Pages 293-308

INFORMATION FROM THE EPO

Decisions of the examining and opposition divisions

Decision of the opposition division dated 20 June 2001^*

Patent proprietor: ICOS Corporation

Opponents:

(1) SmithKline Beecham

(2) Duphar International Research

Headword: Novel V28 seven transmembrane receptor

Article: 52(1), (2) (a), 56, 57, 83, 100(a), (b) EPC

Rule: 23e(b-e), 27(1)(f)

Directive 98/44/EC: Recital 23

Keyword: "DNA sequence encoding a protein without a credible function" - "Inventive step (no)" - "Sufficiency of disclosure (no)" - "Industrial application (no)" - "Patentable invention - mere discovery (no) - technical character (no)"

Headnote:

The disclosure of a predicted function of a protein in combination with a method of verification of this function is not necessarily adequate to sufficiently disclose the function of the protein. In the absence of a disclosed compound (a ligand for a predicted receptor protein), methods utilising this compound (modulating the binding of the ligand) are not considered sufficiently disclosed. A list, in the description, of speculative functions of a protein is not in itself a reliable basis for acknowledging industrial application of this protein. A DNA sequence encoding a protein without a credible function is not a patentable invention.

Facts and submissions

I. European patent No. 0 630 405 was granted in response to European application No. 94 903 271 filed on 17.11.93 claiming priority of US 977 452 of 17.11.92. The mention of the grant of the patent was published in European Patent Bulletin 1998/15 of 8.4.98.

The proprietor of the patent is ICOS CORPORATION. The patent title is "Novel V28 seven transmembrane receptor".

II. Notice of opposition has been filed by two opponents:

(i) SmithKline Beecham (opponent 1) on 7.1.99,

(ii) Duphar International Research (opponent 2) on 8.1.99.

A list of documents D1-D39 has been submitted by the patentee with his response of 8.9.99. The list has been adopted by the opposition division and has been used in the rest of the procedure. Documents published after the filing date of the application have been taken into consideration as expert opinion. Reference has been made to technical decisions T 210/89, T 100/90, T 409/91, T 435/91, T 886/91, T 923/92, T 939/92, T 588/93, T 207/94.

The opponents requested that the patent be revoked in its entirety in accordance with Articles 100(a) and (b) EPC in conjunction with Articles 52(1) and (2)(a), 56, 83 and 57 EPC. (...).

The patentee requested that the oppositions be rejected in toto and that the patent be maintained as granted. (...).

Reasons for the decision

1. The subject-matter of claim 1 relates to a purified and isolated polynucleotide encoding the amino acid sequence of V28 seven transmembrane receptor set out in SEQ ID NO:28 or a fragment thereof possessing at least one ligand/antiligand binding activity or immunological property specific to said V28 seven transmembrane receptor.

Inventive step

2. (i) The patentee submitted that the problem solved by the claimed subject-matter is "the provision of an additional 7TM receptor involved in immunological processes" rather than "the provision of an additional or alternative 7TM receptor" as formulated by the opponents. In support of this view he cited the presence of a cDNA clone of V28 gene in a peripheral blood mononuclear cell cDNA library (example 7) and the presence of V28 transcripts in several tissues of immunological relevance (example 14).

(ii) Both opponents argued that the specification does not contain evidence that V28 is a receptor nor that it is involved in immunological processes and thus the problem as formulated by the patentee is not solved by the claimed subject-matter:

Opponent 1 pointed out that the specification discloses the nucleotide and amino acid sequence of V28 gene but not a ligand binding to said protein and thus receptor function is only predicted based on structural characteristics of the sequence. Furthermore, the specification discloses that V28 protein shares sequence identity with interleukin 8 receptor (IL8R1) (30%) as well as with angiotensin II receptor (AT2R) (28%) which could imply involvement of V28 protein in immunologic or in haematostatic processes (see page 2 of specification). The expression of V28 in several tissues of the immune system indicates that said gene is not necessarily performing a function relating to immunological processes; it may have a house-keeping function relevant to these cells. Moreover, the high expression levels of V28 detected in the promyelocytic cell line THP.1 may indicate involvement of V28 in transformation of this cell line. Opponent 2 argued that unless a ligand is identified for a particular receptor, the function of said receptor remains unknown. The specification does not disclose a ligand for V28 and thus a function as a receptor cannot be acknowledged nor can its involvement in immunological processes.

Both opponents argued that the problem solved by the specification is the provision of an alternative 7TM protein. However, the solution of said problem is not inventive in view of the teachings of document D1 in combination with document D2 or because of the teachings of document D5.

(iii) The patentee repeated his written submissions that although D2 discloses a method of PCR-based cloning many choices had to be made during the course of identifying V28 nucleic acid, ie PCR conditions, cell type to derive the nucleic acid from, cell's growth state and type of nucleic acid library to be probed, in order to arrive at the nucleotide sequence of V28 gene.

3. The opposition division takes the view that it is important to determine the degree of characterisation of the disclosed V28 protein in comparison with the state of the art at the time of filing of the application before a problem is formulated.

(i) The specification discloses a genomic and a cDNA clone encoding a protein, termed V28, presented as SEQ ID NOs: 27 and 28. A partial genomic clone was identified by PCR cloning using degenerate primers designed from regions of high amino acid similarity between IL8 receptor and AT2 receptor. This clone was further used to identify the complete genomic V28 clone. The deduced amino acid sequence of SEQ ID NO 27, presented in SEQ ID NO 28, predicts a structure comprising seven hydrophobic domains (7TM) separated by hydrophilic domains and residues which are conserved within a group of proteins called 7TM receptors. A cDNA clone was isolated from a cDNA library generated from peripheral blood mononuclear cells, indicating expression of V28 gene in said cells. The specification contains a Northern blot analysis showing that V28 gene is expressed in spleen, thymus, tonsil, lymph node, placenta, ovary, testis, kidney and 3 promyelocytic cell lines. Several methods which may be used to identify extracellular and intracellular ligands for V28 protein are disclosed. The methods are based on assays monitoring secondary signal transduction events in mammalian cells expressing V28 gene in the presence and absence of test compounds. No results of said methods are presented.

(ii) The closest prior art document is considered to be document D1 which is a review of 74 proteins which belong to the superfamily of 7TM receptors (also called G-protein coupled receptors, GPR). The document discloses structural features of said proteins including regions of high homology shared among all members of the family, ligand binding domains and signal transduction coupling of said proteins.

(iii) The problem to be solved can be formulated as the provision of the nucleotide sequence encoding an additional 7TM protein which is predicted to function as a receptor.

(iv) The subject-matter of claim 1 relates to a purified and isolated polynucleotide encoding V28 protein as set out in SEQ ID NO:28. Said amino acid sequence has a predicted structure consistent with typical 7TM receptor (specification, page 9, line 46) and thus solves the above-mentioned problem.

This solution cannot be considered to be inventive because document D1 provides a sequence alignment of 74 known 7TM receptors, including IL8 receptor and AT2 receptor, and indicates that sequence similarity is useful in designing cloning strategies for other GPRs (page 1). Similarly, document D5 discloses cloning strategies that led to the identification of 17 different receptors of the 7TM family and refers to the use of degenerate primers in a PCR-based cloning procedure (page 4). Document D2 discloses a procedure whereby degenerate PCR primers are designed so as to identify and amplify receptors of the 7TM family (Figure 1). Therefore, the existence of additional 7TM receptors was predicted in the prior art and the procedure for the identification of said additional members of 7TM receptor family has been well established. Consequently, the disclosure of the primary structure of an additional 7TM protein which is arrived at by following the well established methods disclosed in the prior art is not considered inventive and fails the requirements of Article 56 EPC.

(v) Concerning the argumentation of the patentee that in the process of identifying V28 clone, many choices had to be made, the opposition division takes the view that this kind of choice falls within the routine procedure followed by the skilled persons and does not deviate in any way from the teachings of the prior art document D1 in combination with D2. Furthermore the choice of primers, which is presented by the patentee in support of inventiveness, makes use of the teachings of sequence alignment of D1 (page 2 and Figure 2) and D2 (Table 1) in order to detect conserved regions.

The opposition division agrees with the view of opponent 1 that V28 clone represents an arbitrary choice from seven clones identified (V31, V28, V112, R20, RM3, R2, R12, examples 1-11 of the specification), thus, indicating that the conditions were not optimised in any way to identifying V28 clone specifically. More significantly, the difficulty involved in the choice of conditions would support an inventive step argument directed to a method for the identification of 7TM proteins which is not the subject-matter of the present claim.

(vi) Due to its dependence on the sequence of V28 7TM protein, the subject-matter of claims 2-15, 23 is not considered inventive either.

Sufficiency of disclosure

4. (i) Opponent 1 argued that the specification does not disclose the function of the V28 receptor. Claims 21, 22 relate to in vitro methods involving an antibody specific for V28 protein or agonist or antagonist of V28 protein respectively. These methods are not sufficiently disclosed because the ligand of putative V28 receptor is not disclosed in the specification. For the same reason a fragment or a variant thereof possessing ligand/antiligand binding activity is not sufficiently disclosed (claims 1, 13). The subject-matter of claim 7 relates to "a V28 seven transmembrane receptor" (emphasis added by the opponent) but since the specific properties of V28 are not disclosed in the specification the subject-matter is not sufficiently disclosed. Claims 16-20 relate to an antibody specific for V28 protein, which is suitable for treating inflammation in a mammal. The specification is not enabling for said claim because an antibody specific for V28 protein which antagonises the activity of putative V28 receptor is not disclosed.

(ii) Opponent 2 agreed with opponent 1 and further argued that the subject-matter of claim 13 is not sufficiently supported by the specification because a protein product of V28 gene is a membrane bound protein rather than an isolated protein. Opponent 2 also pointed out that the specification does not disclose sufficiently the function of V28 protein as receptor because the ligand is not disclosed and that, as transpires from the teachings of D3, the identification of said ligand poses an undue burden for the skilled person.

(iii) The patentee repeated the argument that the subject-matter of all claims is enabled by the disclosure of the sequence of V28 protein and thus all claims are sufficiently disclosed. The V28 protein has been verified by later publications to be a receptor (D11-D14) and this was made possible only because of the disclosure of the sequence of V28 gene and protein by the specification. Although the specification does not disclose the natural ligand, a method for identifying other ligands is set out (example 19). Moreover, antibodies are enabled by the specification because they may by produced by routine methods. Furthermore, an antibody may serve as a ligand and thus the isolation of a ligand is also enabled by the disclosure of the sequence of V28 and routine methods.

(iv) Opponent 1 pointed out that the method of example 19 for the identification of a ligand is not practical because it requires the screening of a great number of compounds. Concerning the method of claim 20, the antibody has to be disclosed in the specification as binding and blocking the function of V28 rather than only binding to V28 as any routinely produced antibody would do.

5. The opposition division adopts the view that the specification discloses a V28 7TM protein which is predicted to function as a receptor. The prediction that V28 is a receptor is based on structural elements present in the deduced amino acid sequence SEQ ID NO:28, ie the presence of seven hydrophobic domains separated by hydrophilic domains and the homology to known 7TM receptors. The specification does not demonstrate, in any way, that V28 protein is a receptor. Instead, it discloses several methods which can be used by the skilled person in order to verify the prediction that V28 protein is indeed a receptor (example 19, methods for the identification of ligands of V28).

The implicit assumption in presenting such methods instead of a conclusive demonstration of the predicted function is that such an undertaking falls within routine procedure of the persons skilled in the art. Indeed, there are cases where a predicted function of a protein may be demonstrated in a technically undemanding way (eg predicting a specific enzymatic activity), in which case, the disclosure of predicted function in combination with a method of verification of said predicted function amounts to sufficiently disclosing the function of said protein. The opposition division thus set out to examine the plausibility of verifying that V28 protein is a receptor relying on the disclosure of the specification:

(i) Example 19 relates to an assay based on testing candidate ligand compounds for their ability to act as ligands for V28 and effect a transient calcium flux in a cell that expresses V28 gene. The teachings of the specification do not limit the candidate ligand compounds to any specific group of compounds and thus, the skilled person seeking to identify said ligand has to test millions of available candidate compounds through the method of example 19 in order to identify a ligand for V28. This undertaking constitutes an undue burden for the skilled person seeking to perform the claimed invention, ie obtain a 7TM protein which is definitely a receptor.

(ii) The difficulty of the undertaking is further reflected in the teachings of documents published after the publication date of the specification. The method of example 19 was performed (D3, published one year after the publication of the application) for 11 compounds belonging to a limited class of candidate ligands, namely chemokines, which were selected on the basis of the similarity of V28 protein to chemokine receptors. The authors of D3, following the method of example 19, failed to identify a ligand for V28 receptor among the tested candidate compounds.

(iii) The first document to report the function of V28 protein as a receptor is document D11, published three years after the publication of the application, which discloses that V28 protein functions as a coreceptor for HIV-2 virus. Considering that the first entity identified as binding to V28 protein and demonstrating the function of V28 as a receptor is not a compound at all but a virus, the method of example 19 may even be considered as misleading for the skilled person.

(iv) Lastly, document D14, published three years after the publication of the application and after D11, discloses that the ligand for V28 protein is fractalkine and that binding of fractalkine to V28 protein causes cellular events consistent with the function of V28 as a receptor (Fig. 2 and pages 522-523). Notably, the identification of fractalkine as a receptor for V28 receptor was not achieved by the method of example 19. On the contrary, fractalkine was known to induce adhesion and migration of leukocytes albeit through an unknown receptor. Binding assays of fractalkine to 10 different test receptors showed specific binding to V28- transfected cells and the receptor function was then verified by the induction of chemotaxis of said cells and by indicating signal transduction in said cells mediated by G proteins.

Thus, taking into account the disclosure of the specification, the argumentation of the parties and these post-published documents, for the provision of expert opinion, the opposition division concludes that disclosure of the amino acid sequence of V28 protein and prediction of a function as a receptor in combination with the method disclosed for identification of the respective ligand does not suffice to disclose a receptor protein with SEQ ID NO:28. Consequently the requirement for sufficient disclosure of the subject-matter of the invention as defined in claims 1-15, 23 is not met by the specification contrary to Article 83 EPC.

6. The subject-matter of claims 16-21 relates to an antibody substance specific for V28 protein.

(i) The specification does not disclose any antibody substance which specifically recognises V28 protein. Although it is conceivable that a number of antibodies (including known antibodies) recognise and bind to V28 protein, an antibody that specifically recognises V28 protein, is not disclosed. Furthermore, the assertion of the patentee that generation of such antibodies is routine matter in the art is not followed by the opposition division. An antibody that specifically recognises V28 is understood to mean an antibody that does not recognise any other protein. The generation of such antibodies is not considered a routine matter given the labour intensive exclusion of cross reactivity of the candidate specific antibody with any other protein.

(ii) As discussed above, antibody substances which specifically recognise V28 protein are not enabled by the disclosure of the specification. Even more remote from the disclosure of specific antibodies is the disclosure of specific antibodies for V28 protein which are suitable for treating inflammation in a mammal. The involvement of V28 protein in inflammation is not demonstrated in the specification. Therefore, the identification of specific antibodies suitable for counteracting a speculative activity of V28 protein (ie induction of inflammation) is not enabled by the disclosure of the specification.

(iii) Antibodies suitable for use in a method for modulation of binding of a ligand/antiligand to V28 are also antibodies possessing special properties (for example, spatially hindering or enhancing the binding of a ligand to V28 protein). No such antibodies are disclosed in the specification. The identification of such antibodies necessitates prior identification of the ligand/antiligand molecules or the binding site of said molecules. None of these is disclosed nor enabled by the disclosure of the specification.

7. The subject-matter of claim 22 relates to an in vitro method which relies on the use of an agonist or antagonist of V28 protein. The opposition division does not agree with the patentee that "antibodies are well known class of antagonists". Although it may happen in some cases, for example when the antibody binds the agonist binding site of a receptor and thus antagonises the action of the receptor, the specification does not disclose such a specific type of antibody which acts as an antagonist. No other kind of antagonist is disclosed in the specification and, therefore, the method of said claim is not sufficiently disclosed.

Industrial application

8. (i) Both opponents argued that the lack of disclosure of a ligand of V28 7TM protein or the lack of disclosure of a specific involvement of said protein in a biological process precludes the industrial application of V28 7TM protein. Opponent 2 in particular pointed to the requirements of Rule 23e (3) EPC concerning industrial application of a sequence. Specifically, he referred to Recitals 23 and 24 of European Directive No. 98/44/EC, which has been incorporated into the EPC as of 1 September 1999 by the introduction of Rules 23 b-e EPC. As a note of caution, Opponent 2 also mentioned that in Decision T 210/89 the principle of legal certainty is invoked to stipulate that changes in the Rules of the EPC are non-retroactive.

(ii) The patentee argued that according to Article 57 EPC the requirements for industrial application of an invention are satisfied "if it can be made or used in any kind of industry". It was argued that the specification discloses how to make the V28 protein and discloses also uses of V28 protein mainly as a receptor involved in immunological processes (page 4 and example 14).

Opponent 1 counterargued that the use of a newly identified protein in research is not equivalent to industrial application and cited an oral presentation made by Dr Christian Gugerell during the ECPI Conference (13.10.98).

9. The opposition division does not agree with the patentee that the specification fulfils the requirements for industrial application solely on the grounds that the specification shows that V28 can be made and can be used. The requirements of industrial application of biotechnological inventions are set by Rules 23b-23e EPC which concern European patent applications and patents (emphasis added). Thus, the provisions of said Rules apply to the present procedure and the recitals of European Directive 98/44/EC are applicable as supplementary means of interpretation. In view of the requirements of industrial application as set in Article 57 EPC in conjunction with Rule 23b-e EPC, the invention cannot be acknowledged as industrially applicable because industrial applications are not disclosed in the patent application (Rule 23e(3) EPC).

(i) Potential uses of the invention are disclosed in the specification (p. 3.4) which however are based on a proposed function of the V28 protein as a receptor which is not sufficiently disclosed in the specification (see section 5 above). Thus, the potential uses disclosed in the application are speculative, ie are not specific, substantial and credible and as such are not considered industrial applications.

In more detail: The specification states that host cells expressing products of V28 7TM gene are useful in methods for the large scale production of V28 7TM protein (p. 3). Since the V28 protein is not disclosed to have any function (eg biological which would implicate a therapeutic use nor as a marker which would implicate a diagnostic use), it cannot be seen why it would be useful to produce said protein on a large scale in industry.

The specification states that antibody substances specifically reactive with V28 7TM protein are useful in complexes for immunisation to generate anti-idiotypic antibodies, for purifying V28 peptides and for identifying cells producing the V28 polypeptides (p. 4). Specific antibodies are not disclosed in the specification and may not even be possible to be generated due to high sequence identity shared by a large number of proteins (see Table 1 of specification and above section 6(i)). Therefore, these proposed users are directed to a substance that has not been disclosed and can only be considered as speculative.

The specification further asserts that antibodies, agonists or antagonists of V28 protein are manifestly useful in modulating ligand/receptor binding reactions involved in immunological and/or inflammatory events in vivo (p. 4). As discussed above (section 6(iii)), antibodies suitable for modulating ligand/receptor binding represent a special type of antibody which has not been exemplified in the specification. Furthermore, the involvement of V28 protein in immunological and/or inflammatory events in vivo has not been demonstrated either. The proposed use thus is directed to a potential interference of a speculative activity of V28 protein with a substance which has not been shown to be possible to prepare. Such a use lacks credibility.

(ii) Concerning other potential industrial applications submitted by the patentee later with his letter of 8.9.99 and during the oral proceedings, the opposition division takes the view that they do not meet the requirements of Article 57 EPC in conjunction with Rule 27(1)(f) EPC and Rule 23e(3) EPC.

These applications relate to V28 protein as a participant in immunological processes. However, the present description does not explicitly indicate nor make obvious the involvement of V28 protein in immunological processes and as a consequence it does not meet the requirements of Rule 27(1)(f) EPC as far as industrial application of V28 protein derivable from its involvement in immunological processes.

It was argued that involvement of V28 protein in immunological processes is disclosed in example 7 (isolation of a V28 cDNA clone from peripheral blood mononuclear cells) and in example 14 (expression of V28 gene in immune response relevant tissues as well as in tissues of reproductive and metabolic relevance). However, the specification does not refer to the apparent expression pattern of V28 gene as indicating an involvement of the V28 gene in immunological processes, nor any other process, for that matter. Moreover, the evidence of example 14 does not support the notion that V28 gene is relevant for immunological processes. Since V28 transcripts are detected in a number of tissues of diverse functionality, it is not directly derivable from the specification that V28 protein is relevant for immune response functions. After extensive experimentation carried out by scientific groups unrelated to the present applicant, it became apparent that V28 protein plays a role as coreceptor of HIV-2 virus and in mobility and adhesion of leukocytes (documents D11-D14) thus clarifying the biological role of V28 protein which may lead to relevant industrial application. However, the evidence in the present specification does not explicitly or implicitly indicate the involvement of V28 protein in immunological processes and thus it does not indicate that said invention is capable of exploitation in relevant industrial applications.

Patentability

10. (i) Opponent 1 argued that the disclosure of V28 gene and protein without concrete industrial applicability is not patentable because it lacks technical character (Article 52(1) EPC). Furthermore, the simple isolation of a 7TM protein is considered a discovery and thus not an invention (Article 52(2)(a) EPC).

(ii) Opponent 2 submitted that the subject-matter of claims of the granted patent is not of technical character as implicitly required by Article 52(1) EPC. The invention does not provide a technical contribution to the art. Opponent 2 held that Recital 23 of EU Directive 98/44/EC provides an interpretation rule for assessing the technical nature of DNA-related subject-matter and concludes that application of these principles leads to the conclusion that the alleged invention fails to provide a technical character. In reference to Article 52(2)(a) EPC, he argued that the disclosure of genomic DNA encoding a V28 protein is a discovery rather than an invention.

(iii) The patentee argued that concerning the technical character of V28 gene and protein, the specification discloses that it is a receptor involved in immunological processes. Contrary to the notion that V28 is a discovery, he argued that the specification discloses a cDNA clone not existing in nature as such.

11. Concerning patentability under Article 52(1) and (2) EPC, the opposition division takes the following view:

(i) The opposition division cannot follow the argumentation of the opponents that the disclosure of V28 gene and protein is a mere discovery. Although nucleic acid encoding V28 protein exists as a segment of the human genome and thus is a part of nature, the purified and isolated nucleic acid having that sequence does not exist in nature and thus cannot be discovered. The purified and isolated polynucleotide encoding V28 protein is, de facto, not a discovery. Thus, the specification does not relate to a discovery as specified in Article 52(2)(a) EPC and may constitute a patentable invention under Article 52(1) EPC.

(ii) However, Article 52(1) EPC requires that a patent is granted for an invention which is susceptible of industrial application, which is new and which involves an inventive step. As discussed above (section 3), the present invention fails the criterion of inventive step. Similarly, the present invention fails the criterion of industrial application as discussed above (section 9). Thus, the present specification does not relate to a patentable invention as required by Article 52(1) EPC.

Furthermore, Recital 23 of the Directive reads as follows: "Whereas a mere DNA sequence without indication of a function does not contain any technical information and is therefore not a patentable invention". The opposition division interprets the requirement of an "indication of function" to be a requirement for indications which are more than speculative. In other words, DNA sequences with indications of function which are not substantial, specific and credible shall not be patentable inventions according to Article 52(1) EPC because they lack technical character. The opposition division follows the arguments of opponent 2 that the subject-matter of the patent in suit falls exactly within the wording of the above recital and therefore is not a patentable invention under Article 52(1) EPC.

Decision

The opposition division is of the opinion that the grounds of opposition under Article 100(a) and (b) EPC in conjunction with Articles 56, 83, 57 and 52 EPC prejudice the maintenance of the patent as granted and, therefore, came to the conclusion that the patent has to be revoked in accordance with Article 102(1) EPC.