T 1509/09 (High density oligonucleotide arrays/AFFYMETRIX) 05-07-2012

I. European patent No. 0 853 679, based on the European patent application No. 96 931 598.5 and published as International patent application WO 97/10365 (hereinafter "the application as filed"), was granted with 42 claims. Granted claim 1 read as follows:

1. A method of simultaneously monitoring the expression of a multiplicity of genes, said method comprising:

(a) providing a pool of target nucleic acids comprising RNA transcripts of some of said genes, or nucleic acids derived from said RNA transcripts;

(b) providing a plurality of different probes for analysis of each of the RNA transcripts that are to be monitored; said probes being immobilized as an array on a surface of a substrate in known locations at a density greater than 60 different probes per cm**(2); said array probes including match and control probes; the array comprising more than 100 different probes, each probe attached to the surface through a single covalent bond;

(c) hybridizing said pool of nucleic acids to the array of nucleic acid probes; and

(d) quantifying hybridization of said target nucleic acids to said array by comparing hybridisation of match and control probes wherein said quantifying provides a measure of the levels of transcription of said genes."

II. The patent was originally opposed by four opponents (opponents 01 to 04). With a letter dated 2 February 2006, opponent 03 withdrew its opposition. On 12 September 2006, oral proceedings took place before the opposition division and an intervention under Article 105 EPC was filed on 3 December 2007.

III. In an interlocutory decision dated 11 May 2009, the opposition division considered the Main Request (claims as granted) to contain subject matter that extended beyond the content of the application as filed (Article 100(c) EPC, Article 123(2) EPC) and decided to maintain the patent in suit on the basis of a first Auxiliary Request filed at the oral proceedings on 12 September 2006. Claim 1 of this first Auxiliary Request was identical to claim 1 as granted except for part (b) which read as follows:

"... (b) providing a plurality of different probes for analysis of each of the RNA transcripts that are to be monitored; said probes being immobilized as an array on a surface of a substrate in known locations at a density greater than 60 different probes per cm**(2); said array probes including control probes and a plurality of match probes; the array comprising more than 100 different probes, each probe attached to the surface through a single covalent bond; ..."

(italics by the board to show the amendment introduced into part (b) of granted claim 1 in addition to the deletion of the text "match and" present in granted claim 1(b) after the term "including"; cf. Section I, supra).

IV. Notices of appeal against this decision and statements setting out their grounds of appeal were filed by the patentee (appellant I) and opponents 01 and 04 (appellants II and III, respectively). Appellant I requested the maintenance of the patent as granted.

V. With letter dated 9 February 2010, appellant I replied to the grounds of appeal of the other appellants and filed 10 Auxiliary Requests. The first Auxiliary Request was the Auxiliary Request on which the opposition division had decided to maintain the patent. Except for Auxiliary Requests 2, 9 and 10, all other Auxiliary Requests had originally been filed on 12 July 2006 in preparation of the oral proceedings before the opposition division.

VI. Appellants II and III submitted further comments on appellant I's reply and Auxiliary Requests.

VII. On 10 February 2012, the board summoned the parties to oral proceedings and, in a communication pursuant to Article 15(1) of the Rules of Procedure of the Boards of Appeal (RPBA) annexed thereto, informed the parties of its preliminary, non-binding opinion on some of the substantive issues of the present appeal.

VIII. With letter dated 4 June 2012, appellant I replied to the board's communication and filed a Main Request and 26 Auxiliary Requests. The Main Request and Auxiliary Request 1 to 10 were identical to those filed on 9 February 2010 but in a different order, the claims as granted and the Auxiliary Request on which the opposition division had decided to maintain the patent in suit (previous Main Request and first Auxiliary Request) were now appellant I's Auxiliary Request 9 and 10. Appellant I's Main Request was identical to Auxiliary Request 2 filed on 9 February 2010. Auxiliary Requests 11 to 26 were new in the proceedings and based on combinations of two (AR11 to AR16), three (AR17 to AR24) or four (AR25 and AR26) of the appellant I's previous requests (MR, AR1 to AR10).

IX. With letters dated 12 June 2012 and 16 February 2012, the opponent 02 and the intervener/opponent 05 (parties as of right) informed the board of their intention not to attend the oral proceedings.

X. Oral proceedings took place on 5 July 2012. At these proceedings, appellant I maintained its Main Request (originally filed on 9 February 2012 as Auxiliary Request 2), withdrew all its previous Auxiliary Requests and filed two new Auxiliary Requests (Auxiliary Requests A and B), each with a single claim.

XI. The Main Request contained 42 claims identical to the 42 granted claims except for independent claims 1 and 22. Claim 1 of the Main Request was identical to claim 1 of the first Auxiliary Request on which the opposition division decided to maintain the patent in suit (cf. Section III, supra), except for part (b) which read as follows:

"... (b) providing a plurality of different probes for analysis of each of the RNA transcripts that are to be monitored; said probes being immobilized as an array on a surface of a substrate in known locations at a density greater than 60 different probes per cm**(2); said array probes including control probes and, for each of the RNA transcripts that are to be monitored, a plurality of match probes; the array comprising more than 100 different probes, each probe attached to the surface through a single covalent bond; ..."

(italics by the board to show the amendment introduced into part (b) of claim 1; cf. Section III, supra).

The amendment introduced into part (b) of claim 1 corresponded to parts of the subject-matter of claim 3 as granted.

XII. Claim 1 of Auxiliary Request A, the sole claim of this request, was identical to granted claim 1 (cf. Section I, supra), except for part (b) which read as follows:

"... (b) providing a plurality of different probes for analysis of each of the RNA transcripts that are to be monitored; said probes being immobilized as an array on a surface of a substrate in known locations at a density greater than 60 different probes per cm**(2); said array probes including match and control probes; the array comprising more than 100 different probes, each probe attached to the surface through a single covalent bond; and, for each gene, said array comprising at least 10 different nucleic acid probes complementary to subsequences of that gene; ..."

(italics by the board to show the amendment introduced into part (b) of claim 1 as granted; cf. Section I, supra).

XIII. Claim 1 of Auxiliary Request B, the sole claim of this request, was identical to claim 1 of Auxiliary Request A, except for the introduction of two additional amendments, one in part (b) and one in part (d) of this claim. The amendment in part (b), introduced after the wording "... including match and control probes ...", read as follows:

"..., wherein the control nucleic acid probes comprise mismatch control probes such that for each matched probe there exists a mismatch control probe; ..."

The amendment in part (d) of claim 1, introduced after the wording "... hybridisation of match and control probes ...", read as follows:

"... wherein said quantifying comprises either:

(a) calculating the difference in hybridization signal intensity between each of said nucleic acid probes and its corresponding mismatch control probe; or

(b) calculating the average difference in hybridization signal intensity between each of said nucleic acid probes and its corresponding mismatch control probe for each gene; and ..."

The amendments introduced into parts (b) and (d) of claim 1 corresponded, respectively, to subject-matter of claims 8 and 9 as granted.

XIV. The arguments of appellant I, insofar as they are relevant to the present decision, may be summarized as follows:

Admissibility of the Main Request

The Main Request was filed (as Auxiliary Request 2) in direct reply to the grounds of appeal of appellants II and III within the time limit set by Article 12(1)(b) RPBA and thus, at an early stage of the appeal proceedings. The amendment introduced into part (b) of claim 1 was in line with that introduced into claim 1(b) of the first Auxiliary Request on which the opposition division decided to maintain the patent (cf. Sections III and XI, supra). The amendment was a serious attempt to overcome an objection raised by appellants II and III in their grounds of appeal, it was straightforward and did not add any complexity to the case. On the contrary, it intended to simplify the case and did not involve any examination that could delay the proceedings.

Main Request

Article 100(c) EPC; Article 123(2) EPC

The term "plurality" only meant "more than one" or "at least two", thereby excluding the minimal embodiment considered by the opposition division to be embraced by the granted claims and to lack a basis in the application as filed. Although, in the application as filed, the term "plurality" was found only in the context of a computer-implemented method, the application as filed constantly and consistently referred to a plurality or to a set of match probes (plural) opposed to a single target sequence (singular), as shown by the numerous references to "large numbers of probes" and to the use of several probes found in the application as filed, such as on page 9, lines 29-30, page 21, lines 1-3, 15 and 19-20, page 22, lines 9-10, page 34, lines 18-19, page 36, lines 10-11, page 37, lines 15-16 and page 38, lines 5-7 and 11-12. Thus, there was a basis in the application as filed for using plural terms (plurality) when referring to match probes and singular terms for target sequences. This teaching was also conveyed to the skilled person by references to specific increasing and decreasing numbers of probes found, respectively, on page 5, lines 15-17 and page 22, lines 6-8 of the application as filed. From these references, the skilled person would have understood that, in the method of claim 1, a plurality of probes had to be used for each target gene. There was no lower limit for the number of probes to be used in the method of claim 1 as long as there was more than one (a plurality) for each target gene.

The application as filed explicitly referred also to "a multiplicity of probes", in particular on page 10, line 16, page 38, line 17 and page 39, line 9. Although these references were found in the context of a method of selecting a set of oligonucleotide probes or a method of optimizing a probe set, it was directly and unambiguously derivable from the content of the application as filed that this "multiplicity of probes" was to be used in the method of claim 1, since this method was essential to the disclosure of the application as filed and no other possible use for this "multiplicity of probes" could be derived from the application as filed. This was the sole possible interpretation if the application as filed was read with the mind of a skilled person willing to understand.

Admissibility of Auxiliary Requests A and B

The subject-matter of Auxiliary Request A was filed at the beginning of both the opposition (claim 1 of Auxiliary Request 6 filed on 12 July 2006 in preparation of the oral proceedings before the opposition division) and the appeal proceedings (claim 1 of Auxiliary Request 8 filed on 9 February 2010 in reply to appellants II and III's grounds of appeal and claim 1 of Auxiliary Request 6 filed on 4 June 2012 in reply to the board's communication pursuant to Article 15(1) RPBA). Although Auxiliary Request A was filed at the oral proceedings before the board, the subject-matter of this request was not late filed. Auxiliary Request A had only a single claim and thus, it reduced the complexity of the case and contributed to the procedural economy of the appeal proceedings. In this sense, it was not a reintroduction of a previously withdrawn Auxiliary Request which, with 42 claims, increased the complexity of the case.

The subject-matter of Auxiliary Request B was a combination of subject-matter that was present at the beginning of both the opposition (claims 1 of Auxiliary Requests 2 and 6 filed on 12 July 2006 in preparation of the oral proceedings before the opposition division) and the appeal proceedings (claims 1 of Auxiliary Requests 4 and 8 filed on 9 February 2010 in reply to appellants II and III's grounds of appeal). The subject-matter of Auxiliary Request B was identical to that of claim 1 of Auxiliary Request 15 - filed on 4 June 2012 within the time limit set out by the board in its communication pursuant to Article 15(1) RPBA and in direct reply to the board's preliminary opinion expressed therein. Thus, Auxiliary Request B was not filed at a late stage of the appeal proceedings. The subject-matter of Auxiliary Request B was immediately derivable from a direct combination of subject-matter already present in previous Auxiliary Requests and it clearly addressed in a straightforward manner two objections raised by the opponents at the beginning of the opposition proceedings. None of the other appellants and parties in appeal proceedings could be surprised by the subject-matter of Auxiliary Request B. Moreover, since Auxiliary Request B had only a single claim, it clearly reduced the complexity of the case and contributed to the procedural economy of the appeal proceedings.

Auxiliary Request A

Article 100(c) EPC; Article 123(2) EPC

Basis for the amendment introduced into part (b) of claim 1 of Auxiliary Request A was found on page 5, lines 17-18 and page 6, lines 9-11 of the application as filed. Although reference was made therein to oligonucleotide probes and not to nucleic acid probes, a probe was clearly defined in the application as filed as being always an oligonucleotide (page 11, line 25). It was well-known in the art and clearly derivable from the application as filed that all oligonucleotides were nucleic acids (page 11, line 23). Accordingly, no difference was made in the application as filed between nucleic acid probes and oligonucleotide probes. The terms were used interchangeably and meant the same, as clearly conveyed to the skilled person by the disclosure of the application as filed when taken as a whole.

XV. The arguments of appellants II and III, insofar as they are relevant to the present decision, may be summarized as follows:

Admissibility of the Main Request

No objections were expressed against the admissibility of the Main Request.

Main Request

Article 100(c) EPC; Article 123(2) EPC

In the application as filed, the term "plurality" was found only in the context of a computer-implemented method but not in the method of claim 1 (page 10, line 25 and claims 65 and 73 of the application as filed). Both methods were different and the former could not be a basis for the latter. The term "a plurality" was different from the wording "large numbers" found on pages 21 and 22 of the application as filed, the former comprising embodiments with a low number of probes (two, three, etc.) that were not embraced by the latter wording. Embodiments with a low number of probes were also not supported by the disclosures of specific numbers of probes found on page 5, lines 15-17 (more than 10) and on page 22, lines 6-8 (even 10) of the application as filed. The references in the application as filed to "a multiplicity of probes" were found in the context of methods for selecting and/or optimizing a set of probes which were different from the method of claim 1. There was no disclosure in the application as filed linking these methods with that of claim 1, i.e. stating that all probes selected and/or optimized by these methods had to be used in the method of claim 1.

Admissibility of Auxiliary Requests A and B

Although both Auxiliary Requests were late filed in appeal proceedings, no objections were raised against the admissibility of Auxiliary Request A. However, appellant III noted that since Auxiliary Request 6 filed on 4 June 2012 (claim 1 of Auxiliary Request 6 was identical to claim 1 of Auxiliary Request A) was withdrawn during oral proceedings before the board, Auxiliary Request A reintroduced subject-matter previously withdrawn and thus, its admissibility spoke against procedural economy.

Auxiliary Request B was filed at oral proceedings before the board and thus, at a late stage of appeal proceedings. The subject-matter of this request was not straightforward but only derivable from a combination of different Auxiliary Requests previously filed in appeal proceedings. Although claim 1 of Auxiliary Request B was identical to claim 1 of Auxiliary Request 15 filed by appellant I in reply to the board's communication pursuant to Article 15(1) RPBA, Auxiliary Request 15 was filed one month before the oral appeal proceedings together with a large number of other Auxiliary Requests that contained all possible combinations of subject-matter intending to address several different, but not all, possible objections. According to the case law of the Boards of Appeal, this was a "pick and mix" approach that was not to be allowed (T 745/03 of 22 September 2005 and T 221/06 of July 2008).

Auxiliary Request A

Article 100(c) EPC; Article 123(2) EPC

The sentences on page 5, lines 17-18 and on page 6, lines 9-11 of the application as filed referred to oligonucleotide probes. The definitions of nucleic acid and oligonucleotide found on page 11, lines 19-22 and lines 23-24, respectively, showed that they were different, the former being broader than the latter. Nucleic acid probes were not identical to oligonucleotide probes, they were not merely equivalent and the terms could not be interchangeably used one for the other. Oligonucleotide probes could not be directly and unambiguously equated to nucleic acid probes. There was no basis in the application as filed for the specific wording introduced into part (b) of claim 1 of Auxiliary Request A.

XVI. Appellant I (patentee) requested that the decision under appeal be set aside and that the patent be maintained on the basis of the Main Request filed with letter of 4 June 2012 or, in the alternative, on the basis of Auxiliary Request A or B filed on 5 July 2012 during the oral proceedings before the board.

XVII. Appellant II (opponent 01) and appellant III (opponent 04) both requested that the decision under appeal be set aside and that the patent be revoked.