.) can lower lipoprotein(a) levels. It is unclear whether and when these drugs will be approved. Likewise unclear is whether therapy with these drugs brings any clinical benefit". From this statement, which is the only reference to PCSK9 inhibitors in document D110, it is unclear whether all of the compounds listed are capable of reducing ("can lower") lipoprotein(a) levels or only some of them. As argued by the patent proprietor, the wording "several of" and the open list ending with "etc." could point the skilled person to the latter interpretation. However, the fact that PCSK9 inhibitors are listed in response to the question posed to the expert at the outset, could, however, also point in the other direction, i.e. that all listed new lipid-lowering drugs including PCSK9 inhibitors are also potential Lp(a) lowering drugs. Document D110 therefore does not clearly and unambiguously disclose an Lp(a) lowering effect of PCSK9 inhibitors.

32. The patent proprietor furthermore refers to document D22, also by the author of document D110, which in Table 3 discloses that the effect of PCSK9 inhibitors on Lp(a) levels was unknown. Opponent 1 refers in the same document to the abstract which states that "some medications in development (mimopersen, eprotirome, Propotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors, Cholesterol-ester-transfer protein (CETP-inhibitors) can decrease elevated lipoprotein(a) concentration". In the view of the board, the sentence in the abstract of document D22, similar to the sentence in document D110 cited above, leaves it open whether all medications in the list or only some of them can decrease elevated lipoprotein(a) concentration. Document D22 concludes that "it is conceivable that PCSK-9 inhibitors, which are currently developed for the treatment of hyperlipidemia may also decrease lipoprotein(a) concentration" (page 874, left-hand column).

33. Neither document D110 nor document D22 shows, e.g. in the form of experimental data, results of clinical trials or a reference to such data, an effect of PCSK9 inhibitors on Lp(a) levels. The wording of both documents in this regard is ambiguous or even contradictory (compare the Abstract and Table 3 of document D22). The board therefore concludes that neither document D22 nor document D110 contain a direct and unambiguous disclosure of an effect of PCSK9 inhibitors on Lp(a) levels. At most they contain a suggestion that this might be the case, as in the statement in document D22 introduced with "it is conceivable".

34. Document D22 was published in a scientific journal and contains data (see Table 3). It specifies the PCSK9 inhibitor as a PCSK9 antibody (see Table 3) and thus discloses a further feature of claim 1. Document D22 is therefore a more promising springboard for analysing inventive step then document D110. The difference between the claimed subject-matter and the disclosure of document D22 is that the PCSK9 antibody achieves the therapeutic effect of reducing lipoprotein(a) levels in patients. The objective technical problem can be formulated as providing a compound that effectively reduces lipoprotein(a) levels in patients with elevated Lp(a) levels.

35. To decide whether the solution to this problem was obvious it has to be asked whether the statement in document D22 that it was "conceivable" that PCSK9 inhibitors could decrease Lp(a) levels would have led the skilled person to test this hypothesis with a reasonable expectation of success (see Case Law of the Boards of Appeal, 10th edition 2022, I.D.7.1). In this regard, the common general knowledge of the skilled person and potential positive or negative indicators in the prior art for the expected success at the relevant date as well as potential difficulties and hurdles when setting out to test the hypothesis are relevant.

36. It is undisputed that it was known that anti-PCSK9 antibodies increase the recycling of LDL-receptor (LDL-R) by binding to their target, PCSK9, which causes an increase of the density of LDL-R on the cell surface. This, in turn, decreases LDL-C which is cleared by LDL-R.

37. The patent proprietor pointed to a number of documents which shed doubts on a similar link between anti-PCSK9 antibodies, LDL-R levels and Lp(a) levels. Document D63, a review article published in 2010, i.e. about a year before the priority date of the patent, states that

"Metabolic pathways for in vivo Lp(a) catabolism are not totally clarified. Catabolism occurs primarily in the liver but mechanisms involved are not well known.**(32,33) LDL receptor does not seem to have a crucial role in Lp(a) metabolism. This affirmation is based on the fact that statin administration (which causes LDL receptor upregulation) does not affect significantly Lp(a) plasma concentration.**(27) Likewise, studies in mice have shown that the LDL receptor, apoE, and the asialoglycoprotein receptor do not participate significantly in Lp(a) catabolism.**(32,34)" (see page 264, right-hand column, last paragraph).

Also document D62, a review article published in October 2010, states that "[i]t is believed that plasma concentrations of Lp(a) are determined chiefly by rates of hepatic synthesis of apolipoprotein(a)" and that "[l]ipoprotein(a) is thought to be catabolized primarily by hepatic and renal pathways, but these metabolic routes do not appear to govern plasma Lp(a) levels" (see page 2849, right hand-column, first full paragraph). Further, the review article D61, published in 2011, states that "evidence of a beneficial clinical effect of statins in the presence of elevation of plasma Lp/a) levels is still limited and heterogeneous" (see page 2, right-hand column, second paragraph) and the review article D11, also published in 2011, points out that "some studies even showed an increase in Lp(a) concentrations in response to statin treatment" while it was known that "statins work by upregulating LDL receptor" (page 686, left-hand column, under the heading "Statins"). None of these scientific reviews mentions PCSK9 inhibitors as potential candidates for reducing Lp(a) levels.

38. Opponent 1 referred to other passages in the documents cited by the patent proprietor (D11, D61, D62) and to further documents (D20, D94, D103, D104, D106) to argue that at least a small reduction of Lp(a) through the known LDL-R increasing effect of PCSK9 antibodies was to be expected by the skilled person.

39. In particular, opponent 1 referred to document D11 which states that "there are 2 possible mechanisms for the statin-associated small Lp(a)-lowering effect. First, there is some evidence suggesting that Lp(a) is partially removed from the circulation via the LDL receptor [78], although the LDL receptor does not seem to play a major role in Lp(a) clearance [79]. Second, approximately 10-25% of Lp(a) is converted to LDL when apo(a) is cleaved off and LDL is then cleared by the LDL receptor." (see page 686, left-hand column, second full paragraph) and that "[t]he mechanism through which eprotirome decreases Lp(a) concentrations may be the upregulation of the LDL receptor" (see page 687, right-hand column, penultimate paragraph). This showed that two other compounds which decreased Lp(a) levels (statins and eprotirome) acted through upregulation of LDL-R, similar to PCSK9 inhibitors. Also documents D20, D94, D103, D104, D106 supported the clearance of Lp(a) through LDLR, e.g. D20, title: "Long term statin treatment reduces lipoprotein(a)"; D94, Abstract: "Lp(a) is specifically bound with high affinity to the same receptors of human fibroblasts as LDL"; D103, Abstract: "this receptor [LDL-R] has the potential to play a major role in clearance of Lp(a) from the circulation of intact humans"; D104, title: "Defects in the low density lipoprotein receptor gene affect lipoprotein (a) levels"; D106, abstract: "mutations in the LDL-R demonstrate a clear gene dosage effect on Lp(a) plasma concentrations").

40. In response, the patent proprietor noted that several of the reports cited by opponent 1 had been published many years before the priority date of the patent (i.e. D20: 2003, D94: 1983; D103: 1990, D104: 1989, D106: 2000) and had been superseded by newer teaching such as that in documents D61, D62 and D63 (see point 37. above). Also the review D11, albeit finding some evidence for involvement of LDL-R in removing Lp(a) from the circulation cautioned that "the LDL receptor does not seem to play a major role in Lp(a) clearance [79]" (see page 686, left-hand column, second full paragraph).

41. Opponent 1 further cited document D4 which, in its opinion, showed a genetic link between a PCSK9 genetic variant and increased Lp(a) levels (see page 5, second paragraph, and Table 4). The board agrees with the patent proprietor that these data are not significant because no gene-dosing effect between the heterozygous and the homozygous mutation was observed and the p-value was rather high (0.051). Moreover and importantly, a possible link between a genetic mutation PCSK9 and the level of Lp(a) is no evidence for the potential Lp(a) decreasing effect of an anti-PCSK9 antibody.

42. Having considered and weighed the evidence brought forward by the parties, the board is persuaded that no clear picture of how Lp(a) levels are regulated in the body and whether LDL-R played a role in this emerges from the skilled person's the common general knowledge at the relevant date of the patent. This is reflected in the review articles published shortly before the priority date. Apart from the isolated suggestions in documents D110 and D22 - which are unsupported by any data and were both authored by the same person - no suggestion in the prior art to use PCSK9 inhibitors has been brought forward. The skilled person would therefore have considered the suggestion in document D22 ("it is conceivable") with care and would have had no reasonable expectation that PCSK9 antibodies could reduce Lp(a) levels in patients.

43. In view of the unclear picture with regard to the metabolism and catabolism of Lp(a) in humans and the lack of clear evidence for an involvement of LDL-R, the board concludes that the skilled person at the relevant date of the patent would have had no reasonable expectation of success that PCSK-9 inhibitors would decrease Lp(a) levels in patients.

44. Moreover, as submitted by the patent proprietor and not contested by opponent 1, at the priority date, anti-PCSK9 antibodies had been tested in patients in a phase 1 clinical trial (see document D1) and a phase 2 clinical trial had just started (see document D23). Regulatory approval for clinical use did not follow until 2015. Testing the effect of anti-PCSK9 antibodies on Lp(a) levels in patients, would have required a new clinical study in humans. Since many model animals do not express Lp(a) (see document D133, page 760, first paragraph) it would not have been straightforward to carry out such a a test in animals. Opponent 1 referred to mouse models, but as noted by the patent proprietor, expression of human apo(a) in mice does not lead to Lp(a) in the plasma of the animals because mouse apoB does not form a complex with human apo(a) (see document D133, ibid.). In the absence of encouraging data in the prior art, the board considers that the use of cynomologus monkeys as models (as in document D3, Example 13) would have been difficult due to the extended ethical review that would have been required before embarking on such work. It is established case law that in such a case the skilled person would usually not adopt a "try and see" attitude, but would need to have a reasonable expectation of success (Case Law of the Boards of Appeal, 10th edition 2022, I.D.7.2, citing decisions T 293/07, T 847/07, T 1545/08 and T 1011/17).

45. Since there is also no other prior art document which suggests using anti-PCSK9 inhibitors to lower Lp(a) levels, the claimed subject-matter is inventive (Article 56 EPC).

Documents D1, D3 or D23 as starting points

46. This conclusion on inventive step is not changed when starting from the disclosure of documents D1, D3 and D23, as suggested by opponent 1. Indeed, none of these documents discloses an effect of PCSK9 inhibitors on Lp(a) levels.

47. Document D1 relates to a phase 1 clinical trial of PCSK9 inhibitors. It reports dose-dependent reductions of LDL-C, no change of HDL-C and no dose-limiting toxicity. Lp(a) is mentioned as one of the pharmacodynamic parameters measured, but no results are reported in this regard. Documents D3 and D23 do not mention Lp(a).

48. Opponent 1 argued that starting from document D3, the objective technical problem could be formulated as providing a new use for PCSK9 inhibitors and that merely by repeating the teaching of document D3 (or D1 or D23) which routinely involved measurement of Lp(a) levels the skilled person would have arrived at the subject-matter claimed.

49. The board does not agree with this conclusion. The skilled person, starting from the disclosure in document D3 and seeking a solution to the above formulated problem, would not have found any indication in that document that PCSK9 inhibitors could lower Lp(a) levels, even taking into account common general knowledge or other disclosures in prior art documents (see points 37. to 41. above). From the disclosure in document D1, which is the only document that mentions Lp(a), the skilled person could have concluded that Lp(a) was one of seven pharmacodynamic parameters measured. An effect of the anti-PCSK9 antibody on other parameters than LDL-C (reduced) and HDL-C (no change) is not reported. Even when setting out to find new uses for PCSK9 inhibitors, as suggested by opponent 1, the skilled person would have had no reasonable expectation that Lp(a) levels would be reduced by PCSK-9 inhibitors or that lowering Lp(a) levels would be beneficial for a particular patient group. Since in document D1 the patients were selected for their LDL-C>100 mg/dL and fasting triglycerides <=200 mg/dL levels, determining if anti-PCSK9 inhibitors lowered Lp(a) levels would have required running a new clinical trial with the appropriate patient groups and controls. Nothing in document D1 or in the remaining prior art suggests to embarking on such a research project. As established in point 44. above, the skilled person was also not in a "try and see" situation.

50. The board concludes that also when starting from documents D1, D3 or D23, the skilled person would not have arrived at the claimed subject-matter.

51. The subject-matter of claim 1 is inventive (Article 56 EPC). The same applies to the subject-matter of dependent claims 2 to 12 which share all features of claim 1.