T 2413/13 (Von Willebrand factor concentrate/GRIFOLS) 04-04-2017

Reasons for the Decision

Main request

Claim construction - claim 1

1. The subject-matter of claim 1 encompasses two embodiments, the first referring to von Willebrand factor (VWF) and the second to a complex of Factor VIII/VWF (see section VIII).

2. The opposition division held that the limitation "which contains VWF in a concentration of up to 12 IU VWF:RCo/ml and a proportion of activities between Von Willebrand Factor/Factor VIII of 0.4 or more" applied only to the feature "(2) a complex of Factor VIII/Von Willebrand" and not to the alternative embodiment of claim 1 referring to VWF (see decision under appeal, page 3, third to fifth paragraph). The board agrees with this claim construction.

3. To the skilled reader of claim 1, the comma after the term "(1) Von Willebrand Factor" and before the wording "or (2) a complex of Factor VIII/Von Willebrand" indicates a separation of the two embodiments, i.e. the first embodiment relating to VWF (hereinafter "the first embodiment") and the second embodiment relating to the FVIII/VWF complex (hereinafter "the second embodiment"). The features "which contains VWF (...)" and "(2) a complex of Factor VIII/Von Willebrand" are not separated by a comma. The word "which" would thus be understood by the skilled person to refer back to the solution containing the FVIII/VWF complex but not to the solution containing VWF.

4. This construction is supported by the skilled person's technical understanding: a defined proportion of activities between VWF and FVIII requires the presence of both VWF and FVIII, since the latter's absence would result in an undefined proportion of activities, i.e. not "0.4 or more".

5. The board was not persuaded by the respondent's argument that the concentration limitation mentioned in claim 1 also had to apply to the first embodiment because too high a concentration of VWF would result in too high a viscosity of the protein solution to be filtered and that, therefore, the opposition division's claim construction was wrong. The fact that the skilled person is free to choose the concentration of the VWF in the solution to be filtered does not mean that he would necessarily choose a concentration which is too high.

6. In the board's judgement, the first embodiment of claim 1 is thus directed to a process for obtaining a concentrate of VWF, characterised by preparation of a solution of VWF and nanofiltration of the solution through a filter having a pore size of 20 nanometers, at a maximum pressure of less than or equal to 0.5 bar, in the presence of calcium ion and at a pH greater than 5.5.

7. The board furthermore notes in this context that it was undisputed between the parties that the first embodiment of claim 1 is directed to a process for nanofiltration, while the intended therapeutic use of VWF to treat von Willebrand Disease (VWD) is not a feature of claim 1.

Inventive step - claim 1

Closest prior art

8. The present invention is for obtaining a concentrate of VWF that can be used for the treatment of VWD (see paragraph [0001] of the patent). The opposition division considered the disclosure in document D8 to be the closest prior art. The parties accepted this finding on appeal for the first embodiment of claim 1, and the board sees no reason to differ.

9. Document D8 concerns the development of a human plasma-derived VWF concentrate that has high specific activity and is safe for the treatment of patients with VWD. It discloses the purification of VWF using filtration through filters with a pore size of 35 nm at a pressure of 200 ± 50 mbar, i.e. less than 0.5 bar, followed by dry heating (see abstract and page 102, left-hand column, first paragraph). Nanofiltration efficiently removed lipid-enveloped and non-enveloped viruses with a diameter larger than 35 nm while dry heating inactivated the hepatitis A virus and reduced the titre of porcine parvovirus, used as a model for human parvovirus B19 (see page 102, right-hand column, first paragraph and table 1). Functional activity of the VWF concentrate was determined by measuring the ability of VWF to bind to platelets and FVIII in vitro (see page 102, left-hand column, second paragraph and page 103, paragraph bridging columns).

Technical problem and its solution

10. The process as defined in the first embodiment of claim 1 differs from the process disclosed in document D8 in that a 20 nm filter is used instead of a 35 nm filter and nanofiltration is carried out in the presence of calcium ions and at a pH of greater than 5.5.

11. The parties were in agreement - and the board sees no reason to differ - that the effect of using a 20 nm pore size filter is that more small non-enveloped viruses are removed from the VWF preparation than by filtration over a 35 nm filter (see paragraph [0001] of the patent in suit). The available prior art confirms that virus filters of 20 nm pore size remove small non-enveloped viruses such as the hepatitis A virus and B19 more effectively than a 35 nm pore size filter (see document D1, abstract, third paragraph and page 123, left-hand column, second paragraph).

12. The respondent did not dispute that, whereas the patent discloses that the FVIII/VWF complex dissociates in the presence of CaCl2 in a concentration greater than 0.02 M (see paragraph [0020]), it is silent on a technical effect associated with the presence of calcium ions during the purification of uncomplexed VWF. Accordingly, the presence of calcium does not have any technical effect in the context of the first embodiment of the claimed invention and thus cannot contribute to an inventive step within the meaning of Article 56 EPC (see Case Law of the Boards of Appeal, 2016, 8th edition, section I.D.9.1.2).

13. Paragraph [0036] of the patent discloses that a pH of greater than 5.5 is required "to prevent denaturation", albeit without specifying whether this concerns denaturation of VWF or of the FVIII/VWF complex. The board notes in this context that the VWF concentrate of document D8 has a high specific activity (see point 9 above), which indicates to the skilled person that it too is not denatured.

14. In view of the above considerations, the problem to be solved by the subject-matter of claim 1 vis-à-vis the disclosure of document D8 can thus be formulated as the provision of a process for obtaining a VWF concentrate having improved (virus) safety over the VWF concentrate disclosed in document D8. The board is satisfied that the problem is solved by the claimed subject-matter.

Obviousness

15. It needs to be established whether or not the skilled person, starting from the teaching in document D8 and faced with the objective technical problem (see point 14), would arrive at the claimed invention in an obvious manner.

16. Document D1 concerns the viral safety of FVIII, i.e. another plasma protein, and reports on the implementation of a nanofilter with a pore size of 20 nm in the manufacturing process to improve the viral safety of the FVIII product CROSS EIGHT M**(®) (see abstract). In virus-spiking tests, filters of 20 nm were found to remove small non-enveloped viruses more effectively than a 35 nm filter. Thus, while large viruses, such as pseudorabies virus and bovine viral diarrhoea virus, were completely removed by both 35 and 20 nm filters, small viruses, such as encephalomyo-carditis virus, porcine parvovirus, the hepatitis A virus and human parvovirus B19, were removed only by the 20 nm filter, which thus markedly improves the viral safety of the FVIII product (see page 123, left-hand column, second paragraph and Table 3).

17. As regards the biochemical properties of FVIII, document D1 reports that "no structural differences between the FVIII obtained after filtration with Planova 35N or Planova 20N" were found (see page 123, left-hand column, third paragraph). Document D1 continues by stating that "furthermore, the contents and multimeric structure of vWF, which forms a complex with FVIII and stabilises FVIII, were investigated using enzyme immunoassays and immunoblotting assays, respectively. As a result, the contents of vWF were similar to those usually found (0.007 - 0.015 U of vWF/U of FVIII:C), and no differences were observed in the multimeric structure (Fig. 4)" (see paragraph bridging the columns on page 123). Figure 4 depicts an immunoblotting analysis of FVIII and VWF after filtration with a 20 nm and a 35 nm filter, respectively (see legend of Figure 4). The importance of this finding is also mentioned as follows in the discussion section of the article: "in particular, it was important that the contents and composition of the vWF multimer were not affected by filtration through a 20-nm filter, because vWF may play a vital role in stabilizing FVIII" (see page 124, right-hand column, last paragraph).

18. Thus, document D1 informs the skilled person not only that removing small non-enveloped viruses by filtration with a filter of a pore size of 20 nm is technically feasible (see point 16) but also that filtration with a filter of 20 nm yields VWF with a preserved multimeric structure (see point 17).

19. The respondent submitted that the skilled person seeking a solution to the objective technical problem would not turn to document D1, which was concerned with concentrates of FVIII, rather than of VWF. Relying on documents D16 and D26, it argued that the product obtained in document D1 was not suitable for treating VWD and also that the conformational changes of VWF mentioned in document D1 would have discouraged the skilled person from using a 20 nm filter to obtain a VWF product that was suitable for treating VWD. Furthermore, based on the disclosure in document D3, it argued that the skilled person would have expected that VWF could not be filtered using a filter smaller than 35 nm.

19.1 The respondent is right in arguing that document D16 states that commercial FVIII concentrates, except those specifically prepared to retain all VWF forms, are of limited efficacy in treating VWD (see page 43, second paragraph) and that, according to document D26, the FVIII product of document D1 is not functional for the treatment of VWD (see Table 3). The board notes, however, that the skilled person would be aware that the process disclosed in document D1 is directed at the purification of FVIII, i.e. not of VWF, and comprises an immuno-affinity chromatography step with an anti-FVIII antibody (see page 120, right-hand column, first paragraph and Figure 1). The skilled person would also know that this purification step leads to a low content in VWF in the FVIII product, thereby rendering it unsuitable for the treatment of VWD.

19.2 In the board's judgement, the fact that document D1 concerns a FVIII product and not a product that can be used to treat VWD would thus not have deterred the skilled person from considering its teaching as regards the removal of small non-enveloped viruses with a 20 nm filter from concentrates of a plasma protein (see point 16). Furthermore, the skilled person interested in VWF would have learned from Figure 4 of document D1 that the multimeric structure of VWF is the same in the 35 nm and the 20 nm filtrate. From document D8 the skilled person would already know that filtration over a 35 nm filter yields a product that is suitable for the treatment of VWD (see point 9). Accordingly, the board considers that the skilled person would have no reason to doubt that filtration over a 20 nm filter also yields a product that is suitable for the treatment of VWD. Finally, there is nothing in document D1 to indicate that the VWF is inactive after filtration through a 20 nm filter.

19.3 In relation to the mention in document D1 of conformational changes which might have made it possible for the FVIII/VWF complex to pass through the 20 nm pore size filter, the board refers to point 17, above, and notes that document D1 is silent on whether or not such conformational changes impair the activity of VWF.

19.4 The board notes that, whereas document D3 discloses that "improvement in purity and low protein concentration have made nanofiltration of VWF solution on 35 nm membranes possible" (page 31, left-hand column, third paragraph), it does not disclose that VWF should only be filtered over a 35 nm filter or that it cannot be filtered over a filter with a smaller pore size, e.g. 20 nm. In any case, at the effective date of the first embodiment of claim 1, the skilled person would also have been aware of the teaching of document D1, which was published about three years after document D3, and thus of the fact that high molecular forms of VWF pass equally well through filters with a pore size of 20 nm as through filters with a pore size of 35 nm.

19.5 The respondent has also referred to document D2, which discloses that filtration over a filter having a pore size of 15 nm leads to a significant reduction in the percentage of the highest-molecular-weight (> 15 mer) VWF multimers (see abstract and page 332, right-hand column, second paragraph). In the board's judgement, however, this disclosure would not deter the skilled person from using a 20 nm filter, i.e. a filter with a larger pore size appearing to be suitable for the filtration of VWF in the light of the teaching of document D1 (see point 18).

19.6 To summarise, the board considers that the disclosure of document D1 would have motivated the skilled person faced with the objective technical problem of providing a process for obtaining a VWF concentrate having an improved virus safety to use a 20 nm filter instead of a 35 nm filter in the nanofiltration of a solution of VWF.

20. As regards the technical features "at a maximum pressure of less than or equal to 0.5 bar, in the presence of calcium ion and at a pH greater than 5.5" (see point 6), the board notes that document D8 discloses that the filtration of VWF was carried out by applying a constant working nitrogen pressure of 200 ± 50 mbar (see page 102, left-hand column, first paragraph), whereas in document D1 it was found that the pressure could be varied between 0.2 and 0.8 kgf/cm**(2)(i.e. between 196 and 784 mbar) without affecting the FVIII yield (see Table 1 and page 123, left-hand column, first paragraph).

21. In the board's judgement, the skilled person aware of these teachings would have considered that a pressure of 200 ± 50 mbar was a suitable option for the filtration of VWF, given that this was the pressure applied in document D8 for the filtration of VWF and that it also fell within the range employed in document D1 for the filtration of an even bigger molecule, the FVIII/VWF complex.

22. The board further considers that, in the absence of any explicit guidance in document D8 as regards the pH of the solution to be filtered, the skilled person would have turned to document D1 for guidance. This document discloses that the solution comprising the FVIII/VWF complex applied to the 20 nm filter contained 40 mM calcium chloride at pH 6.35 (see page 120, right-hand column, first paragraph and Figure 1). By applying these conditions to the VWF solution to be filtered the skilled person would arrive at the claimed process in an obvious manner.

23. In view of the above considerations the board concludes that the subject-matter of the first embodiment of claim 1 lacks inventive step (Article 56 EPC) and that the main request must be rejected.

Auxiliary request I

Inventive step - claim 1

24. One of the differences between the subject-matter of claim 1 of this request and that of claim 1 of the main request is that the process is for the production of a VWF filtrate that is now explicitly defined as suitable for the treatment of VWD (see section VIII).

Closest prior art, technical problem and its solution

25. In the board's judgement, for the subject-matter of this claim 1 too, document D8 is the closest prior art. The problem this subject-matter is designed to solve vis-à-vis the disclosure in that document can be formulated as the provision of a process for obtaining a VWF concentrate with improved (virus) safety that is suitable for the treatment of VWD. The board is satisfied that the problem is solved by the claimed subject-matter.

Obviousness

26. The respondent maintained that the skilled person would not consult document D1 and would have no reasonable expectation that filtration through a 20 nm filter would successfully result in a product that was suitable for the treatment of VWD (see section X).

27. However, in the board's judgement, the skilled person faced with the objective technical problem would have turned to document D1 for the same reasons as set out above in the context of the main request. In brief, document D1 informs the skilled person not only that removing small non-enveloped viruses by filtration with a filter of a pore size of 20 nm is technically feasible (see point 17) but also that filtration over a 20 nm filter yields VWF with the same multimeric structure as filtration over 35 nm filter. The skilled person would consider this product to be suitable for the treatment of VWD (see points 17 and 19.2).

28. Therefore, in the board's judgement, the skilled person would have had no reason to adopt a sceptical attitude. Moreover, to find out whether VWF is indeed suitable for the treatment of VWD after filtration through a 20 nm filter, it suffices to perform well-known, routinely carried-out in vitro tests such as those disclosed in document D8 (see point 9 above). In doing so the skilled person would have had either some expectation of success or, at worst, no particular expectations of any sort but only a try-and-see attitude, which does not, however, equate to an absence of a reasonable expectation of success (see decision T 91/98 of 29 May 2001, reasons, point 8 and decision T 1045/98 of 22 October 2001, reasons, point 17).

29. In view of the above considerations the board concludes that the subject-matter of claim 1 of auxiliary request I lacks inventive step (Article 56 EPC).

Auxiliary request II

Admission into the appeal proceedings

30. This claim request was filed during the oral proceedings, after the board had stated its opinion that the subject-matter of claim 1 of auxiliary request I did not comply with the requirements of Article 56 EPC.

31. Claim 1 of auxiliary request II differs from claim 1 of auxiliary request I in that the first embodiment relating to VWF has been deleted (see section VIII). It amounts to an amendment to the respondent's case and its admission is thus at the board's discretion (Article 13 RPBA).

32. The respondent submitted that the request should be admitted into the appeal proceedings because it addressed an objection discussed during the oral proceedings by limiting the subject-matter of claim 1 to the second embodiment. It conceded that the request had been filed late but argued that the focus of the debate had shifted from the second embodiment of claim 1 to the first embodiment.

33. The board notes, however, that both appellants had raised objections that the first embodiment of claim 1 lacked inventive step, based on a combination of the disclosure in document D8, the closest prior art and document D1, in their statements of grounds of appeal (see section V above). Furthermore, the respondent was already aware prior to the oral proceedings that the board agreed with the construction the opposition division had given claim 1 in the decision under appeal (see section VII).

34. The board concedes that the fact that the debate in the oral proceedings focused on inventive step of the first embodiment of claim 1, present in all claim requests on file prior to the oral proceedings, might, subjectively, have come as a surprise to the respondent. Objectively, however, it does not qualify as an unforeseeable development in the proceedings that would justify admitting amended claims submitted for the first time during the oral proceedings, when the objection thereby addressed has been in the appeal proceedings from the beginning. Moreover, that the board found against the respondent in the oral proceedings does not as such justify admitting a claim request which could - and, when taking the circumstances of the case into account, should - have been filed earlier.

35. The appellants and the board prepared the case on the basis of the claim requests on file prior to the oral proceedings. None of these claim requests was limited to the second embodiment of claim 1.

36. It was also not immediately apparent to the board that the new claim request was clearly and obviously allowable.

37. Given the circumstances of the present case, the board considered that not even the fact that the claim request had been filed in the afternoon of the first of the two days scheduled for oral proceedings, i.e. at a point in time when more than one day was still remaining, could tip the balance in the respondent's favour. As a general rule, oral proceedings are scheduled with the aim of ensuring that a final decision can be taken at the end of the oral proceedings in accordance with Article 15(6) RPBA and, hence, on the assumption that all relevant issues will be addressed at the oral proceedings. In the present case it should be borne in mind that the board started the discussion at the oral proceedings with the topic of inventive step and a number of other issues had not yet been addressed at all, meaning there was a risk that the remaining time might not have been sufficient to terminate the appeal case without infringing the parties' right to fair proceedings.

38. Therefore, the board decided not to admit auxiliary request II into the appeal proceedings because it was late-filed, it could have been filed earlier and admitting the request into the proceedings at this stage would have run counter to the need for procedural economy and to the principle of procedural fairness (Articles 13(1) and (3) RPBA).

Auxiliary requests III to VII

Inventive step - claim 1

39. While claim 1 of each of these requests has been amended with respect to claim 1 of the main request (see section VIII), no argument was submitted by the respondent why any of these amendments rendered the claimed subject-matter inventive over the combination of the teaching of document D8 with the disclosure of document D1.

40. The board considers that the subject-matter of claim 1 of auxiliary requests III to VI relates to, inter alia, the nanofiltration of a solution containing only VWF and thus corresponds to the first embodiment of claim 1 of the main request. Claim 1 of auxiliary request VII additionally requires that the filtrate be suitable for the treatment of VWD.

41. The reasoning set out above for claim 1 of the main request (see points 8 to 23) thus applies mutatis mutandis also to the subject-matter of claim 1 of auxiliary requests III to VI, while the reasoning set out above for claim 1 of auxiliary request I (see points 24 to 29) applies mutatis mutandis to the subject-matter of claim 1 of auxiliary request VII. This has not been contested by the respondent.

42. Therefore, the subject-matter of auxiliary requests III to VII also lacks inventive step (Article 56 EPC).

Conclusion

43. The board concludes that none of the claim requests considered by it meets the requirements of Article 56 EPC. Accordingly, the patent cannot be maintained on the basis of any of these claim requests and, in the absence of any other, allowable claim request in these proceedings, must be revoked.