T 2002/13 (Methicillin resistant Staphylococcus/BECTON DICKINSON) 17-05-2017

The patent application and the related technical field

1. The highly conserved mecA gene, which encodes a ß-lactam-resistant penicillin binding protein (PBP) with ß-lactam-resistant transpeptidase activity, is present in methicillin-resistant Staphylococcus aureus (MRSA) strains, but absent from methicillin-sensitive S. aureus (MSSA) strains (cf. paragraph [0004] of the patent application). The mecA gene is carried by a mobile genetic element, named staphylococcal cassette chromosome mec (SCCmec), which integrates at a specific site in the chromosome of the MSSA strains, namely at the 3' end of an open reading frame orfX encoding a putative 159-amino acid polypeptide (cf. paragraph [0005]). The nucleotide sequences at the right extremity of the SSCmec sequences are polymorphic. The mec right extremity junction (MREJ), which has a length of ~ 1 kb, includes sequences from the polymorphic SCCmec right extremity as well as from the bacterial chromosomal DNA to the right of the SCCmec integration site, i.e. the orfX open reading frame (cf. paragraphs [0006] to [0009]). MREJ types i to x had been characterized in the prior art. The patent application discloses the nucleic acid sequences of MREJ types xi to xx as well as methods for detecting and quantifying these MREJ types. The patent as granted relates to embodiments which concern the sequence of SEQ ID NO: 17, 18 or 19, a MREJ type xi nucleic acid sequence.

Main request and auxiliary requests 1 to 3

2. The main request and auxiliary requests 1 to 3 filed with the statement of grounds of appeal are identical to auxiliary request I and auxiliary requests III to V underlying the decision under appeal, respectively. These requests were considered by the opposition division and a decision was taken thereupon. Hence, they are part of the present proceedings.

Main request

Article 123(2) EPC

The feature "having within the right extremity of SCCmec the sequence of SEQ ID NOs 17" in the preamble of claim 1

3. In the decision under appeal, the opposition division found that the feature "having within the right extremity of SCCmec the sequence of SEQ ID NOs 17" did not have a basis in the patent application (cf. point 4.2.6.2 of the decision). The board shares the view of the opposition division on this issue.

4. In line with the established case law of the Boards of Appeal, the claims must be read with a mind willing to understand and make technical sense of them, ruling out thereby illogical or technically meaningless interpretations (cf., inter alia, T 190/99 of 6 March 2001). The claims are directed to a person skilled in the art, who in the present case is a person skilled in amplification (polymerase chain reaction, PCR) techniques and familiar with MRSA in general, and the detection and identification of MREJ types in particular.

5. The "sequence of SEQ ID NO: 17" referred to in claim 1 stands for a specific nucleic acid sequence which is identified as a MREJ sequence - indeed, a MREJ type xi sequence - because it has the polymorphic mec right extremity of the SCCmec sequence and a fragment of the orfX chromosomal sequence of S. aureus (see the nucleic acid sequence "mrej_xi" shown in Figure 3 of the patent application). Thus, the sequence of SEQ ID NO: 17 cannot be within the right extremity of SCCmec but it actually includes part of the SCCmec sequence. The contested feature in claim 1 is therefore not ambiguous or open to interpretation but technically inaccurate or plainly wrong. This has not been disputed by the appellant who acknowledges that a skilled person would immediately recognize the feature of claim 1 as erroneous.

6. However, even if, as the appellant contends, the skilled person immediately recognizes the feature in claim 1 as being technically inaccurate or erroneous, this does not allow him/her to disregard it, since the feature is part of the claim and defines the claimed subject-matter - even though erroneously. The case law on which the appellant relied, namely T 190/99 (supra), rules out illogical or technically meaningless interpretations of an otherwise technically meaningful feature of a claim. However, the case law does not allow the reader to disregard an illogical or technically inaccurate feature of a claim and hence to interpret such a feature in a correct manner. Thus, if a claim includes contradictory features, such as the contested feature in the preamble of claim 1 and the feature referring to SEQ ID NO: 17 as an MREJ type xi sequence in the characterizing part of claim 1 (cf. point IX supra), this contradiction cannot be resolved by merely disregarding the technically inaccurate feature and considering only the convenient technically meaningful feature. All the less so when assessing the compliance of these two features with Article 123(2) EPC. In the board's view, any other approach would provide an unwarranted advantage to the patentee/appellant. Hence, the case law on which the appellant relied does not support its case.

7. For the purpose of Article 123(2) EPC, the relevant question is whether the illogical or technically inaccurate feature fulfils the same criterion that has also to be fulfilled by a logical or technically meaningful feature, namely whether it is directly and unambiguously derivable from the patent application. This is, according to the established case law, the "gold standard" for assessing the compliance with Article 123(2) EPC (cf. G 2/10, OJ 2012, page 376, point 4.3 of the Reasons for the Decision).

8. In the decision under appeal, the opposition division considered that the passage in paragraph [0082] of the patent application, when read within the whole disclosure of Example 3, did not provide a basis for the feature "having within the right extremity of SCCmec the sequence of SEQ ID NOs 17" (cf. point 4.2.6.2 of the decision under appeal). The board shares the view of the opposition division.

9. At the beginning of Example 3 of the patent application, it is stated in paragraph [0081] that "[t]he sequences obtained for 15 of the 17 strains non-amplifiable by the MRSA-specific primers detecting MREJ types i to x previously described were compared to the sequences available from public databases. In all cases except MRSA strain CCRI-12845, the orfX portion of the MREJ sequence had an identity close to 100% to publicly available sequences for orfX ... While the orfX portion of most MREJ fragments (SEQ ID NOs.: 15-20, 25-26, 39-42, 55-56) shared nearly 100% identity with publicly available S. aureus orfX sequences, with the exception of strain CCRI-12845, the DNA sequence within the right extremity of SCCmec itself was shown to be different from those of MREJ types i, ii, iii, iv, v, vi, vii, viii, ix, and x ... Thus, ten different novel MREJ sequence types are reported herein: MREJ types xi to xx." (emphasis by the board). This disclosure characterizes the sequence of SEQ ID NO: 17 as a MREJ sequence (the novel MREJ type xi sequence) which has two different parts (subsequences), namely a first part which is the sequence found within the polymorphic right extremity of SCCmec, and a second part which is a sequence having a 100% identity with publicly available S. aureus orfX sequences. Indeed, the second sentence of paragraph [0082] confirms that the sequence of SEQ ID NO: 17 is a MREJ sequence ("[t]hese new sequences were designated as MREJ type xi (SEQ ID NOs.: 17-19)"; emphasis by the board).

10. In the first sentence of paragraph [0082], on which the appellant relied as the literal basis for the contested feature in claim 1, it is stated that "[t]he sequences within the right extremity of SCCmec obtained from strains CCRI-12157, CCRI-12198, and CCRI-12199 (SEQ ID NOs.: 17, 18, and 19) were nearly identical to each other, ... " (emphasis by the board). Contrary to appellant's view, this sentence does not provide a literal basis of the feature in claim 1 because it does not reproduce verbatim the wording of the contested feature in claim 1. After defining the sequence of SEQ ID NO: 17 as a MREJ sequence in paragraph [0081] and, indeed, as a MREJ type xi sequence according to the second sentence of paragraph [0082], the first sentence in paragraph [0082] can only be understood as referring to one part (subsequence) of said MREJ type xi sequence of the sequence of SEQ ID NO: 17, namely the polymorphic mec right extremity of SSCmec, whilst the complete MREJ type xi sequence of the sequence of SEQ ID NO: 17 is found within the specific strain CCRI-12157. Contrary to appellant's argument, the board does not see any ambiguity in the first sentence of paragraph [0082] and if, arguably, there were any, then it is certainly not reproduced verbatim in the feature of claim 1, a feature which is, in itself, clear and unambiguous but, as acknowledged by all parties, technically inaccurate.

11. The appellant further argued that the meaning of the wording "sequence of SEQ ID NO: 17" (underlining by the board) as in claim 1 differs from that of "sequence SEQ ID NO: 17", because the former refers only to a part of the nucleic acid sequence listed in SEQ ID NO: 17, namely the part (subsequence) within the right extremity of SCCmec (cf. point XV supra).

The board is not aware of any general convention widely accepted in the particular technical field under consideration corroborating appellant's interpretation and there is no evidence on file to support such a convention. In any case, appellant's interpretation is not directly and unambiguously derivable from the patent application itself. On the contrary, references in the patent application using the wording "the sequence of SEQ ID NO" in the context of probes or oligonucleotides, such as in paragraph [0028] and claims 48, 49 and 53 of the patent application, concern full-length or complete sequences and not fragments, parts or subsequences thereof.

12. For these reasons, Article 123(2) EPC is contravened.

The feature "wherein said second primer hybridizes with a chromosomal sequence of S. aureus" in the characterizing part of claim 1

13. In the decision under appeal (cf. point 2.1.4), the opposition division found that the feature "wherein said second primer hybridizes with a chromosomal sequence of S. aureus" did not have a basis in the patent application. The board shares the view of the opposition division on this issue.

14. In claim 1, the first primer is defined as hybridizing "with said SSCmec element right extremity of an MREJ type xi sequence selected from the group consisting of SEQ ID NOs: 17 and complements thereof", and the second primer as hybridizing "with a chromosomal sequence of S. aureus" (cf. point IX supra). Whilst hybridization of the first primer is specified to be within the MREJ type xi sequence, in principle the second primer may hybridize with any region of the S. aureus chromosomal sequence. However, as the appellant argued (cf. point XV supra), the region where the second primer hybridizes is not arbitrary because claim 1 further requires that an amplicon is specifically generated if such MRSA strain is present in said sample, a functional feature characterizing thus the second primer (cf. points IX supra).

15. Leaving aside the possible interpretations of this functional feature put forward by the respondents during the opposition and appeal proceedings (particularly regarding the term "specifically"), it is worth noting that claim 1 does not specify any length or length range for the specifically generated amplicon. It is known in the nucleic acid amplification field that the length of an amplicon depends on many variables and design preferences and, for standard purposes, it may be between about 100 bp and about 1000-1500 bp. Indeed, this is the length range of the amplicons generated for MREJ types xi to xx as disclosed in Table 11 of the patent application. According to document (35), the orfX gene of S. aureus putatively encodes a 159 amino acid polypeptide and has a length of less than about 700 nucleotides (cf. page 1450, right-hand column second paragraph, and page 1455, Figure 3 of document (35)). Thus, with an amplicon of 1500 bp in length and a first primer hybridizing adjacent to the SSCmec insertion site, the second primer may well hybridize with a S. aureus chromosomal sequence far beyond the orfX chromosomal sequence of S. aureus shown schematically in Figure 1 of the patent application. Therefore, the functional feature characterizing the second primer in claim 1 allows this primer to hybridize with chromosomal sequences of S. aureus outside the orfX sequence. The decisive question is thus whether such an embodiment is directly and unambiguously derivable from the patent application.

16. There is a first reference to "bacterial chromosomal DNA" in paragraph [0009] of the patent application but this reference is clearly directed only to the part (subsequence) of the S. aureus chromosomal sequence within the MREJ sequence. In the same sentence, the MREJ sequence is defined as being of "approximately 1 kilobase" in length and thus, although the length of the bacterial chromosomal DNA is not explicitly indicated, this chromosomal DNA is clearly limited to the DNA directly adjacent to the SCCmec insertion site and present within the MREJ sequence, i.e. the orfX sequence of S. aureus. This is in line with the disclosure in paragraph [0034], wherein the reference to "chromosomal DNA adjacent to the right SCCmec integration site" is also limited to the chromosomal sequence within the MREJ sequence (cf. page 11, lines 5-7 of the patent application). Indeed, immediately thereafter reference is made in the same paragraph to the use of "the novel MREJ sequences" disclosed in the patent application as "parental sequences from which primers and/or probes useful in the detection and identification of MRSA ... are derived" (cf. page 11, lines 7-12 of the patent). It is in the light of this disclosure that the selection of DNA sequences "from proprietary, or from selected database sequences" referred to in paragraph [0050] must be understood. An understanding supported by the disclosure in paragraph [0052], wherein all references to the design of sequences and/or selection of public database sequences are also explicitly linked to the novel MREJ sequences disclosed in the patent application and therefore, not extending beyond the orfX sequence comprised within said MREJ sequences.

17. As a basis for a second primer hybridizing with a S. aureus chromosomal sequence different from the orfX sequence, the appellant referred to the primer of the sequence of SEQ ID NO: 44 (cf. point XV supra). The board cannot accept appellant's argument. The primer of sequence of SEQ ID NO: 44 is located within the orfX sequence of S. aureus and does not extend beyond this sequence. The sequence of SEQ ID NO: 44 is found at positions 1382 to 1404 in the (NCTC8325) sequence of Figure 3 of document (35), starting 14 nt 5'-upstream of the predicted start codon of the orfX gene. The primer of SEQ ID NO: 44 overlaps with the cR2 primer described in document (35) as being "located in orfX" (cf. page 1454, left-hand column first two lines, and page 1455, Figure 3 of document (35)). Indeed, in the patent application, the primer of sequence of SEQ ID: 44 is disclosed as annealing to the 5' end of orfX and used in an isolation/sequencing strategy of the MREJ types xi to xx disclosed in Example 2 of the patent application (cf. page 23, paragraphs [0070], [0072], and Figures 1 and 2 of the patent application). Moreover, as stated by the respondents (cf. point XVI supra), the disclosure in the patent application of a single primer with a specific sequence and a particular hybridization location, such as the sequence of SEQ ID NO: 44, cannot be considered to be a basis for a broad generalization of the second primer to hybridize with any possible S. aureus chromosomal sequence.

18. Also for these reasons, claim 1 contravenes Article 123(2) EPC.

Conclusion

19. The appellant's request to maintain the patent on the basis of claims 1 to 21 according to the main request cannot be granted.

Auxiliary requests 1 and 2

Article 123(2) EPC

20. Claim 1 of auxiliary request 1 includes the feature "wherein said second primer hybridizes with a chromosomal sequence of S. aureus" in the characterizing part of the claim (cf. point X supra). This feature contravenes Article 123(2) EPC for the same reasons as given for the main request (cf. points 13 to 18 supra).

21. Claim 1 of auxiliary request 2 includes the feature "having within the right extremity of SCCmec the sequence of SEQ ID NOs 17" in the preamble of the claim (cf. point XI supra). This feature offends against Article 123(2) EPC for the same reasons as given for the main request (cf. points 3 to 12 supra).

22. Thus, the patent cannot be maintained on the basis of either request.

Auxiliary request 3

Article 123(3) EPC

The feature "wherein each of said first and second primer hybridizes with said sequence of SEQ ID NO: 17 of complements thereof"

23. In the decision under appeal (cf. page 6, first paragraph), the opposition division found that the feature "wherein each of said first and second primer hybridizes with said sequence of SEQ ID NO: 17 of complements thereof" did not extend the scope of protection as compared to the granted claims. The board does not agree with the opposition division on this issue.

24. Claim 1 as granted defines a first primer hybridizing "with said SSCmec element right extremity of an MREJ type xi sequence selected from the group consisting of SEQ ID NOs: 17 [...] and complements thereof" and a second primer that "hybridizes with a chromosomal sequence of S. aureus to specifically generate an amplicon if such MRSA strain is present in said sample" (cf. point I supra). The sequence of both the first and second primer may be located closely or immediately adjacent to the SCCmec insertion site defining the MREJ type xi of sequence of SEQ ID NO: 17 but, whilst the first primer must necessarily hybridize with a sequence within the SCCmec element right extremity of said MREJ type xi, the second primer may hybridize with any S. aureus chromosomal sequence, not necessarily within the MREJ type xi of sequence of SEQ ID NO: 17. All possible combinations of first and second primers fulfilling these conditions form the population of primer pairs that can be used in the method according to claim 1 as granted.

25. Amended claim 1 of auxiliary request 3 defines the first and second primers by the feature that "each of said first and second primer hybridizes with said sequence of SEQ ID NO: 17", and further requires that they "specifically generate an amplicon if such MRSA strain is present in said sample" (cf. point XII supra). Thus, even though the first primer is not explicitly required to hybridize with the SCCmec element right extremity of the MREJ type xi of sequence of SEQ ID NO: 17, a detection of the MRSA strain in the sample implicitly requires that at least one of the primers, if not both of them, must necessarily hybridize with sequences located within the polymorphic right extremity of the SCCmec because it is this specific polymorphic sequence which characterizes the MREJ type xi MRSA strain and allows its detection (cf. paragraphs [0007], [0012] and [0034], and claim 1 of the patent application).

26. The second primer in the method of claim 1 of auxiliary request 3 does not hybridize with any chromosomal sequence of S. aureus - as in claim 1 as granted, but only with the MREJ type xi sequence of SEQ ID NO: 17. Although this definition of the second primer is narrower than the definition of the second primer found in claim 1 as granted, the second primer as defined in claim 1 of auxiliary request 3 may now hybridize not only with the orfX sequence closely or immediately adjacent to the SCCmec insertion site defining the MREJ type xi sequence of SEQ ID NO: 17, but it may also hybridize with the insertion site itself, as well as with the SCCmec right extremity as far as this second primer, together with an appropriate first primer, specifically generate an amplicon if an MREJ type xi MRSA strain is present in the sample. A method using such combinations of first and second primers does not fall within the scope of granted claim 1. Since in the amended claim 1 the protection conferred by claim 1 as granted has been extended, the amendment is not allowable under Article 123(3) EPC.

27. Thus, the appellant's request to maintain the patent on the basis of claims 1 and 2 according to auxiliary request 3 fails.

Auxiliary requests 4 and 5

28. The sets of claims according to auxiliary requests 4 and 5 were not before the opposition division and were first filed during the appeal proceedings. They were filed by the appellant at the earliest stage of the appeal proceedings, namely together with the statement setting out its grounds of appeal (cf. point IV supra), and, purportedly, are intended to overcome the adverse findings on Article 123(2) EPC in the decision under appeal. The board, exercising its discretion under Article 12(4) RPBA, decides to admit them into the appeal proceedings.

Articles 123(2) and (3) EPC

29. Claim 1 of auxiliary request 4 includes the feature "having within the right extremity of SCCmec the sequence of SEQ ID NO: 17" in the preamble of the claim, and the feature "wherein each of said first and second primer hybridizes with said sequence of SEQ ID NO: 17 or complements thereof" in the characterizing part of the claim. For the same reasons as given for the main request (cf. points 3 to 12 supra), the first feature contravenes Article 123(2) EPC. Moreover, the second feature offends against Article 123(3) EPC for the same reasons as given for auxiliary request 3 (cf. points 23 to 27 supra).

30. Claim 1 of auxiliary request 5 includes the feature "wherein each of said first and second primer hybridizes with said sequence of SEQ ID NO: 17 or complements thereof" in the characterizing part of the claim. This feature contravenes Article 123(3) EPC for the same reasons as given for auxiliary request 3 (cf. points 23 to 27 supra).

31. Thus, the patent cannot be maintained on the basis of either request.

Final conclusion

32. It the absence of any allowable request, the patent cannot be maintained.