T 0218/97 (t-PA deletion mutants/GENENTECH) 06-11-2001

I. European Patent EP 0 365 597 has been granted on the basis of 33 claims, claims 1 to 4, 8, 11, 21, 25 and 33 of which read:

"1. The use of an amino acid deletion variant human t-PA protein in the preparation of a medicament for the treatment of vascular disease in a patient for which t-PA plasma half-life longer than that exhibited by natural t-PA and/or clearance rates less than the clearance rate exhibited by natural t-PA is advantageous, wherein said deletion variant provides human t-PA protein exhibiting plasma half-life longer than that exhibited by natural t-PA and/or clearance rates less than the clearance rate exhibited by natural t-PA protein."

"2. The use of a variant t-PA of claim 1, such longer half-life and/or lower clearance rate resulting from a deletion which comprises at least a portion of the finger or Kringle 1 domain."

"3. The use of a variant t-PA protein of claim 2 wherein the deletion includes at least a portion of the growth factor domain."

"4. The use of variant t-PA of claim 1 wherein said t-PA variant is devoid of at least a portion of the finger domain."

"8. The use of variant t-PA of claim 1, wherein said t-PA variant is devoid of at least a portion of the Kringle 1 domain."

"11. The use of variant t-PA of any of the preceding claims wherein said variant t-PA additionally has Glu at amino acid 275."

"21. The use of variant t-PA of any one of the preceding claims wherein the t-PA variant has been prepared by expression in a suitable host of a recombinant vector which encodes the variant."

"25. A method for providing a variant human t-PA protein exhibiting an enhanced half-life or decreased clearance rate relative to natural t-PA, the method comprising the steps of:

(a) obtaining a t-PA variant comprising t-PA modified by deletion which comprises at least a portion of the finger or Kringle 1 domain;

(b) comparing the pharmacokinetics of said variant to that of natural t-PA; and

(c) selecting a variant t-PA so obtained which exhibits a longer half-life and/or decreased clearance rate relative to the natural t-PA."

"33. Des 1-44 Glu 275 t-PA."

II. It has been revoked by the opposition division because of lack of novelty (Article 54 EPC) in view of document (B) (cf infra) and an oral disclosure made at the International Symposium on "Biotechnology in Clinical Medicine" held on April 13 to 15, 1987 in Rom.

III. The decision of the opposition division has been based on a main and an auxiliary request submitted during the oral proceedings, both containing 24 claims. Claims 1, 7, 11, 12, 13 and 24 of the main request read:

"1. The use of an amino acid deletion variant human t-PA protein produced in a recombinant host cell in the preparation of a medicament for the treatment of vascular disease in a patient for which t-PA plasma half-life longer than that exhibited by natural t-PA and/or clearance rates less than the clearance rate exhibited by natural t-PA is advantageous, wherein said deletion results in said variant human t-PA protein exhibiting plasma half-life longer than that exhibited by natural t-PA made in the same host cell and/or clearance rates less than the clearance rate exhibited by natural t-PA protein made in the same host cell."

"7. The use of variant t-PA of any one of the preceding claims wherein said t-PA variant is devoid of at least a portion of the finger domain"

"11. The use of an amino acid deletion variant human t-PA protein in the preparation of a medicament for the treatment of vascular disease by bolus administration in a patient for which t-PA plasma half-life longer than that exhibited by natural t-PA and/or clearance rates less than the clearance rate exhibited by natural t-PA is advantageous, wherein said deletion results in said variant human t-PA protein exhibiting plasma half-life longer than that exhibited by natural t-PA and/or clearance rates less than the clearance rate exhibited by natural t-PA protein, said t-PA variant being devoid of at least a portion of the kringle 1 domain; but excluding variant t-PAs which consist only of the 527 amino acid sequence of mature t-PA but with a deletion within the region Glu85-Asp179 and with the sequence 275 to 277 either absent or consisting of 1 to 3 amino acids."

"12. The use of variant t-PA of claim 11, wherein said t-PA variant comprises natural t-PA devoid of amino acids 92-179."

"13. The use of variant t-PA of claim 11, wherein the deletion includes at least a portion of the growth factor domain."

"24. Des 1-44 Glu275 t-PA."

Claims 1 to 24 of the auxiliary request were identical to the corresponding claims of the main request, except for the mention in claims 1 and 2 of the fact that the t-PA variant is brought to the patient by bolus administration.

IV. An appeal has been introduced against this decision by the patentee/appellant I.

V. Opponent 2/appellant II has introduced an appeal against the reasons having led to this decision.

VI. Opponent 1/respondent had indicated in his letter of 1. September 2000 his intention no longer to actively participate to the appeal procedure.

VII. The Board issued a communication pursuant to Article 11(2) of the rules of procedure of the boards of appeal giving its preliminary, non-binding opinion on inter alia the priority assessment of the claims and the admissibility of the appeal by opponent 2/appellant II in view of the requirement mentioned in Article 107 EPC for an appellant to be adversely affected by the decision under appeal, whereby the concept of "adversely affected" does not relate according to decision T 73/88 (EPO OJ 1992, 557) to the reasons of the decision.

VIII. Oral proceedings were held on 6 November 2001.

IX. During the oral proceedings, his attention having been drawn by the Board to a possible contradiction between claim 12 and the disclaimer of claim 11 of the main and auxiliary requests, on which the opposition division based its decision, the appellant I/patentee submitted a new main and a new auxiliary request, both with 22 claims. Claim 1, 10 and 11 of the main request read:

"1. The use of an amino acid deletion variant human t-PA protein produced in a recombinant host cell in the preparation of a medicament for the treatment of vascular disease in a patient for which t-PA plasma half-life longer than that exhibited by natural t-PA and/or clearance rates less than the clearance rate exhibited by natural t-PA is advantageous, wherein said deletion includes all or a portion of the finger region, and results in said variant human t-PA protein exhibiting a plasma half-life of at least 12 minutes or at least 2 times longer than that exhibited by natural t-PA made in the same host cell and/or clearance rates less than 2 ml/min/kg or half or less the clearance rate exhibited by natural t-PA protein made in the same host cell, with the exclusion of t-PA lacking functionally and structurally intact finger, growth factor and kringle 1 domains and where the catalytic site essential for fibrinolytic activity is blocked by a removable blocking group."

"10. The use of an amino acid deletion variant human t-PA protein in the preparation of a medicament for the treatment of vascular disease by bolus administration in a patient for which t-PA plasma half-life longer than that exhibited by natural t-PA and/or clearance rates less than the clearance rate exhibited by natural t-PA is advantageous, wherein said deletion includes at least a portion of the kringle 1 domain, and results in said variant human t-PA protein exhibiting a plasma half-life of at least 12 minutes or at least 2 times longer than that exhibited by natural t-PA made in the same host cell and/or clearance rates less than 2 ml/min/kg or half or less the clearance rate exhibited by natural t-PA protein made in the same host cell, with the exclusion of t-PA lacking functionally and structurally intact finger, growth factor and kringle 1 domains and where the catalytic site essential for fibrinolytic activity is blocked by a removable blocking group, [and excluding also variant t-PAs which consist only of the 527 amino acid sequence of mature t-PA but with a deletion within the region Glu85-Asp179 and with the sequence 275-277 either absent or consisting of 1-3 amino acids."]

"11. The use of variant t-PA of claim 10, wherein said t-PA variant comprises natural t-PA devoid of amino acid 92-179."

(Emphasis in bold or italics and bold and deletion by strikeout [] made by the Board).

The claims of the auxiliary request were identical to those of the main request, except for the mention of a "bolus administration" in claims 1 and 2 and the addition of "...more particularly myocardial infarction following reperfusion, deep vein thrombosis, peripheral vascular disease, or patients requiring t-PA but who are not in life-threatening situations,..." in claims 1, 2 and 10.

X. Appellant II/opponent 2 at the onset of the oral proceedings withdrew his appeal and thereby became respondent.

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

(A) EP 0 386 240

(B) EP 0 196 920

(BM1a) P. Cambier et al., Journal of Cardiovascular Pharmacology, 1988, Volume 11, pages 468-472

XII. In view of the admissibility under Article 114 EPC of the declarations of Drs. Kresse and Albert appellant I/patentee argued that their relevance was highly questionable and that their submission at the oral proceedings before the opposition division by opponent I was an abuse of the procedure, because said evidence had been in the possession of opponent I since April 1987. Decisions T 534/89 (OJ EPO 1994, 464) and T 17/91 (26 August 1992) were mentioned in this context.

In view of Article 123(2) EPC appellant I/patentee justified the deletion of the disclaimer in new claim 10 by the fact that document (A) in its first priority only disclosed a single mutant with a deletion between Cys84 and Cys180 which did not conflict with the mutant of the patent in suit devoid of amino acids 92-179. The introduction of the numerical values for the half-life and the clearance of the variant t-PA was an answer to the objection raised by appellant II/opponent 02 in view of Figure 2 of document (B).

XIII. Appellant II/opponent 2 pleaded in favour of the admittance of the declarations of Drs. Kresse and Albert into the proceedings because of their relevance, since they disclosed t-PA deletion mutants with an increased half-life.

He further submitted that the deletion of the disclaimer of new claim 10 resulted in a new technical and factual framework, which had not been considered by the first instance, this justifying a remittal of the case to the opposition division under Article 111(1) EPC.

No objection under Article 123(2) EPC against the amendments of the new main and auxiliary requests had been raised.

XIV. Appellant I/patentee, who had no objection against a remittal to the first instance, requested that the decision under appeal be set aside and that the patent be maintained on the basis of the main or auxiliary requests filed during oral proceedings.

XV. Appellant II/opponent 2 requested that the appeal be dismissed.

XVI. A few days after the decision of the Board has been announced and the oral proceedings closed, submissions from both appellants were received.