T 1120/12 (Amyloidogenic disease/JANSSEN) 22-11-2016

1. The appeal is admissible.

2. Oral proceedings were held and the appeal proceedings continued in the absence of the duly summoned respondent in accordance with Rule 115(2) EPC and Article 15(3) RPBA. In accordance with the latter provision, the respondent was treated as relying on its written case, i.e. on the content of the reply to the statement of grounds of appeal being the sole substantive submission filed by the respondent. By not attending the oral proceedings, the respondent availed itself of the opportunity to present any comments on the issues addressed at the oral proceedings.

Validity of the claimed priority

3. The opposition division held that the subject-matter of claim 1 of the patent as granted could not be accorded the priority date because the fragments Abetal-7 and Abeta3-7 were not disclosed in the application from which priority was claimed (see section I). Accordingly, document D1 was considered state of the art in accordance with Article 54(2) EPC.

4. The respondent has not argued differently and the board also concurs with finding of the opposition division in this respect. Accordingly, the effective date for the claimed subject-matter in patent in suit is the filing date.

Inventive step (Article 100(a) EPC in combination with Article 56 EPC; Article 56 EPC)

Main request and auxiliary request 3 - claim 1

5. The claimed invention relates to fragments of a peptide termed Abeta or beta-amyloid peptide being the principle constituent of amyloid deposits, so-called senile plaques, formed in the brain of patients with Alzheimer's disease. Abeta peptide is an internal fragment of 39 to 43 amino acids of a precursor protein called amyloid precursor protein (APP). Mutations in APP are thought to promote generation of Abeta and the deposition thereof and thereby to cause Alzheimer's disease.

6. Claim 1 (see sections I and V) is inter alia for fragment 1-7 or 3-7 of Abeta (i.e. Abeta1-7 and Abeta3-7) linked to a carrier peptide for use in inducing an immune response against Abeta thereby preventing or treating a disease associated with amyloid deposits of Abeta in the brain of a patient.

7. During the oral proceedings the board decided that the the subject-matter of claim 1 in the aspects relating to fragment Abeta1-7 lacked an inventive step. In view of the following reasoned negative judgement in this respect a decision of the board on the aspects of the claim relating to Abeta3-7 is not required.

The closest prior art

8. In order to assess whether or not a claimed invention meets the requirements of Article 56 EPC, the boards of appeal apply the "problem and solution" approach, which requires as a first step the identification of the closest prior art. In accordance with the established case law of the boards of appeal, the closest prior art is a teaching in a document conceived for the same purpose or aiming at the same objective as the claimed invention (Case Law of the Boards of Appeal of the European Patent Office, 8th edition 2016, I.D.3.1).

9. Like the opposition division in the decision under appeal, the appellant considered document D1 to represent the closest prior art. Document D1 is an earlier patent application by the same applicant as the proprietor of the patent in the field of the prevention and treatment of amyloidogenic disease, such as Alzheimer's disease (AD). The disclosures of document D1 and the patent overlap to a large extent. Both documents also have examples I to X and a large portion of example XI in common.

10. The common disclosure of the two documents, which therefore constitutes a teaching comprised in the prior art, relates in its most pertinent parts inter alia to the immunisation of so-called PDAPP mice with Abeta or with non-conjugated and conjugated smaller fragments thereof originating from different parts of Abeta. Joint example III discloses that the immunisation of PDAPP mice with the human aggregated long form of Abeta, i.e. Abeta1-42, results in the prevention of Abeta plaque formation and reduction of amyloid plaque deposits already established in the brain. Joint example IV discloses the screening of four specific human Abeta fragments conjugates, i.e. linked to a carrier peptide (see patent [0185]) in the immunisation of PDAPP mice to determine which epitopes convey the response reported on in example III. A reduction of established amyloid plaques, including a reduction in total Abeta in the brain of PDAPP mice, was achieved by immunisation with a conjugated Abeta1-5 fragment being derived from the N-terminus of human Abeta. Immunisation of PDAPP mice with conjugates of the three other human Abeta fragments which were screened, i.e. sheep anti-mouse IgG-conjugated Abeta1-12, Abeta13-28 and Abeta33-42 fragment conjugates, as well as an aggregated Abeta25-35 fragment, did not significantly reduce either the amount of established amyloid plaques or the total amount of Abeta in the brain of PDAPP mice (see document D1, page 52, lines 15 to 23 and page 53, lines 23 to 28 and the patent paragraphs [0189] and [0193]).

11. Although the respondent has not contested the appropriateness of document D1 to represent the closest prior art, it was however argued that the entire content of document D1 ought to be considered and not merely the Abeta1-5 fragment conjugate disclosed therein.

12. The board can concur with the respondent, that rather than solely the disclosure of the Abeta1-5 fragment, the whole teaching in document D1 represents the closest prior art for the skilled person. Hence and in this context, the relevant insights disclosed in document D1 are that, whereas immunisation with conjugates of the human Abeta1-12, Abeta13-28 and Abeta33-42 fragments (and an aggregated human Abeta25-35 fragment of Abeta), i.e. four fragments spanning the whole of the Abeta1-42 form of Abeta, did not lead to a reduction of established amyloid plaques, including a reduction in total Abeta in the brain of PDAPP mice, as could be observed for immunisation with the aggregated Abeta1-42, this effect was however achieved by immunisation with the conjugated human Abeta1-5 fragment. Of particular note in this context is that, whereas the conjugate of the human Abeta1-5 fragment is able to achieve the desired technical effect, the larger human Abeta1-12 fragment conjugate, comprising the Abeta1-5 fragment, failed to do so.

The technical problem and its solution

13. According to established case law of the boards of Appeal the technical problem is formulated by taking into account those features distinguishing the claimed invention from the disclosure of the closest prior art and the technical effects caused thereby.

14. The subject matter of claim 1 relates to the human Abeta1-7 fragment conjugate as therapeutically useful in inducing an immune response against Abeta and thereby preventing or treating a disease associated with amyloid deposits of Abeta in the brain of a patient.

15. As to features distinguishing this human Abeta1-7 fragment from the fragments disclosed in the closest prior art, the Abeta1-7 fragment is two amino acids longer than the Abeta1-5 fragment, but 5 amino acids shorter than the Abeta1-12 fragment. As to the effect caused by this difference the board is satisfied that for the purpose of the present assessment examples IX and XI of the patent can be accepted to demonstrate the same technical effect for the Abeta1-7 fragment conjugate as for the Abeta1-5 fragment conjugate disclosed in document D1 in terms of a reduction of established amyloid plaques, including a reduction in total Abeta in the brain of PDAPP mice.

16. The respondent has submitted however, that there was a further feature distinguishing the claimed compounds from those of the closest prior art. It was argued that in particular the last sentence of paragraph [0040] of the patent explicitly described the surprising advantage of the claimed Abeta fragment as the reduction of the potential for side-effects that other fragments might cause. This reduction of the potential for side-effects was provided by the absence of T-cell epitopes in the Abeta1-7 fragment (see paragraph [0255] of the patent and document D4) this absence accordingly being a further distinguishing feature.

17. The board notes in this context however that both document D1 (see page 56, line 24 to page 57, line 3) and the patent in suit (see paragraph [0200]) equally disclose: "These results show that AN 1792 and AN 1528 stimulate strong T cell responses, most likely of the CD4**(+) phenotype. The absence of an Abeta-specific T cell response in animals immunized with Abetal-5 is not surprising since peptide epitopes recognized by CD4**(+) T cells are usually about 15 amino acids in length, although shorter peptides can sometimes function with less efficiency. Thus the majority of helper T cell epitopes for the four conjugate peptides are likely to reside in the IgG conjugate partner, not in the Abeta region. This hypothesis is supported by the very low incidence of proliferative responses for animals in each of these treatment groups. Since the Abetal-5 conjugate was effective at significantly reducing the level of Abeta in the brain, in the apparent absence of Abeta-specific T cells, the key effector immune response induced by immunization with this peptide appears to be antibody."

18. Accordingly, the board is of the opinion that rather than being a feature distinguishing the claimed Abeta1-7 conjugate from the Abeta1-5 conjugate disclosed in the closest prior art, the reported lack of T-cell epitopes in the Abeta1-7 conjugate constitutes a feature in common between the claimed subject-matter and the Abeta1-5 conjugate disclosed in the prior art.

19. The board can concur with the appellant that, as such, there is no explicit disclosure in document D1 that a T-cell response against Abeta was undesirable and an advantage aspired. The board considers however that the skilled person would infer from the disclosure in document D1 that the presence of T-cell epitopes is not required for successfully formulating Abeta fragment conjugates having the required therapeutic utility.

20. In view of these considerations the board can agree with the respondent and the opposition division that the problem to be solved, starting from the disclosure in document D1, was not therefore merely the provision of alternative peptides for the treatment of diseases associated with amyloid deposits Abeta in the brain, such as Alzheimer's disease, as was argued by the appellant.

21. The board judges that, rather, the technical problem to be solved is the identification of further conjugates of peptides derived from Abeta for the treatment of diseases associated amyloid deposits Abeta in the brain, such as with Alzheimer's disease, which do not generate a T-cell response against Abeta. The solution to this problem are, inter alia, conjugates with Abeta1-7.

Obviousness

22. Document D1 teaches already a fragment of Abeta1-42 which reportedly solves the technical problem underlying the present invention, i.e. the Abeta1-5 conjugate. Furthermore, the skilled person was taught in document D1 (see point 15 above) that peptide epitopes recognised by CD4**(+) T cells are usually about 15 amino acids in length and also the respondent has submitted that T-cell epitopes are normally 9 amino acids or longer, but could occasionally be shorter in synthetic peptides (see document D5). Accordingly, the skilled person would not expect to generate T-cell epitopes by adding one or a few further amino acids of the N-terminal part of the Abeta1-42 to the Abeta1-5 conjugate.

23. On the other hand, the skilled person was taught in document D1 that the human Abeta1-5 conjugate fragment was able to achieve the desired technical effect whereas the slightly larger human Abeta1-12 fragment conjugate, comprising the Abeta1-5 fragment, failed to do so.

24. The board judges that the above considerations would incite the skilled person having the desire of formulating further conjugates of peptides derived from Abeta for the treatment of diseases associated with Alzheimer's disease, which do not generate a T-cell response against Abeta, i.e. conjugates other than the Abeta1-5 fragment, to formulate slightly extended versions of the Abeta1-5 conjugate, such as Abeta1-6, Abeta1-7 and Abeta1-8 in the firm believe of a reasonable expectation that these fragments successfully solve the objective technical problem.

25. The respondent has argued additionally that the data in table 16 on page 46 of the patent demonstrated that at least three epitopes were responsible for amyloid deposit clearing, i.e. occupying residues 1-5, 3-6 and 3-7 of Abeta. These three fragments were able to induce three different classes of antibodies, i.e. IgG2b, IgG1and IgG2a, respectively. The claimed Abeta1-7 fragment was sufficiently long to include all three of these epitopes and thus unexpectedly able to induce three classes of antibodies which were effective in clearing deposits. Accordingly, Abeta1-7 conjugates were thus characterised by a further advantageous property, i.e. the ability to induce multiple classes of antibodies that were effective in clearing amyloid deposits in the absence of a T-cell response against Abeta, which reduces the possibility of side-effects. This was not obvious in the light of the prior art.

26. However, the board notes that the respondent has provided no arguments whether, and in how far, the alleged advantageous structural particulars of Abeta1-7 related to the presence of multiple epitopes also advantageously contributed to the technical effect aimed to be achieved by the invention, namely the treatment of diseases associated with amyloid deposits Abeta in the brain, such as Alzheimer's disease by means of a reduction of established amyloid plaques, including reduction of total Abeta in the brain of patients. In fact, it has been acknowledged by the respondent that there is no direct correlation between antibody titer and therapeutic efficiency. In the absence of such correlation these structural particulars referred to by the respondent can, in the opinion of the board, not contribute to the non-obviousness of the subject-matter of claim 1.

27. In view of these considerations the subject-matter of claim 1 of the main request and auxiliary request 3 lacks an inventive step.

Auxiliary requests 1 and 2 - claims 1

28. Claim 1 of both auxiliary request 1 and 2 (see section V) relate to the same subject-matter as for which the board came to a negative conclusion on inventive step. Accordingly, the above findings apply mutatis mutandis to these claims.

29. The subject-matter of claim 1 of auxiliary requests 1 and 2 thus lacks an inventive step.

Auxiliary request 4 - admission into the proceedings (Article 12(2), (4) RPBA)

30. According to Article 12(4) RPBA, everything presented by the parties under Article 12(1) RPBA, in particular in the reply to the grounds of appeal (cf. Article 12(1)(b) RPBA), shall be taken into account by the board if and to the extent it relates to the case under appeal and meets the requirements of Article 12(2) RPBA, the board having the power to hold inadmissible facts, evidence or requests which could have been presented or were not admitted in the first instance proceedings. Article 12(2) RPBA inter alia provides that the reply to the statement of grounds of appeal shall contain a party's complete case, set out clearly and concisely why it is requested that the decision under appeal be upheld and should specify expressly all the facts, arguments and evidence relied on.

31. Claim 1 of auxiliary request is for a pharmaceutical composition comprising the Abeta1-7 fragment conjugate and an adjuvant. The request, in relation to which the appellant had requested that it not be admitted into the proceedings, was filed with the reply to the appellant's statement of grounds of appeal.

32. The board considers the appellant's argument that no reasons were given why this claim request was only filed in appeal, which alludes to the aspect that this auxiliary request not only could, but also should have already been filed during opposition proceedings, of little weight in the circumstances of the present case. Following a preliminary opinion of the opposition division that the patent as granted fulfilled the requirements of the EPC, the opposition had been rejected during the oral proceedings before the opposition division without any new aspects arising. Therefore, the board cannot identify a situation during the opposition proceedings in which the filing of an auxiliary request by the respondent was procedurally required to such extent that this omission should be detrimental to the respondent at the appeal stage. The respondent's presentation of this auxiliary request at the appeal stage only is therefore not procedurally objectionable.

33. However, when filing this claim request together with the reply to the statement of grounds of appeal, the respondent has not explained how this request would remedy all issues addressed by the appellant in relation to the patent as granted. In particular, claim 1 of auxiliary request 4 is based on granted claims 13 and 15 and the latter claims had been objected to by the appellant in the notice of opposition for lack of inventive step. In such a situation, the mere information in the respondent's reply to the statement of grounds of appeal as to where in the application as filed the basis for the claimed subject-matter can be found, and addressing the topic of sufficiency of disclosure, but omitting any explanation as to why the claimed subject-matter of this auxiliary claim request involved an inventive step did not, in the board's view, represent a sufficient substantiation of this claim request within the meaning of Article 12(2) RPBA.

34. In view of these considerations the board did not admit auxiliary request 4 into the proceedings in accordance with Article 12(4) RPBA.