T 1354/15 (RNA interference mediators II/WHITEHEAD INSTITUTE) of 1.3.2018

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.

Reasons for the Decision

Admission of document (15) into the proceedings

1. Together with its statement of grounds of appeal, the appellant submitted document (15) as further evidence in support of its objection of lack of sufficient disclosure as regards both the length of the duplex in the dsRNA of from 21 to 23 nucleotides, and the extent to which the dsRNA must correspond to the mRNA being targeted. The respondent objected to the admission of the new evidence into the proceedings.

2. The appellant did not put forward any reasons for the late filing of document (15), and the board is not aware of any circumstances that may have prevented the appellant from filing this evidence in opposition proceedings. It should be noted that the invention defined by the claims according to the main request is identical to the invention according to the auxiliary request filed on 23 July 2014 during the opposition proceedings, in respect of which the opposition division expressed the provisional opinion that the requirements of Article 83 EPC were fulfilled (see section 6.5 of the opposition division's communication dated 24 October 2014 issued in preparation of the oral proceedings). In particular, the opposition division held that, as regards the disclosure of the extent to which the dsRNA must correspond to the mRNA being targeted, the opponent's objection did not appear to be justified (see section 3.3.3 of the communication). This is precisely the objection that document (15) purportedly supports.

3. In view of the above, the board considers that, upon receipt of the opposition division's communication, the present appellant had to be aware that the evidence submitted in support of the objection of lack of sufficient disclosure was not convincing. Hence, any additional evidence could - and should - have been filed in reply to the opposition division's communication.

4. Under these circumstances, the board decides to exercise its discretion under Article 12(4) of the Rules of Procedure of the Boards of Appeal (RPBA) to not admit document (15) into the proceedings.

Article 123(2) EPC - added matter

5. The appellant did not contest the adverse finding in the decision under appeal concerning claims 1 and 4 specifying that the 21 to 23 nt dsRNA corresponds to a (specific) mRNA (see section 2.3.2 of the decision).

6. As regards the findings concerning the disclaimer included in claims 1, 4, 7 and 8 (see section 2.3.3 of the decision under appeal), the appellant referred to various passages of decision G 2/10 of the Enlarged Board of Appeal (supra), in particular to sections 4.5, 4.5.4, 4.5.1 and 4.7 to support its argument that disclaiming a specific sequence which was itself not disclosed in the application as filed as an embodiment of the invention, offended against Article 123(2) EPC.

7. The disclaimer at issue was introduced in examination proceedings in order to establish novelty over document D3 (document (7) in appeal proceedings) which is comprised in the state of the art pursuant to Article 54(3)(4) EPC 1973. It is undisputed that the subject-matter excluded by way of the disclaimer in question is not disclosed in the application as filed. Hence, in the board's view the criteria established in decision G 2/10 (supra), which concerns "[A]an amendment to a claim by the introduction of a disclaimer disclaiming from it subject-matter disclosed in the application as filed ..." (see Order, item 1a; emphasis added by the board), cannot be applied to assess whether or not the amendment introducing the disclaimer contravenes Article 123(2) EPC.

8. This view is in line with the recent decision G 1/16 of the Enlarged Board of Appeal dated 18 December 2017, confirming that "... the gold standard disclosure test referred to in decision G 2/10 is not the relevant test for examining whether a claim amendment by an undisclosed disclaimer complies with the requirements of Article 123(2) EPC." (see point 49.1, first paragraph of the Reasons). Rather, the disclaimer must fulfil one of the criteria set out in point 2.1 of the order of decision G 1/03 (OJ EPO 2004, 413), and its introduction may not provide a technical contribution to the subject-matter disclosed in the application as filed. In particular, it may not be or become relevant for the assessment of inventive step or for the question of sufficiency of disclosure. Moreover, the disclaimer may not remove more than necessary either to restore novelty or to disclaim subject-matter excluded from patentability for non-technical reasons (G 1/16, supra, Order).

9. The appellant did not dispute that in the present case one of the criteria set out in point 2.1 of the order of decision G 1/03 (supra), namely that the introduction of the disclaimer restores novelty by delimiting the claim against state of the art under Article 54(3) and (4) EPC, is fulfilled. However, it argued that, since the disclaimer specifies not merely the specific RNA sequence disclosed in document (7), but also the C18 linker group linking the 3' end of one strand to the 5' end of the other strand, it removes more than necessary to restore novelty.

10. The board disagrees with this view. The L-dsRNA described in document (7) is characterized not only by its nucleotide sequence, but also by the C18 linker between the two strands (see page 18, lines 13 to 15 of document (7)). A disclaimer specifying merely the sequence of the L-dsRNA would remove more than necessary to restore novelty over document (7) and, consequently, its introduction would offend against Article 123(2) EPC. Contrary to the appellant's view, the fact that the application as filed does not contemplate such linkers does not result in the skilled person being presented with new technical information which goes beyond the content of the application as filed. Excluding the specific L-dsRNA having a C18 linker does not provide any technical contribution to the subject-matter disclosed in the application as filed, and does not become relevant either for the assessment of inventive step or for the question of sufficiency of disclosure.

11. For these reasons, the subject-matter of claims 1, 4, 7 and 8 does not extend beyond the content of the application as filed.

Article 83 EPC - sufficiency of disclosure

12. The finding in the decision under appeal that the technical information provided in the application as filed enabled the skilled person to carry out the invention as claimed, with a reasonable amount of trial and error (see section 3.3 of the decision), was contested by the appellant relying on document (6) as evidence. The appellant argued, essentially, that two essential features required for the dsRNA to be functional in mediating RNA interference, namely the minimum length of the duplex and the degree of sequence correspondence to the targeted mRNA, are neither specified in the claims nor disclosed in the specification.

13. As support for its argument that the disclosure in the application as filed is insufficient because it does not include any information on the minimum length of the duplex, purportedly an essential feature for the dsRNA to be functional in mediating RNA interference, the appellant referred to Figure 3A and the sentence bridging pages 2708 and 2709 in document (6). However, the sole dsRNA shown in Figure 3A which mediates RNA interference less efficiently (Akt1 5A+5B) is 19 nt, a length which is not within the range of 21 to 23 nt specified in the claims. Moreover, as apparent from the sentence on which the appellant relied ("We concluded from this result that the duplex length itself, but not the base pairing of the antisense siRNA with the target mRNA, seems to determine the minimal length of functional siRNAs"; emphasis added by the board), even the authors of document (6) did not consider the results shown in Figure 3A to be a conclusive evidence for a requirement of a minimal length of the duplex. It should be noted that, in comparison to the other dsRNAs tested, the Akt1 5A+5B dsRNA has not only a shorter duplex, but also its individual strands are shorter (19 nt instead of 21 nt). Hence, from the results shown in Figure 3A it cannot be established without any doubt that the observed reduced efficiency in RNA interference is linked to the shorter duplex length, let alone that such an effect can be expected for dsRNAs of 21 to 23 nt in length.

14. As concerns the degree of sequence correspondence to the targeted mRNA, it was found in the decision under appeal that, because of the functional feature "mediates RNA interference of an mRNA to which it corresponds" in claim 1, there was no requirement for the claims to specify the degree of sequence correspondence. In fact, according to the jurisprudence of the Boards of Appeal - which are not bound by any claim interpretation made by the courts of member states of the EPC - this functional feature must be construed as meaning that the dsRNA is "suitable for mediating RNA interference of an mRNA to which it corresponds". Accordingly, since claim 1 encompasses only dsRNA molecules that are suitable for mediating RNAi, the relevant question for assessing whether the requirement of Article 83 EPC is fulfilled, is whether with the technical information provided in the application as filed on hand, a person skilled in the art could determine without undue burden whether or not a dsRNA corresponding to a particular target mRNA is suitable for mediating RNA interference of that mRNA. A method for assessing RNA interference is disclosed in the application as filed (see Example 5). Moreover, such methods were - undisputedly - part of the common general knowledge of the skilled person at the priority date. Thus, the appellant's argument cannot be accepted.

15. In view of the above, the board is of the opinion that the requirements of Article 83 EPC are satisfied.

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

16. The findings on novelty in the decision under appeal have been contested in appeal only insofar as they concern document (7), which forms part of the state of the art under Article 54(3)(4) EPC 1973.

17. The appellant referred to Example 2 and the statements on page 4, lines 11 and 12 of document (7) as being relevant to the novelty of the subject-matter of claims 1, 4, 5, 7 and 8. In Example 2 a dsRNA of 21 bp in length, in which the two strands of the dsRNA are linked to each other via a C18 linker (L-dsRNA) is described (see page 18, lines 13 to 15). However, this dsRNA molecule is excluded from the scope of claims 1, 4, 7 and 8 by the disclaimer "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", which was introduced in examination proceedings to delimit the claimed subject-matter against document (7). As regards claim 5, the appellant has not contested the opposition division's finding that, while the claim specifies that the dsRNA of from 21 to 23 nt is for use in a method of treating a disease or condition associated with the presence of a protein in an individual, the YFP protein targeted by the L-dsRNA described in Example 2 of document (7) is not associated with any known disease or condition.

18. The passage on page 4, lines 11 and 12 to which the appellant referred, reads:

"Nach einem weiteren Ausgestaltungsmerkmal weist die dsRNA 10 bis 1000, vorzugsweise 15 bis 49, Basenpaare auf"

[In a further embodiment, the dsRNA has 10 to 1000, preferably 15 to 49 base pairs; translation by the board]

Contrary to the appellant's view, the disclosure of a range of length of 10 to 1000, preferably 15 to 49 base pairs does not amount to the disclosure of each of the intermediate lengths, and in particular of a range of 21 to 23 nt in length as specified in the claims. Moreover, it cannot be derived directly, unambiguously and beyond reasonable doubt from document (7) that a dsRNA with a length within the range of 15 to 49 bp is suitable for mediating RNA interference by directing cleavage of the specific mRNA to which its sequence corresponds. As the opposition division indicated in the decision under appeal, there is evidence on file showing that a dsRNA of 49 base pairs in length is ineffective in targeting the degradation of the specific mRNA to which its sequence corresponds (see document (9), page 3194, right-hand column, lines 4 and 5 from the bottom).

19. Hence, the arguments put forward by the appellant fail to convince the board that the claimed subject-matter lacks novelty.

Article 56 EPC - inventive step

20. The appellant did not contest the finding in the decision under appeal that the claimed subject-matter was not obvious to a person skilled in the art at the priority date, but contended that the problem of providing alternative dsRNA molecules that mediate mRNA specific RNA interference is not solved over the whole scope of the claims.

21. As observed above in connection with Article 83 EPC, claim 1 is directed to dsRNA molecules of from 21 to 23 nt in length which are suitable for mediating RNA interference of mRNAs to which they correspond. Contrary to the appellant's view, dsRNA molecules like those "with potentially only a single point of overlap" are not suitable for that purpose and are thus not within the scope of the claim. Hence, the appellant's objection of lack of inventive step fails.

Article 113(1) EPC - right to be heard

22. In its communication in preparation of the oral proceedings, the board expressed a reasoned provisional opinion on some of the issues to be discussed. The grounds and evidence on which the present decision is based, are known to the appellants as they are essentially those on which the decision under appeal and/or the board's provisional opinion were based. Even though it was given the opportunity to make written and/or oral submissions thereon, the appellant neither replied in substance to the board's communication nor attended the oral proceedings.

Order

For these reasons it is decided that:

The appeal is dismissed.