T 1354/15 (RNA interference mediators II/WHITEHEAD INSTITUTE) 01-03-2018

Summary of Facts and Submissions

I. European patent No. 2 361 981 with the title "RNA sequence-specific mediators of RNA interference" was granted on the European application No. 10184660.8 (in the following "the application as filed"). The application is a divisional application of the European patent application No. 08168152.0 (EP 2 028 278) which is in turn a divisional application of the European patent application No. 01922870.9 filed under the Patent Cooperation Treaty on 30 March 2001 and published as WO 01/75164.

II. The patent, which was granted with 9 claims, was opposed on the grounds for opposition of Article 100(a) in conjunction with Articles 54, 56, and 53(c), and of Article 100(b) and 100(c) EPC.

III. In an interlocutory decision pursuant to Articles 101(3)(a) and 106(2) EPC posted on 5 May 2015, an opposition division found that, account being taken of the amendments introduced into claims 1 to 8 filed as main request on 16 March 2015 and the adapted description filed at the oral proceedings, the patent and the invention to which it relates met the requirements of the EPC.

IV. Independent claims 1, 4, 5, 7 and 8 according to the main request read as follows:

"1. Isolated double stranded RNA of from 21 to 23 nucleotides that mediates RNA interference of an mRNA to which it corresponds, provided that the double stranded RNA is not ucg agc ugg acg gcg acg uaa, chemically linked at the 3' end to the 5' end of the complementary RNA by a C18 linker group.

4. Isolated dsRNA of from 21 to 23 nucleotides that directs cleavage of specific mRNA to which its sequence corresponds, provided that the double stranded RNA is not ucg agc ugg acg gcg acg uaa, chemically linked at the 3' end to the 5' end of the complementary RNA by a C18 linker group.

5. Double stranded RNA of from 21 to 23 nucleotides for use in a method of treating a disease or condition associated with the presence of a protein in an individual comprising administering to the individual dsRNA of from 21 to 23 nucleotides that targets the mRNA of the protein for degradation.

7. A pharmaceutical composition comprising dsRNA of from 21 to 23 nucleotides that mediates RNA interference and an appropriate carrier, provided that the double stranded RNA is not ucg agc ugg acg gcg acg uaa, chemically linked at the 3' end to the 5' end of the complementary RNA by a C18 linker group.

8. Use of dsRNA of claim 1 to 4 for specifically inactivating gene function in vitro, provided that the double stranded RNA is not ucg agc ugg acg gcg acg uaa, chemically linked at the 3' end to the 5' end of the complementary RNA by a C18 linker group."

Dependent claims 2 and 3 are directed to embodiments of the isolated double stranded RNA of claim 1, and dependent claim 6 to an embodiment of the double stranded RNA of claim 5.

V. The opponent (appellant) lodged an appeal against the interlocutory decision of the opposition division and submitted a statement setting out the grounds of appeal which included document (15) as additional evidence.

VI. By letter dated 8 January 2016, the patent proprietors (respondents) replied to the grounds of appeal, re-filed the set of claims according to the main request underlying the decision under appeal, and submitted five additional sets of claims as auxiliary requests 1 to 5.

VII. Both parties requested oral proceedings as a subsidiary request.

VIII. The parties were summoned to oral proceedings. In a communication sent in preparation of the oral proceedings, the board expressed its provisional opinion on procedural issues and various substantive issues concerning Articles 123(2), 83, 54 and 56 EPC.

IX. In reply to the board's communication, the appellant informed the board that it would not attend the oral proceedings. The appellant did not make any submissions in substance.

X. Oral proceedings were held on 1 March 2018 in the presence of the respondents.

XI. The following documents are referred to in this decision:

(6): F. Czauderna et al., 2003, Nucleic Acids Research, Vol. 31, No. 11, pages 2705 to 2716;

(7): WO 00/44895, filed on 29 January 2000 and published on 3 August 2000;

(9): T. Tuschl et al., 1999, Genes & Development, Vol. 13, pages 3191 to 3197; and

(15): S.M. Elbashir et al., 2001, The EMBO Journal, Vol. 20, No. 23, pages 6877 to 6888.

XII. The submissions made by the appellant concerning issues relevant to this decision, were essentially as follows:

Article 123(2) EPC - added matter

In light of decision G 2/10 of the Enlarged Board of Appeal (OJ EPO 2012, 376), the introduction of a disclaimer excluding subject-matter described in document (7) was in contravention of Article 123(2) EPC. According to that decision, an amendment to a claim by way of introduction of a disclaimer infringed Article 123(2) EPC if the subject-matter remaining in the claim after the introduction of the disclaimer was not, be it explicitly or implicitly, directly and unambiguously disclosed in the application as filed. The findings in decision G 2/10 (supra) concerned not only disclaimers excluding from the scope of a claim subject-matter which was identified as an embodiment in the specification of the same patent, but also "undisclosed" disclaimers.

A disclaimer of a specific sequence which is itself not disclosed as an embodiment of the invention in the application as filed, inevitably created a subgroup on the basis that the remaining subject-matter, namely the broad claim minus the specific sequence of document (7), was neither explicitly nor implicitly disclosed in the application as filed.

Moreover, the disclaimer was not merely directed to the specific sequence disclosed in document (7), but rather to a sequence that is chemically linked at the 3' end to the 5' end of the complementary RNA by a C18 linker group. Such linkers were not contemplated in the patent in dispute and thus when disclaimed provided a new subgroup and new technical information beyond the content of the application as filed.

Article 83 EPC - sufficiency of disclosure

The claimed invention was not sufficiently disclosed in the application as filed. It was not apparent from claim 1 to what extent the individual oligonucleotides overlapped with each other to form the duplex in a dsRNA. Since claim 1 did not specify that the duplex is of 21 to 23 nucleotides in length, it encompassed also a dsRNA consisting of two RNA strands of 21 nt in length which overlapped at only a single nucleotide position. However, as shown in Figure 3A of document (6) a minimal length of the duplex of 19 nucleotides was a critical factor for RNA interference ("RNAi"). Hence, a preferred embodiment of the invention identified in paragraph [0019] of the patent as having a 3' overhang on at least one of the strands of from about 1 to 6 nucleotides, would not be able to exert an RNA interference effect.

The claims made no mention of the degree of correspondence that is necessary and at what positions in the molecule in order for it to be effective in exerting RNA interference. The data in Figure 3B of document (6) explicitly showed that there was a significant reduction in inhibition when mismatches were introduced into the centre of the molecules. The claims were not limited to any degree of specificity and covered embodiments that clearly did not work. In order for the skilled person to perform the invention across the scope of the claims, he/she was faced with the undue burden of having to identify what length of duplex was required in a sequence of 21-23 nucleotides as well as the degree of specificity to the target DNA. Decision T 1326/08 of 10 January 2012, in particular paragraph 3.3 was relevant in this respect.

While the opposition division interpreted the claims such that the wording "that mediates RNA interference" was a functional limitation, the Courts of different member states of the EPC, including the UK, would not necessarily see the term in question as a functional limitation, but merely as a property of all isolated dsRNA of from 21 to 23 nucleotides. Accordingly, the claim should be interpreted such that it related to any sequence of 21 to 23 nucleotides in dsRNA which corresponds to some extent with the target mRNA. On such an interpretation the specification would be clearly insufficient. It was also to be noted that functional limitations could only be generally used in certain circumstances, namely when there was no better way to define the invention (see T 68/85, OJ EPO 1987, 228).

Article 54(3)(4) EPC 1973 - novelty

The claimed subject-matter lacked novelty in light of document (7). Besides a specific sequence of 21 nt, which had been specifically disclaimed, document (7) described dsRNA molecules of between 15 and 49 bp which mediated the inhibition of gene expression (see page 4, paragraph 2). Hence, molecules having all of the individual lengths between the range of 15 to 49 were disclosed in document (7). The disclosure of dsRNA molecules with all of the structural features of the claim, namely a double stranded RNA sequence of from 21 to 23 nt would inevitably lead to RNA interference. Even though it had not been appreciated in document (7) that the inhibitory effect of dsRNA arises because of its effect on mRNA, at the relevant date it had been well known that gene expression occurs via mRNA. Hence, a skilled person reading Example 2 would realize that the YFP gene expression was reduced by virtue of the dsRNA exerting an inhibitory effect.

It was well established case law of the Boards of Appeal (e.g., decisions T 701/09 of 3 August 2011 and T 1523/07 of 24 November 2009) that direct and unambiguous disclosure was not limited to explicit or literal statements, but included disclosure which any person skilled in the art would objectively consider as necessarily implied in the explicit context, e.g. in view of general scientific laws. It was implicit in a disclosure of a dsRNA sequence characterized as inhibiting the expression of a target gene that the sequence exhibited a sufficient degree of correspondence with the mRNA transcribed from the target gene in order to inhibit its expression. Since the technical effects associated with the dsRNA molecules were the same, the mere selection of a narrower range of 21 to 23 nt could not be considered novel. The criteria for a novel selection outlined in decision T 279/89 of 3 July 1991 were not met.

Article 56 EPC - inventive step

The claims embraced dsRNA sequences with potentially only a single point of overlap. Such molecules could never result in RNA inhibition of a corresponding mRNA. As a result, the claimed subject-matter did not exert its technical effect across the whole scope of the claims, and lacked therefore an inventive step.

XIII. The submissions by the respondents, insofar as they are relevant to the present decision, may be summarised as follows:

Admission of document (15) into the proceedings

Document (15) had been filed late and should not be admitted into the proceedings. The document was intended to address deficiencies in document (6) which had been cited in opposition proceedings as being relevant to sufficiency. However, the opponent had had ample opportunity to address this point in the proceedings before the opposition division.

Article 123(2) EPC - added matter

The disclaimer introduced into claim 1 did not single out compounds or sub-classes of compounds or other so-called intermediate generalisations in the sense of decision G 2/10 (supra), nor provided new technical information. Its scope was precisely in line with what was disclosed in document (7), namely a molecule having a specific RNA sequence which includes a C18 linker. Hence, the subject-matter of claim 1 did not extend beyond the content of the application as filed.

Article 83 EPC - sufficiency of disclosure

Document (6) was unsuitable to show that the disclosure in the application as filed is insufficient. The dsRNA described in Figure 3A of that document as being less effective at inhibiting mRNA expression did not fall under the scope of the claims because it consisted of two strands of 19 nt each which formed a duplex of 17 bp. As regards the degree of correspondence to the target sequence, the dsRNAs used in the experiment underlying Figure 3B of document (6) were only 19 bp in length. The fact that the claims did not specify a given degree of correspondence did not in itself render the disclosure insufficient. It was stated in paragraph [0005] of the application as filed that perfect correspondence of the sequences was not necessary, but the correspondence must be sufficient to enable the dsRNA to direct RNAi cleavage of the target mRNA. The skilled person was able to design a dsRNA corresponding to a target, and then test whether the dsRNA mediated RNA interference. There was no evidence, either in document (6) or elsewhere, that the invention as claimed cannot be worked.

Article 54(3)(4) EPC 1973 - novelty

The opposition division was correct to conclude that the claimed subject-matter was novel over document (7). The suggestion of a range of 15 to 49 bp in document (7) did not amount to a disclosure of each intermediate value, let alone to the disclosure that the whole range of 15 to 49 bp dsRNA molecules would inhibit gene expression. In fact, document (6) confirmed that molecules at the shorter end of this range would not be effective, while document (9) confirmed that 49 bp dsRNA is "ineffective in vitro". The test set out in decision T 279/89 of 3 July 1991 was met.

Article 56 EPC - inventive step

The argument that the technical problem was not solved over the whole scope of the claim, was flawed. dsRNA molecules having a single base pair overlap were excluded from the scope of the claim by the functional limitation that the molecules "mediate RNA interference" or "direct cleavage of the specific mRNA".

XIV. The appellant (opponent) requested in writing that the decision under appeal be set aside and the patent be revoked.

XV. The respondents (patent proprietors) requested that the appeal be dismissed.