T 1528/06 (Concentré de fibrinogène/CAF-DCF) of 16.5.2008

Summary of Facts and Submissions

I. European patent No. 0 771 324 was granted with 11 claims on the basis of European patent application No. 95 927 599.1 filed on 14 July 1995 in French language (and published as WO-A-96/02571).

II. Notice of opposition was filed by the opponent requesting the revocation of the European patent on the grounds of Article 100 (a) and (b) EPC. The opposition division maintained the patent on the basis of the claims of the main request then on file.

III. The appellant (opponent) filed an appeal against the decision of the opposition division.

IV. Oral proceedings were held on 16 May 2008. The parties who used the English language in all their submissions in the appeal procedure agreed that the English language also be used during the oral proceedings as well as in the written decision. The board therefore announced that the written reasons would be provided in English. The parties were however reminded that new claims had to be submitted in French. The respondent submitted a new main request (claims 1 to 7), of which independent claims 1 and 7 read as follows.

"1. Procédé d'obtention du concentré de fibrinogène caracterisé en ce qu'il est dépourvu de contaminants viraux, en ce que sa pureté est supérieure à 98%, et en ce qu'il est dépourvu de protéases, caracterisé en ce que l'on soumet une fraction solubilisée de plasma comprenant du fibrinogène à un traitement chimique d'inactivation virale par addition de solvant/détergent, à deux ou plusieurs étapes de précipitation dans une solution comprenant un acide aminé, de préférence la Glycine, et à pH acide, et une ou plusieurs étape(s) de filtration du fibrinogène purifié, de préférence sur filtre de carbone activé."

"7. Composition pharmaceutique, cosmétique ou colle biologique comprenant un concentré de fibrinogène, caracterisé en ce qu'il est dépourvu de contaminants viraux, en ce que sa pureté est supérieure à 98%, et en ce qu'il est dépourvu de protéases."

Dependent claims 2 to 6 related to specific embodiments of the process of claim 1.

V. The following documents are cited in the present decision:

Dl EP-A-0 131 740;

D2 EP-A-0 378 208;

D4 US-A-5,252,709;

D5 US-A-4,295,855;

D6 EP-A-0 555 135;

D7 EP-A-0 099 445.

VI. The submissions by the appellant (opponent), insofar as they are relevant to the present decision, can be summarized as follows:

Admissibility

- The claims of the late filed main request were not clearly allowable having regard to all relevant provisions of the EPC.

Article 83 EPC

- Since the respondent argued that SDS-polyacrylamide gel electrophoresis, as carried out in Example 1 of document D5, was unreliable for measuring the purity of the fibrinogen concentrate, the patent, involving the same unreliable method for measuring purity, was insufficient in contravention of Article 83 EPC.

Novelty of claim 7

- Example 1 of document D5 disclosed a fibrinogen preparation consisting solely of fibrinogen fraction 1 as shown by SDS-polyacrylamide gel electrophoresis. This preparation was also protease free owing to the addition of the protease inhibitor trans-p-aminomethylcyclohexanecarboxylic acid (AMCHA).

- As regards the feature in present claim 7 that the fibrinogen composition had to be virus free (cf. "dépourvu de contaminants viraux"), paragraphs [0007], [0008], [0033], [0079] and [0090] of the patent showed that chemical viral inactivation did not allow to completely eliminate the viral contaminants and that an additional, optional UVC irradiation step (see paragraph [0079]) was necessary to inactivate non enveloped viruses (such as parvoviruses). Therefore, the claimed composition could be no more virus free than that disclosed in Example 1 of document D5.

Inventive step of process claim 1

- The closest prior art was represented by document D5 because it aimed at producing high purity fibrinogen by removing non-clottable proteins (column 1, lines 5 to 10) by using of a precipitation step involving an acidic solution of an amino acid which caused a precipitation of fibrinogen without any substantial co-precipitation of proteins other than fibrinogen (column 3 lines 1 to 13). The precipitation step could be repeated in order to improve purity (column 4, lines 46 to 54). Example 1 on column 12, lines 38 to 64 disclosed the use of two precipitation steps using an acidic solution of an amino acid (glycine) followed by a filtration step to produce a high purity fibrinogen concentrate.

- Therefore, the only difference between the technique described in Example 1 of document D5 and the claimed method lay in the additional solvent/detergent chemical viral inactivation step.

- As stated in paragraph [0021] of the patent, the problem to be solved was the provision of a highly purified fibrinogen concentrate, free from viral contaminants and biological molecules such as proteases.

- The patent did not show that the above problem had actually been solved since it could not be derived from the examples that a concentrate according to the invention ( > 98% purity; free from proteases and virus-free) could indeed be obtained, inter alia because there was a "lack of synergy" in the essential steps of present claim 1; there were mistakes in Example 1; in Example 3, it was stated that the solution could be "treated with UVC rays"; Examples 1 and 3 comprised far more steps than the essential purification steps indicated in claim 1.

- Otherwise, assuming that the examples in the patent showed that a concentrate according to the invention could arrived at, the skilled person wishing to solve the above problem would look for prior art techniques for inactivating viruses. He/she would come across document D1, which disclosed the combined use of a solvent and a detergent to inactivate the viruses present in blood protein containing compositions. It would therefore be an obvious step for the skilled person to use the known solvent/detergent viral inactivation step of D1 in combination with the known purification process of document D5 in order to provide a purified fibrinogen concentrate which meets the requirements of the known problem set out above. Documents D2, D4, D6, D7 were further documents teaching the use of a solvent/detergent to inactivate the viruses present in blood protein containing compositions.

Inventive step of claim 7

- Documents D4, D5 and D6 disclosed the preparation of a fibrinogen concentrate and thus made it available in all grades of purity (see decision T 990/96, OJ EPO 1998, 489).

- Moreover, the method of claim 1 which could be used to prepare the fibrinogen concentrate, was the obvious combination of known purification steps without any unexpected benefit. There was thus nothing inventive in providing a known substance with a higher purity.

VII. The submissions by the respondent (patentee), insofar as they are relevant to the present decision, can be summarized as follows:

Admissibility of the claim request

- The claim set filed at the oral proceedings completely corresponded to the claims of the 8th auxiliary request filed on 16 April 2008, i.e. one month before the oral proceedings before the board, with only minor amendments. These claims no longer comprised former claim 11 to an installation and claims to the fibrinogen concentrate itself. Under these circumstances nothing had changed except that an amendment was necessary to enter into the process claim the definition of the fibrinogen concentrate of former claim 1 which had been deleted.

Article 83 EPC

- The objection under Article 83 EPC raised by the appellant was rather one of lack of clarity.

Novelty of claim 7

- The fibrinogen preparation described in Example 1 of document D5 contained the protease inhibitor AMCHA and it was thus not suitable for use as pharmaceutical/cosmetical composition.

- The examples of document D5 did not show that a fibrinogen concentrate with a purity of more than 98% could be obtained, but merely that fibrinogen with clottability of 92-96% could be prepared (see column 14, lines 18, 34 and 54). However, clottability was the percentage of thrombin-clottable proteins based on total proteins (see col. 2, lines 37-38). Therefore a fibrinogen solution with a clottability of 92-96% had to be interpreted as having a purity of fibrinogen of lower than 92-96%.

- The purity of the fibrinogen concentrate as measured on a SDS-polyacrylamide gel did not correlate with the clottability.

Inventive step of process claim 1

- Examples 1 and 3 of the patent clearly demonstrated that a preparation comprising the virus free and protease free fibrinogen concentrate of more than 98% purity could be obtained when performing the method of claim 1.

- It was not obvious to remove proteases from fibrinogen using a combination of applying a solvent/detergent step on a fibrinogen comprising plasma solubilized fraction with at least two amino acid precipitations, followed by a filtration step. Synergy between the different purification steps was thus present.

Inventive step of claim 7

- The prior art did not make available fibrinogen in all grades of purity.

- It was not obvious to remove proteases from fibrinogen.

VIII. The appellant (opponent) requested that the decision under appeal be set aside and that the European patent No. 0 771 324 be revoked.

The respondent (patentee) requested that the decision under appeal be set aside and that the patent be maintained in amended form on the basis of claims 1 to 7 of the main request submitted at the oral proceedings of 16 May 2008.

Reasons for the Decision

Language of the proceedings

1. The parties used the English language in all their submissions in the appeal procedure and during the oral proceedings (with exception of the claim requests which were submitted in French as the language of the proceedings). They also agreed that the written reasons of the decision be provided in English. This way to proceed is in keeping with decision J 18/90 (OJ EPO 1992, 511; see also decision T 788/91 of 25 November 1994), according to which the board may use in decisions an official language (here: English) other than the language of the proceedings (here: French), provided all the parties to the proceedings give their agreement.

Admissibility of late-filed claims

2. The new main request (claims 1 to 7) has been submitted by the respondent during the oral proceedings. Such a late-filed claim request is according to the established jurisprudence of the Boards of Appeal only admitted if it is clearly allowable having regard to all relevant provisions of the EPC and provided that the circumstances are such that the opponents are not disadvantaged in their right to give proper consideration to the new amendments.

3. In the present case, the claims filed at the oral proceedings correspond to the claims of the 8th auxiliary request filed on 16 April 2008, with only minor amendments. These claims no longer comprise former claim 11 to an installation for the preparation of a fibrinogen concentrate and former claims 1 to 3 to the fibrinogen concentrate itself. In view of these deletions, an amendment was necessary to enter the definition of the fibrinogen concentrate given in former claim 1 into the present process claim 1 and into claim 7. Since the 8th auxiliary request (of which the present claims represent a simpler version) had been filed one month before the oral proceedings before the board and did not give rise to surprising new legal or factual issues, the conclusion cannot be drawn that the appellant is disadvantaged in its right to give proper consideration to the amendments of the respondent's case. Therefore, the board considers this request to be admissible under Article 114(2) EPC and Article 13(1) RPBA.

Article 123(2)(3) EPC

4. The appellant does not raise any objection under this Article against the claims of the main request filed at the oral proceedings and the board also sees none.

Article 83 EPC

5. In the context of the novelty issue, when it comes to the discussion of whether or not the feature "purity higher than 98%" in the claims is able to distinguish over document D5, the respondent notes a contradiction between the statement made in col. 12, lines 62-64 of document D5 ("SDS-polyacrylamide gel electrophoresis showed that it consisted solely of fibrinogen fraction 1") on the one hand, and the clottability of 92-96% referred to in the Examples of document D5, on the other hand (according to col. 2, lines 37-38, clottability is the percentage of thrombin-clottable proteins based on total proteins), suggesting a fibrinogen purity lower than 92-96%. In the light of this inconsistency, the respondent argues that SDS-polyacrylamide gel electrophoresis, as carried out in Example 1 of document D5, is not appropriate for measuring the purity of the fibrinogen concentrate.

6. In response to the above argument, the appellant maintains that, by the same token, the patent in suit is insufficient, since it also relies on SDS-polyacrylamide gel electrophoresis for measuring the purity of the fibrinogen concentrates.

7. The board first observes that the two methods (SDS-polyacrylamide gel electrophoresis versus clottability assay) may lead to divergent results in view of the fact that the clottability measures the quantity of biologically active molecules, whereas SDS-polyacrylamide gel measures denaturated molecules. Therefore, this expected discrepancy does not mean that SDS-polyacrylamide gel electrophoresis is not appropriate for measuring the purity of the fibrinogen concentrates.

Secondly, Table 1 and note "(e)" to this table on page 5 of the patent provide instructions to the skilled person as to how to measure the fibrinogen purity via densitometric analysis of the SDS-PAGE polyacrylamide gels (i.e., the area under the curve relating to the fibrinogen band should represent more than 98% of the total area).

Since there is no evidence before the board showing that the skilled person would be prevented from putting into practice the above instructions, it must be concluded that the patent is not insufficient under Article 83 EPC.

Novelty of claim 7

8. The fibrinogen composition according to claim 7 exhibits a purity higher than 98%, is free from viral contaminants and is free from proteases.

9. The appellant relies on Example 1 of document D5 for questioning the novelty of the claimed composition, arguing that this Example discloses a fibrinogen preparation which i) consists solely of fibrinogen fraction 1 as shown by SDS-polyacrylamide gel electrophoresis (see column 12, lines 62-64); ii) is devoid of protease activity owing to the addition of the protease inhibitor AMCHA and iii) is virus-free.

10. For the sake of argument, the board assumes in the appellant's favour that the composition of Example 1 of document D5 satisfies the requirement "purity higher than 98%" ("pureté supérieure à 98%") in present claim 7.

11. As regards feature (iii) above ("virus-free"), the appellant maintains that the patent relates to cases where the chemical viral inactivation does not allow to completely eliminate the viral contaminants (see in particular paragraph [0079]). However, claim 7 only covers the situation where all the viruses have been completely inactivated, e.g., by an additional UVC irradiation step, in view of the intended pharmaceutical or cosmetical use (see paragraph [0003] of the patent).

12. In the board's judgement, feature (iii) ("virus-free") in present claim 7 cannot be unambiguously derived from document D5. In fact, the appellant himself acknowledged in the Opposition Statement (see page 10) that "D5, however, does not disclose a product which is viral free".

13. Since document D5 already fails on feature (iii) above, the board needs not to decide whether or not the presence of AMCHA in the composition described in Example 1 of document D5 would interfere with the fibrinogen's use as a pharmaceutical/cosmetical composition or as a biological glue.

14. In conclusion, the novelty of the subject-matter of present claim 7 is acknowledged.

Inventive step

Claim 1

Closest prior art

15. The closest prior art is represented by document D5 because it aims at producing high purity fibrinogen by removing non-clottable proteins (see column 1, lines 5 to 10). Example 1 of this document discloses on column 12, lines 38 to 64 the use of two precipitation steps using an acidic solution of an amino acid (glycine) to produce a high purity fibrinogen concentrate. However, this concentrate is not free from proteases since it is explicitly stated in this example that the protease inhibitor AMCHA is added when dialysing the fibrinogen solution for 24h.

Problem to be solved

16. The problem to be solved is the provision of a process for producing a highly purified fibrinogen concentrate, which is free from proteases (and which thus no longer requires the addition of AMCHA) and wherein viral contaminants have been inactivated (see paragraphs [0021] and [0024] of the patent). As regards the feature "free from proteases", it is the board's understanding that the meaning of this expression ("dépourvu de proteases") does not encompass the mere absence of protease activity but it rather means the absence of the corresponding protein bands on the gel (see note "(h)" to Table 1 of the patent and compare with paragraph [0070]).

Has the problem been solved?

17. The appellant argues that the patent does not show that the above problem has actually been solved since it cannot be derived from the examples that a concentrate according to the invention (purity higher than 98%; free from proteases and virus-free) could indeed be obtained. This is because (i) there is a "lack of synergy" in the essential steps of present claim 1; (ii) there are mistakes in Example 1; (iii) it is stated in Example 3 that the solution could be "treated with UVC rays"; and (iv) Examples 1 and 3 comprise far more steps than the essential purifications steps indicated in claim 1.

18. As for the mistakes noted by the appellant (on page 4, glycine is mentioned twice on lines 49 and 51 and on page 5, line 1, there is a filtration on AKS-4-AKS-7 filter which does not make sense), the board is of the opinion that the skilled person will not be misled by the incriminated passages, in view of note (a) to Table 1, summarizing the method described in Example 1.

19. As regards the feature virus-free, a solvent/detergent step is already present as an essential step in the method of claim 1 so that possible virus contaminants may be eliminated. However, additional virus inactivation steps such as heat treatment or UVC irradiation should be seen as an optional step for the method of claim 1.

20. As for the "lack of synergy" in the essential steps of present claim 1 argued by the appellant, a comparison between "Methode I(a)" on the one hand, and "Methode II(b)", "Methode III(c)" or "Methode IV(d)", on the other hand (see Table 1 on page 5 of the patent) shows that it is the performance of at least two amino acid precipitations combined with one or more filtration steps, that renders possible the preparation of a fibrinogen concentrate of more than 98% purity, which is also protease-free. In fact, comparative examples "II(b)" to "IV(d)" demonstrate that amino acid precipitations alone are not able to remove proteases. Therefore, the board disagrees to the appellant's view that there is a "lack of synergy" in the essential steps of present claim 1. This conclusion is in keeping with the board's finding that the process described in Example 1 of document D5, which lacks the final filtration step(s) recited in claim 1, fails to yield a protease-free fibrinogen concentrate (see point 15 supra and point 24 infra).

21. The above comparison also suggests that other steps described in the examples but not listed in claim 1 are optional steps which are not critical for achieving this goal.

22. In conclusion, the board is satisfied that the above problem has been solved.

Is the proposed solution obvious over a combination of D5 with D1, D2, D4, D6 or D7?

23. The appellant maintains that the only difference between the technique described in Example 1 of document D5 and the claimed method lies in the additional solvent/detergent chemical viral inactivation step and that hence it would be obvious for the skilled person to use the known purification process of document D5 in combination with the known solvent/detergent viral inactivation step of D1 (or of any of documents D2, D4, D6 or D7) in order to solve the problem set out above.

24. However, when comparing the process described in Example 1 of document D5 (col. 12, lines 43-44: first precipitation with glycine --> line 44: first recovery by filtration of the precipitate --> lines 44-52: second precipitation with glycine --> line 53: second recovery by filtration of the precipitate --> line 53: "final dissolution") with that described in the patent (see paragraphs [0055] to [0060] and note (a) to Table 1), it becomes apparent that the method according to the invention includes an additional step of filtration performed on the result of the "final dissolution" (see paragraph [0060]), which is, in the understanding of the board, one of the essential features of claim 1 and meant by the term "...et une [ou plusieurs] étape[(s)] de filtration du fibrinogène purifié" (emphasis added). This necessary additional step of filtration is distinct from and should not be confused with any of the "first and second recovery by filtration of the precipitate". As emphasized under point 20 supra, the inclusion of final filtration step(s) is critical for obtaining a protease-free fibrinogen concentrate.

25. Therefore, combining the process described in Example 1 of document D5 with the known solvent/detergent viral inactivation step of D1 (or of documents D2, D4, D6 or D7) would not yield the claimed process, and hence a protease-free fibrinogen concentrate. Therefore, the appellant's line of argument based on the combination of the teaching of document D5 with that of any of documents D1, D2, D4, D6 or D7 for arriving at the method of claim 1 is not convincing.

26. It must be concluded that the method of claim 1 and dependent claims 2 to 6 does not follow from the prior art in an obvious way.

Inventive step of claim 7

27. The appellant argues that documents D4, D5 and D6 disclose the preparation of a fibrinogen concentrate and thus make it available in all grades of purity (see decision T 990/96, supra).

28. The board does not accept that the only possible distinctive feature of the fibrinogen concentrate of claim 7 vis-à-vis the fibrinogen concentrate preparation disclosed in these documents lies in the achievement of a higher degree of purity. The product covered by present claim 7 is indeed a fibrinogen concentrate meeting certain criteria, inter alia that of being devoid of proteases (i.e., absence of protease bands on the SDS gel: see point 16 supra). Therefore, the decisive issue to be answered by the board is whether or not applying the conventional methods for purifying fibrinogen (see documents D4, D5 and D6) pointed out by the appellant would result in fibrinogen concentrate according to present claim 7, being inter alia devoid of proteases. There is no evidence before the board that this is the case.

29. In a different line of argument the appellant maintains that the method of claim 1 which could be used to prepare the fibrinogen concentrate, is the obvious combination of known purification steps without any unexpected benefit and that hence the fibrinogen concentrate resulting from said method lacks an inventive step.

However, this argument must fail in view of the board's conclusion that the method of claim 1 does not follow from the prior art in an obvious way (see point 26 supra).

30. It must be concluded that the subject-matter of claim 7 satisfies the requirements of Article 56 EPC.

ORDER

For these reasons it is decided that:

1. The decision under appeal is set aside.

2. The case is remitted to the department of first instance with the order to maintain the patent on the basis of claims 1 to 7 of the main request submitted at the oral proceedings of 16 May 2008 and of a description to be adapted.