T 1048/10 (NaV1.8 specific zinc finger proteins/Sangamo BioSciences, Inc.) of 10.2.2014

Summary of Facts and Submissions

I. This appeal was lodged by the applicant (hereinafter "appellant") against the decision of the examining division to refuse European patent application number 05 732 830 published as WO2005/100392 pursuant to Article 97(2) EPC.

II. The decision under appeal dealt with a single request.

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

D3: Jamieson et al., Nature Reviews, May 2003, page 361-368

D6: Lai et al., Pain, 2002, 95(1-2):143-152

IV. The examining division took the view that claims 1, 4, 5, 7 and 9 of the request before it related to subject-matter which lacked clarity (Article 84 EPC) and was not sufficiently disclosed (Article 83 EPC). In particular, the examining division held that the subject-matter of these claims was only defined by certain given desired properties of the polypeptides which they encode.

Claims 1 and 9 of this request read:

"1. Pharmaceutical composition comprising a nucleotide

encoding a polypeptide, wherein the polypeptide comprises:

(i) a zinc finger DNA-binding domain that is engineered

to bind to a target site in a gene selected from the group consisting of VR1, NaV1.8 and TrkA; and

(ii) a transcriptional repression domain;

such that the nucleic acid can be expressed in one or

more cells of the subject to be treated, whereby the

polypeptide is capable of binding to the target site

and repressing transcription of the gene.

9. A polypeptide comprising

(i) a zinc finger DNA-binding domain that is engineered

to bind to a target site in a gene selected from the group consisting of VR1, NaV1.8 and TrkA; and

(ii) a transcriptional repression domain;

such that the nucleic acid can be expressed in one or

more cells of the subject to be treated, whereby the

polypeptide is capable of binding to the target site

and repressing transcription of the gene."

V. With the statement of the grounds of appeal dated 14 April 2010 the appellant requested that the decision of the examining division be set aside and a patent be granted on the basis of an amended main request or, in the alternative, on the basis of auxiliary requests 1 to 4. In addition, the appellant filed more prior art including document (D3) and an auxiliary request for oral proceedings.

VI. On 19 July 2013 the board sent a summons to oral proceedings scheduled for 23 October 2013.

VII. The appellant in a letter of 9 August 2013 requested a postponement of the oral proceedings for the 23 October 2013 since it had already arranged oral proceedings before the examining division for a different case on the same day.

VIII. The board in a letter of 23 August did not accede to the appellant's request to change the date of the oral proceedings.

IX. The board informed the appellant of its preliminary view in its communication dated 6 September 2013. The board considered the subject-matter of the main request and of auxiliary requests 1 to 4 to comply with the requirements of Articles 123(2) and 54 EPC. Moreover, in the board's opinion the arguments of lack of clarity and sufficiency (Articles 84 and 83 EPC) brought forward by the examining division were considered unpersuasive as regards the subject-matter of claims 1, 4, 5, 7 and 9 in the request before it. These claims corresponded to claims 1, 4, 5, 7, 9 and 13 of the main request filed with the statement of the grounds of appeal. The board indicated to the appellant that it was thus inclined to set aside the impugned decision of the examining division in respect of the issues under Article 83 and 84 EPC. However, the board raised new objections of lack of inventive step (Article 56 EPC) against the subject-matter of all requests that were on file at the time. The board introduced in addition further prior art into the present appeal proceedings, including document (D6).

X. The appellant filed on 19 September 2013 a response to the board's preliminary view and withdrew its main and auxiliary requests 1 to 3 filed with the statement of the grounds of appeal. In addition, it made its former auxiliary request 4 filed with the statement of the grounds of appeal its new main and sole request. It also submitted supplemental experimental data to further support its arguments for the presence of an inventive step.

XI. The board informed the appellant in a telephone conversation dated 16 October 2013 (recorded in minutes dated 17 October 2013) that it considered the subject-matter of the sole remaining request inventive and that the oral proceedings scheduled for the 23 October 2013 could be cancelled if an adapted description would be filed by the appellant.

XII. The appellant in response submitted on the 18 October 2013 adapted pages of the description (pages 1 to 3, 21, 21a, 23 to 26, 28 to 34, 48, 65 and 69) and an amended request comprising claims 1 to 5 in which clerical errors were corrected.

Claims 1, 4 and 5 of the sole request read:

"1. Pharmaceutical composition comprising a nucleic

acid encoding a polypeptide, wherein the polypeptide

comprises:

(i) a zinc finger DNA-binding domain that is engineered

to bind to a target site in a NaV1.8; and

(ii) a transcriptional repression domain;

such that the nucleic acid can be expressed in one or

more cells of the subject to be treated, whereby the

polypeptide is capable of binding to the target site

and repressing transcription of the gene; wherein the

target site has a sequence SEQ ID NO. 122 and wherein

the DNA binding domain is of the C2H2 class.

4. A nucleic acid encoding a polypeptide comprising

(i) a zinc finger DNA-binding domain that is engineered

to bind to a target site in a NaV1.8 gene; wherein the

target site is SEQ ID NO. 122 and wherein the DNA

binding domain is of the C2H2 class; and

(ii) a transcriptional repression domain;

such that the nucleic acid can be expressed in one or

more cells of a subject to be treated, whereby the

polypeptide is capable of binding to the target site

and repressing transcription of the gene.

5. A polypeptide comprising

(i) a zinc finger DNA-binding domain that is engineered

to bind to a target site in a NaV1.8 gene; wherein the

target site is SEQ ID NO. 122 and wherein the DNA

binding domain is of the C2H2 class and

(ii) a transcriptional repression domain;

whereby the polypeptide is capable of binding to the

target site and repressing transcription of the gene."

The subject-matter of claims 2 and 3 were dependent on claim 1.

XIII. The board informed the appellant in a further telephone conversation on 18 October 2013 (recorded in minutes of the same date) the that the request and the pages of the description adapted thereto as filed on the 18 October 2013 by the appellant complied with the requirements of the EPC except for a clerical error on page 21a of the description. The appellant agreed that the board should correct the term "nucleic" on page 21a, in the second paragraph, first line into "nucleic acid" to reflect the appropriate wording of claim 4 of the sole request. The board then cancelled the oral proceedings.

XIV. The appellant requested that the decision under appeal be set aside and that a patent be granted on the basis of claims 1 to 5 and description pages adapted thereto filed with its letter of 18 October 2013 and corrected by the board in agreement with the appellant (see section XIII, above).

Reasons for the Decision

Note by the board

1. In an appeal relating to a decision of an examining division refusing a European patent application, the board of appeal has the power to examine whether the application or the invention to which it relates meets the requirements of the EPC (Art. 111(1) EPC). Hence the board can consider requirements that the examining division did not take into consideration in the examination proceedings or which it regarded as having been met (Headnote, decision G 10/93 (OJ EPO 1995, 172)).

2. Therefore, issues under Articles 123(2), 54 and 56 EPC not elaborated in the decision under consideration by the examining division will be addressed by the board in the present case.

Article 123(2) EPC

3. The board observes that the subject-matter of claim 1 is derivable from original claim 1 in combination with paragraph 82, table 6 on page 28 and paragraphs 161, 162 and 209 of the application as filed.

4. The subject-matter of claim 2 has its basis in claim 5 of the application as filed.

5. The subject-matter of claim 3 is derivable from the disclosure on page 19, line 6 of the application as filed.

6. The subject-matter of claim 4 is derivable from original claim 1 in combination with paragraph 82 and table 6 on page 28 of the application as filed.

7. Finally, the subject-matter of present claim 5 is considered to be based on original claim 1 in combination with paragraph 82 and table 6 on page 28 of the application as filed.

8. The board therefore considers that the subject-matter of claims 1 to 5 complies with the requirements of Article 123(2) EPC.

Article 84 EPC

9. The subject-matter of claims 1, 4, 5, 7 and 9 of the request in the first instance proceedings was held to lack clarity and support by the examining division because the subject-matter of these claims was exclusively defined by desired properties without providing any structural information. In addition compounds fulfilling the desired functions were not considered to be part of the general knowledge.

10. The board observes that the subject-matter of claims 4 and 5 of the request considered by the examining division is no longer upheld by the appellant in the present request. Moreover, the subject-matter of claims 1 and 9 of the request before the examining division corresponds to claims 1 and 5 of the present request. However, these two claims have been considerably amended by the appellant in the present request by restricting the target gene of the claimed zinc finger construct to NaV1.8 and by additionally defining a specific target site within this gene characterised by the structural information of SEQIDNO: 122 (see sections IV and XII, above). The subject-matter of claim 7 before the examining division and claim 2 of the present request is identical and has remained unaltered.

11. Nevertheless, the essence of the main lack of clarity objection of the examining division (see point 9 above) has remained unchanged in the present case because the zinc finger DNA-binding domain and the repressor domain of claims 1, 2, 4 and 5 are still not characterised by structural features in the form of defined nucleic acid or amino acid sequences.

12. In the case under consideration, where the characterising part of the independent claims 1, 4 and 5 is a functional feature directed to a result to be achieved ((i) "a zinc-finger DNA-binding domain that is engineered to bind to a target site in NaV1.8", and (ii) "a transcriptional repression domain....that can be expressed.... whereby the polypeptide is capable of binding to a target site and repressing transcription of the gene") in accordance with the well-established case law of the Boards of Appeal, the requirements of Article 84 EPC are only met if, (i) from an objective viewpoint, such features cannot otherwise be defined more precisely without restricting the scope of the invention and if (ii) these features provide instructions which are sufficiently clear for the expert to reduce them to practice without undue burden, if necessary with reasonable experiments (see Case Law of the Boards of Appeal of the EPO, 7th edition 2013, II.A.3.4). In other words, clarity demands that the skilled person is able to understand the teaching of the claim and that he or she is able to implement it in view of the information provided in the application or from common general knowledge.

13. Having regard to the requirements of Article 84 EPC above the board notes that the technical contribution of the application lies in the provision of several exemplary zinc finger proteins (ZFPs) (a total of 58 individual ZFPs are listed in tables 2 to 5 and 7 of the present application) of which 44 (see tables 4 and 7) bind to 32 different defined target sites in the claimed target gene NaV1.8 which sequence was known before the priority date (see table 6 and paragraph 82 of the application). The board furthermore observes that the involvement of NaV1.8 in triggering chronic pain, which is also known as neuropathic pain, is known from the art before the priority date of the present application (see paragraph 5 of the application and document (D6), abstract). The board cannot see how in view of the many exemplary NaV1.8 specific ZFPs and the target sites provided in the application the subject-matter of claims 1, 4 and 5 can be otherwise than functionally defined without unduly restricting the scope of the claims. The incorporation of the structural information regarding the ZFPs would restrict the scope of protection to only a small part of the invention and is in view of the contribution of the application unacceptable. Hence the board considers the first criterion identified (see (i) in point 12 above) as met.

14. The board is moreover of the opinion that the second criterion, namely the instructions provided in the application for the skilled person in combination with common general knowledge to put the invention into practise, is met (see (ii) in point 12 above). ZFPs in general are known to bind to DNA in a sequence-specific manner by a finger domain which comprises a zinc atom coordinated by conserved cysteines and/or histidines (see paragraph 76 of the present application). The application lists as mentioned above 44 exemplary NaV1.8 specific ZFPs and 32 exemplary NaV1.8 specific target sites (see tables 4, 6 and 7). Also the nucleic acid sequence for the complete human NaV1.8 gene was known at the relevant date and could be freely obtained from the public sequence depository GenBank (see paragraph 82 of the application). The board further observes that there were at least three different methods known at the priority date for making ZFPs against a known target sequence. The application itself mentions two of them, namely rational design and phage display, whereas the "mix and match" approach was known from the prior art (see page 34, paragraph 107 to page 41, first paragraph of the present application and document (D3), page 362, paragraph bridging col. 1 and 2). Finally, the board notes that the application discloses information for the skilled person which repressor domains are suitable for the claimed ZFPs, such as for example the "Kox domain" (see page 41, lines 14 to 19 and paragraph 140 of the application as filed).

15. In view of the above observations the board considers that the instructions given to the skilled person in the present application in combination with his or her common general knowledge at the relevant date are complete with regard to the support required for the subject-matter of claims 1, 2, 4 and 5. Consequently, the subject-matter of the claims of the present request complies with the requirements of Article 84 EPC.

Article 54 EPC

16. The examining division did not say in its decision whether or not the subject-matter of the claims before it complied with the requirements of Article 54 EPC.

17. The board, in view of the available prior art documents, is satisfied that the subject-matter of claims 1 to 5 of the present request is novel and thus complies with the requirements of Article 54 EPC.

Article 83 EPC

18. The examining division decided that the application in respect of the subject-matter of claims 1, 4, 5, 7 and 9 of the request before it was, with regard to its functional definition, insufficiently disclosed because ZFPs other than those being structurally defined in the application as filed but falling under the scope of these claims did not belong to the common general knowledge and the skilled person was unable to determine the nature of these compounds without undue burden in the absence of clear structural features defining them.

19. The board, however, is of the opinion that the application in respect of the subject-matter of present independent claims 1, 4 and 5 is sufficiently disclosed for the following reasons. As outlined above under points 13 and 14, the application provides not only a vast number of exemplary NaV1.8 specific ZFPs falling under the scope of the independent claims but it also provides ample information for the skilled person how to obtain further ZFPs having the desired properties. In this respect it is noted that the complete sequence information of the NaV1.8 target gene was publicly available at the relevant date and that the application furthermore provides assays allowing the skilled person to test whether the prepared ZFPs have the desired repressor activity on the transcription of NaV1.8 (see section VII, starting on page 47 and example 4 on page 68 of the application as filed). Suitable repressor domains for this purpose are disclosed in the application (see page 41, lines 14 to 19 and paragraph 140 of the application as filed). Admittedly, the preparation and testing of all these ZFPs amounts to much work, but in the board's view this is not tantamount to undue burden, in particular since there are no doubts as to the outcome.

20. Hence, the board cannot concur with the decision of the examining division that it would place an undue burden on the skilled person to prepare ZFPs having the desired properties because at the relevant date, it would seem in view of the matters mentioned in point 19 above to have been a question of routine procedure to provide ZFPs binding to a known target site in the NaV1.8 gene. This is confirmed by document (D3) referring explicitly to the increasingly routine use of ZFPs fused to an activator or repressor domain to control gene expression of a target gene and that specific ZFPs could be obtained within a time period of 2 weeks (see page 364, column 1, last paragraph to column 2, first paragraph and figure 4 of document (D3)).

21. Consequently, the board is satisfied that the application as filed provides sufficient information allowing the skilled person to carry out the invention over the whole scope as presently referred to in claims 1 to 5 and thus complies with the requirements of Article 83 EPC.

Article 56 EPC

22. The examining division has not considered in its decision whether or not the subject-matter of the claims before it complied with the requirements of Article 56 EPC.

23. The subject-matter of present claim 1 relates to a pharmaceutical composition comprising a nucleic

acid encoding a polypeptide, which comprises:

(i) a zinc finger DNA-binding domain that is engineered to bind to a target site in a NaV1.8; and

(ii) a transcriptional repression domain;

such that the nucleic acid can be expressed in one or

more cells of the subject to be treated, whereby the

polypeptide is capable of binding to the target site

and repressing transcription of the gene; wherein the

target site has the sequence SEQ ID NO. 122 and wherein the DNA binding domain is of the C2H2 class.

Closest prior art

24. The closest prior art is generally a prior art document disclosing subject-matter conceived for the same purpose or aiming at the same objective as the claimed invention and having the most technical features in common, i.e. requiring the minimum of structural modifications. Ideally, the purpose or objective should be something already mentioned in this prior art document as a goal worth achieving (see decision T 298/93 of 19 December 1996, point 2.2.2 of the reasons).

25. The board takes the view that the invention underlying the present application serves the purpose of providing a compound which represses NaV1.8 gene expression and is thus suitable for human therapy, in particular the treatment of neuropathic pain (see present claim 3; paragraph 6 of the application as filed). In the light of the criteria for identifying the closest prior art as elaborated by the Boards of Appeal, a document aiming at the same purpose, i.e. treatment of neuropathic pain by a compound which represses NaV1.8 gene expression, is considered to be the most appropriate starting point for the objective assessment of inventive step following the criteria of the "problem and solution approach".

26. Document (D6) discloses an antisense molecule directed against position 107 to 129 of the coding region of NaV1.8 thereby repressing its expression. This specific repression allows the treatment of chronic neuropathic pain in an animal model (see document (D6), page 143, abstract, column 2, line 10 to page 144, column 1, line 20; page 144, column 1, fourth paragraph). Document (D3) however, relates to ZFPs and their therapeutic potential in the treatment of human diseases. Inter alia it suggests the possibility of using ZFPs for the treatment of neuropathic pain. However, document (D3) neither discloses a ZFP for this particular treatment nor does it identify genes being involved in this disease (see document (D3), page 361, abstract, page 366, column 1, third paragraph to column 2, first paragraph). In view of these observations, the board rather considers that document (D6) constitutes the closest prior art.

Problem

27. The board observes that the present application does not indicate any superior effect of a ZFP directed against the target site identified by SEQ ID NO. 122 of present claim 1 in the treatment of neuropathic pain over the antisense molecule known from document (D6). Hence, the problem to be solved in view of the closest prior art would be the provision of an alternative repressor of NaV1.8 gene expression for a therapeutic use.

Solution

28. In view of the provision of: (1) the specific structural information for the target site in NaV1.8 (SEQ ID NO. 122) in combination with functionally defined ZFPs comprising a DNA binding and a repressor domain of present claims 1, 4 and 5; (2) the provision of the sequence information for a particular ZFP with the number 7235 characterised by SEQ ID NOs. 161, 174, 93, 175, 176 and 176 (see table 6 and 7 of the present application) which binds to SEQ ID NO. 122 as target site; and (3) the provision of several exemplary ZFPs repressing successfully NaV1.8 gene expression in the application as filed (see example 4 and figure 6), the board is satisfied that the solution to the problem mentioned above is credibly provided.

Obviousness

29. It remains to be assessed whether or not the subject-matter of independent claims 1, 4 and 5 is obvious or not in the light of the teaching of the prior art.

30. The skilled person knows from document (D6) that neuropathic pain could be successfully treated by specifically repressing the transcription of the NaV1.8 gene with antisense molecules. ZFPs with repressor domains are like antisense molecules generally known in the art to bind specifically to and repress the transcription of genes of interest. The skilled person is furthermore aware of the fact that this particular property of ZFPs renders them interesting for the development of novel human therapeutics, e.g. for the treatment of neuropathic pain (see document (D3), page 361, abstract; page 366, column 1, last paragraph to column 2, first paragraph).

31. Consequently, the board is of the opinion that the skilled person would have reasonably considered the use of ZFPs as suitable alternative repressors to antisense molecules for a therapeutic use, such as the treatment of neuropathic pain. But was there any reasonable expectation of success to arrive at the subject-matter of claims 1, 4 or 5 as presently claimed?

32. The board observes, that document (D3) which relates exclusively to ZFPs only suggests the use of ZFPs for the treatment of neuropathic pain but discloses neither any particular target gene that is involved in the aetiology of this disease nor provides any ZFPs that have been successfully used in its treatment. It does however provide the general teaching for the skilled person that ZFPs can only be generated against pre-determined DNA sequences and, when used to control gene transcription, should optimally regulate only its intended gene (see document (D3), page 361, column 2, second paragraph and page 362, column 2, last paragraph). In the board's view, the skilled person would interpret this teaching in the sense that the target gene sequence has to be known and the particular sub-sequence recognised by the ZFP has to be specific for this particular gene to avoid any possible side-effects. Moreover, document (D3) mentions that a general obstacle for their successful in vivo use is the limited access of ZFPs to potential target genes due to the occlusion of human DNA by nucleosomes and chromatin condensation leaving only less than 1% of the DNA in a differentiated human cell in fact available for ZFP binding (see document (D3), page 363, column 2, first paragraph). This teaching suggests to the skilled person that not all known target genes are equally suitable for ZFP binding and that moreover even the specific target regions within such a gene are not equally suitable due to the access restrictions caused by the overall human DNA structure.

33. The skilled person being conservative and aware of all these limitations regarding ZFPs as indicated above would have therefore selected the NaV1.8 gene because (1) it was known to be involved in the aetiology of neuropathic pain and (2) it was the only known gene from the art whose transcription could be regulated in vivo by a an antisense molecule rendering it thus suitable for the treatment of this disease (see document (D6), abstract). Although this teaching suggests to the skilled person that the NaV1.8 gene has a certain accessibility for a repressor at the site used by the antisense, he or she is aware of the facts that (1) the results obtained for the antisense molecule are not directly transferable to a ZFP molecule due to their difference in size and their different mode of interaction with genomic DNA and (2) other sites might be even less suitable for the ZFP due to access restrictions. In view of this limited expectation of success the board is of the opinion that the skilled person had no motivation to select a target site in the NaV1.8 gene which is different from the one used in document (D6) by the antisense molecule. The board observes in this respect that the antisense molecule is directed against a site in the NaV1.8 gene which is located at nucleotide position 107 to 129 of its coding region (see document (D6), page 144, column 1, fourth paragraph). This particular site is the only one disclosed in document (D6) and there are no indications given that other regions in the NaV1.8 gene than this particular one could be used as a target site for further antisense molecules allowing a significant reduction of its gene transcription.

34. The location of the ZFP target site characterised by SEQ ID NO. 122 and its encoding sequence in present claims 1, 4 and 5 is, however, to be found between position 3 and 24 of the coding region of NaV1.8 (see table 6, last line on page 28 in combination with the disclosure of paragraph 93 of the application). Accordingly, this site is more than 100 nucleotides further downstream of the target site indicated in document (D6). In view of the reasons provided above, the board is of the opinion that the skilled person not only had no motivation to select this particular target site in NaV1.8 for a ZFP repressor, but that also had no reasonable expectation of success that any ZFP binding to this particular position in the NaV1.8 gene would in fact achieve a rate of repression that would be sufficient for any therapeutic use.

35. This finding of the board is moreover supported by the supplementary experimental data as submitted by the appellant with its letter of 19 September 2013. These data clearly provide evidence that the position of the target site in the NaV1.8 gene strongly influences the repression efficiency of the ZFP on NaV1.8 gene transcription (see the table provided in these data). This shows that the accessibility of the genomic NaV1.8 DNA at a particular target site is in fact a key factor for the binding and hence repression efficiency of the ZFP molecule used.

36. Hence, the board acknowledges the presence of an inventive step for the subject-matter of claims 1, 4 and 5 (Article 56 EPC). The subject-matter of claims 2 and 3 is dependent thereon and is therefore inventive as well.

Further matter

37. The board is furthermore satisfied that the pages of the description as submitted by the appellant on the

18 October 2013 have been appropriately adapted to claims 1 to 5.

Order

For these reasons it is decided that:

The decision under appeal is set aside.

The case is remitted to the department of first instance with the order to grant a patent on the basis of claims 1 to 5 and the pages 1 to 3, 21, 23 to 26, 28 to 34, 48, 65 and 69 of the description, all filed with the letter of 18 October 2013, including an amended page 21a filed with the same letter but wherein the term "nucleic" in the second paragraph, first line is replaced by "nucleic acid" and pages 4 to 20, 22, 27, 35 to 47, 49 to 64, 66 to 68 and figures 1 to 8 of the description as filed.