T 0070/05 (Apoptosis receptors /GENENTECH) 07-02-2006

Reasons for the Decision

Article 123(2) EPC

1. The examining division acknowledged that the set of claims then under consideration met the requirements of Article 123(2) EPC (cf. point 1 of the decision under appeal). The present set of claims is directly derivable from that before the examining division (cf. point VII supra). The appellant has indicated a basis in the application as filed for the amendments. The board is satisfied that the conditions of Article 123(2) EPC are complied with.

Article 54(3)(4) EPC

2. The key issue to be decided in the present case is whether the decision under appeal was correct in holding that document D1 is entitled to its claimed priority right from document D1a and, consequently, whether it is a prior art document under Article 54(3)(4) EPC that anticipates the subject-matter of the present application.

3. The criteria for assessing the right to priority have been laid down in the opinion of the Enlarged Board of Appeal G 2/98 (supra), which in point 9 of the Reasons for the Opinion states that "a narrow or strict interpretation of the concept of "the same invention", equating it to the concept of the "same subject-matter" referred to in Article 87(4) EPC ... is necessary to ensure a proper exercise of priority rights in full conformity inter alia with the principles of equal treatment of the applicant and third parties ... and legal certainty ... and with the requirement of consistency with regard to the assessment of novelty and inventive step". It is further stated "that priority of a previous application in respect of a claim in a European patent application in accordance with Article 88 EPC is to be acknowledged only if the person skilled in the art can derive the subject-matter of the claim directly and unambiguously using common general knowledge, from the previous application as a whole".

4. The criteria as defined in decision G 2/98 are to be applied both in assessing the right of document D1 to the claimed priority from document D1a and in assessing whether the subject-matter of the request now under consideration is entitled to the claimed priority from documents P1 and P2. The same standard must apply both for the present application and for document D1.

5. Since the filing date of the present application (31 March 1997) is later than the filing date of document D1 (17 October 1996), the disclosure of document D1 - including subject-matter which is not entitled to the priority right from document D1a - may anticipate the subject-matter of the application that is not entitled to any priority right, i.e. neither from document P1 nor from document P2. Thus, the board deems it appropriate first to assess whether the request under consideration comprises subject-matter not entitled to the claimed priorities.

Entitlement of the request under consideration to the claimed priority date of documents P1 or P2

6. In the board's judgement, subject-matter related to an isolated "Apo-2 ligand inhibitor" (Apo-2LI) polypeptide consisting of amino acid residues 1 to 181 of SEQ ID NO: 1 and having the biological activity of inhibiting apoptosis in at least one type of mammalian cell in vivo or in vitro, i.e. the subject-matter of claims 1 to 5, as well as subject-matter related to an isolated nucleic acid encoding these polypeptides, i.e. the subject-matter of claims 15 to 19 as far as they are dependent on claims 1 to 5, is entitled to the first claimed priority date of document P1.

In fact, the first priority document P1 discloses in Figure 1 (SEQ ID NO: 1) the amino acid sequence of the Apo-2LI polypeptide. Reference is made on page 9 of this document to this sequence and, as preferred embodiments, to biologically active variants having at least 90%, more preferably 95% sequence identity, and, optionally, to one or more cysteine-rich domains (cf. page 9, lines 8 to 24 and claims 1 to 4). Nucleic acids encoding the Apo-2LI polypeptides and related products (vectors, host cells) are also referred to in the description of document P1 (cf. inter alia page 11, line 5 to page 12, line 5, page 15, line 11 to page 32, line 13, page 54, examples and claims 17 to 20), including references to a signal sequence or pre-sequence of the Apo-2LI which directs its insertion in the membrane of human cells (cf. page 18, lines 6 to 9 and page 55, lines 30 to 32). A definition of the biological activity of these Apo-2LI polypeptides, namely the ability to reduce or inhibit apoptosis (cf. page 13, line 34 to page 14, line 11), as well as experimental demonstration of this activity is also found in document P1 (cf. pages 66 to 67, examples 10 and 11 and claim 23).

7. The board also considers that subject -matter related to an isolated Apo-3 polypeptide consisting of amino acid residues 1 to 417 of SEQ ID NO: 6 and having the biological activity of inducing apoptosis in at least one type of mammalian cell in vivo or in vitro, i.e. the subject-matter of claims 6 to 9, the corresponding mature Apo-3 polypeptide (residues 25 to 417 of SEQ ID NO: 6), i.e. the subject-matter of claims 10 to 13, or the extracellular domain consisting of residues 1 to 198 of SEQ ID NO: 6, i.e. the subject-matter of claim 14, as well as subject-matter related to an isolated nucleic acid encoding all these polypeptides, i.e. the subject-matter of claims 15 to 19 as far as they are dependent on claims 6 to 14, is entitled to the second claimed priority date of document P2.

In fact, the second priority document P2 discloses in Figure 8 (SEQ ID NO: 10) the amino acid sequence of the Apo-3 polypeptide. Reference is made on page 12 of this document to the mature and the full-length native Apo-3 sequences and, as preferred embodiments, to biologically active variants having at least 90%, more preferably 95% sequence identity, and the possible presence of deletions of about one to 24 amino acid residues (including a single amino acid deletion at residue 236) (cf. page 12, lines 2 to 23 and claims 1 to 5). Document P2 further discloses an extracellular domain comprising residues 1 to 198 of Figure 8 (SEQ ID NO: 10) and a death domain comprising residues 338 to 417 of Figure 8 (SEQ ID NO: 10) (cf. inter alia page 7, lines 28 to 35, claims 6 to 7). Further domains are also identified, namely a signal sequence (residues 1-24), a transmembrane domain (residues 199-224) and an intracellular domain (residues 225-417) (cf. inter alia page 71, lines 6 to 10). Nucleic acids encoding the Apo-3 polypeptides and related products (vectors, host cells) are also referred to in the description of document P2 (cf. inter alia page 14, line 23 to page 15, line 21, page 18, line 24 to page 34, line 23, pages 70 to 77, examples 9 to 15 and claims 15 to 20), including a signal sequence or pre-sequence of the Apo-3 which directs its insertion in the membrane of human cells (cf. page 21, lines 2 to 4). A definition of the biological activity of these Apo-3 polypeptides, namely the ability to induce or stimulate apoptosis (cf. page 17, lines 14 to 26), as well as experimental demonstration of this activity is also found in document P2 (cf. pages 72 to 75, examples 11 to 13). Document P2 also comprises the disclosure of the first priority document P1 as regards Apo -2LI referred to in point 6 supra and it clearly identifies the Apo-2LI polypeptides as specific fragments of the Apo-3 polypeptide (cf. page 71, lines 29 to 32).

In conclusion, whereas the subject-matter concerned with Apo-2L is entitled to the first claimed priority date of document P1 (1 April 1996), the subject-matter concerned with Apo-3 is entitled to the second claimed priority date of document P2 (23 September 1996).

8. Since all subject-matter of the request under consideration is entitled either to the first or the second claimed priority date - both earlier than the filing date of document D1 (17 October 1996), it is only the subject-matter of document D1 that is entitled to the priority date from document D1a which is relevant for the assessment of novelty.

The disclosure of document D1

9. Document D1 discloses two death-domain-containing receptors, namely the DR3-V1 (DR3 Variant 1) (Figure 1, SEQ ID NO: 1, 2) and the DR3 (Figure 2, SEQ ID NO: 3, 4) receptors, derived respectively from a human testis tumour cDNA library and a human HUVEC cDNA library. The amino acid sequences of these two receptors are identical except for their respective signal peptide which for DR3-V1 is predicted to consist of about residues 1-35 (Figure 1, SEQ ID NO: 2) and for DR3 of about residues 1-24 in Figure 2 (SEQ ID NO: 4), and wherein residues 25-35 of DR3-V1 are identical to residues 14-24 of DR3 (cf. page 10, line 30 to page 11, line 14). Due to possible sequence errors and the known variability of cleavage sites, reference is made to a range of possible lengths for these signal sequences - in particular for DR3-V1 anywhere in the range of about 25 to about 45 (cf. page 11, lines 15 to 24).

10. Several domains of these receptors, DR3-V1 and DR3, are identified in document D1. In particular for DR3-V1 the ligand binding (extracellular) domain is identified within residues from about 36 to about 212, the transmembrane domain within residues from about 213 to about 235 and the intracellular domain within residues from about 236 to about 428, this latter domain including a death domain at residues from about 353 to about 419 (Figure 1, SEQ ID NO: 2) (cf. inter alia page 6, lines 15 to 19 and page 31, lines 18 to 25). Reference is also made to fragments of these receptors, in particular fragments corresponding to the extracellular domains or to soluble polypeptides comprising all or part of the extracellular and intracellular domains but lacking the transmembrane domains (cf. inter alia page 30, lines 6 to 20, page 40, line 29 to page 41, line 5).

11. Based on the very specific nucleotide and amino acid sequences of these two receptors, document D1 refers to more generic products, such as polynucleotides hybridizing under stringent hybridization conditions to (a portion of) the disclosed nucleic acid sequences, allelic and non-naturally occurring variants which encode for fragments, analogs or derivatives of these receptors, isolated nucleic acid molecules or polypeptides that are at least 90% identical to the disclosed sequences, etc. (cf. inter alia page 14, line 26 to page 15, line 25, page 16, lines 13 to page 20, line 14, page 28, line 11 to page 29, line 5, page 30, lines 15 to 20).

12. It is worth noting at this point that the amino acid sequence of the DR3 receptor disclosed in document D1 (Figure 2, SEQ ID NO: 4) corresponds exactly to the amino acid sequence of the Apo-3 receptor disclosed in the present application (Figure 4, SEQ ID NO: 6).

Entitlement of document D1 to the claimed priority date of document D1a

13. There is no reference to the DR3 receptor in the priority document D1a. The disclosure of document D1a relates only to DDCR (death-domain-containing receptor), which according to document D1 corresponds to the DR3-VR1 receptor (cf. page 4, line 22 and page 9, line 10 in document D1). However, the amino acid sequence of the DDCR receptor disclosed in document D1a is not identical to the amino acid sequence of the DR3-V1 receptor disclosed in document D1. The residues at positions 229, 232 to 240, 256 and 260 of the DDCR receptor in document D1a differ from the ones indicated in document D1 for the DR3-V1 receptor (cf. Figures 1 and SEQ ID NO: 1, 2 of documents D1 and D1a).

Thus, the specific full-length sequences of the DR3 and the DR3-V1 receptors of document D1 cannot enjoy priority from document D1a.

14. Document D1a also identifies several domains of the DDCR receptor, in particular the ligand-binding (extracellular) domain from about residue 30 to about 215, the transmembrane domain from about 215 to about 240 and the intracellular domain from about 240 to about 428, which includes the death domain from about 350 to about 420 (cf. page 11, lines 9 to 19). Although the definition of these DDCR domains is very similar to the one given in document D1 for the DR3-V1 domains, they are not strictly the same. In particular, the extracellular domain of the DR3-V1 receptor is identified as within residues from about 36 to about 212 (cf. point 10 supra), whereas the corresponding extracellular domain of the DDCR receptor is defined from about residue 30 to about residue 215.

Thus, in accordance with the "narrow or strict interpretation" laid down in decision G 2/98 (supra), the specific extracellular fragment of the DR3-V1 receptor as defined in document D1 cannot enjoy priority from document D1a.

15. It may be considered that the disclosure of document D1a relating to the extracellular domain of DDCR is not limited to a very specific extracellular fragment (from residue 30 to residue 215) but that it includes a group of possible DDCR extracellular fragments for which the exact location "may vary slightly (e.g.; the address may "shift" by 1 to 5 residues) depending on the criteria used to define the domain" (cf. page 11, lines 9 to 26). However, even in such a case the selection of the most appropriate lower limit of the range explicitly disclosed in document D1a (corresponding to the first residue of the DDCR extracellular fragment), namely "residue 35", does not correspond to the specific one disclosed in document D1 for the DR3-V1 receptor, namely "residue 36".

16. Since in document D1 the length of the signal sequence of the DR3-V1 receptor is said to vary in the range of about 25 to about 45 amino acids (cf. page 11, lines 15 to 24), it may also be argued that the disclosure of document D1 is not limited to a specific extracellular fragment but that it discloses a group of possible DR3-V1 extracellular fragments for which the first residue might vary from about residue 26 to about residue 46 (the extracellular fragments extending further to about residue 212).

17. If only for the reason that, by the use of the word "about", the exact extent of both groups of DDCR and DR3-V1 extracellular fragments is left open-ended, it might also be envisaged that these two groups comprise a common subgroup of shared extracellular fragments. However, no matter its size (number of sequences) or importance, this subgroup of extracellular fragments is not disclosed as such in document D1a nor it is singled out as such in document D1. Moreover, precisely because of this open-ended formulation, the number of possible sequences belonging to this subgroup is clearly not limited. Nevertheless, the question arises whether such a subgroup of extracellular fragments in document D1 is entitled to claim priority from the corresponding subgroup in document D1a, even though the specific extracellular fragments and other possible subgroups - comprising non-shared sequences - do not enjoy such priority.

18. According to decision G 2/98 (supra), "the use of a generic term or formula in a claim for which multiple priorities are claimed ... is perfectly acceptable ... provided that it gives rise to the claiming of a limited number of clearly defined alternative subject-matters" (cf. point 6.7 of the Reasons for the Opinion). In the present case and for the reasons given above, the common subgroup is not clear by itself nor it is clearly limited in documents D1 or D1a. The fact that this common subgroup might be intellectually envisaged as falling within the disclosure of documents D1 and D1a does not in itself amount to a clear and unambiguous disclosure, i.e. individualized as such (cf. T 1127/00 of 16 December 2003, points 5 to 7 of the reasons). Nor can this common subgroup be derived directly and unambiguously as such from document D1a itself (cf. G 2/98, supra, point 9 of the Reasons).

Thus, in accordance with decision G 2/98 (supra), the generic extracellular fragments of the DR3-V1 receptor as defined in document D1 do not enjoy priority from document D1a.

19. A similar reasoning applies to the more generic products referred to in document D1, such as polynucleotides hybridizing under stringent hybridization conditions to (a portion of) the disclosed nucleic acid sequences, allelic and non-naturally occurring variants which encode fragments, etc. (cf. point 11 supra). The presence of a possible subgroup of generic products common to a corresponding subgroup in the priority document D1a - which is not, however, disclosed in document D1 nor in document D1a - cannot be an appropriate basis for acknowledging any priority right. This criterion is also in line with the established case law of the Boards of Appeal for which the disclosure of a generic group in an earlier document does not entitle a specific member (in the present case a subgroup) of that generic group disclosed in a later application to priority from the earlier document (cf. "Case Law", supra, IV.B.1, page 236 and inter alia T 77/97 of 3 July 1997).

20. It is also the board's opinion that, based on a disclosure of a "wrong" nucleotide or amino acid sequence in the priority document - independently of the reasons for the possible mistakes, either arising from unintended sequencing or typing errors or else arising from a conscious choice to file an application at a very early stage and thus, comprising doubtful or incomplete data - it would not be fair to acquire a right over a broad area from which, only later on, the "correct" sequence might be selected and disclosed in a patent application. The possible advantages conferred by such a practice would only encourage and, in the long term, lead to a mischievous use of priority rights.

Thus, the board considers that the generic products of the DR3-V1 receptor as referred to in document D1 do not enjoy priority from document D1a.

21. In the present case and in view of the above considerations, it is not necessary for the board to enter into the merit of appellant's reasoning as regards the absence of a credible identification for an exploitable biological function or activity of the DDCR receptor in the priority document D1a (cf. Section IX supra).

Conclusion

22. Since document D1 does not contain any subject-matter entitled to the priority date of document D1a and all the subject-matter of the request under consideration enjoys earlier priority dates either from document P1 or document P2 (cf. points 6 to 8 supra), document D1 is not relevant for the assessment of novelty.

23. Since document D1 is the only document cited in the decision under appeal as anticipating the claimed subject-matter, novelty of this subject-matter is acknowledged.