T 2743/17 (Protofibril specific antibodies/BIOARCTIC NEUROSCIENCE) 09-01-2020
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Antibodies specific for soluble amyloid beta peptide protofibrils and uses thereof
Main request - grounds for opposition - added subject-matter (yes)
auxiliary request 1 - admitted (no)
Summary of Facts and Submissions
I. The appeal of the patent proprietor (appellant) lies from the opposition division's decision revoking European patent No. 1 781 703. The patent, entitled "Antibodies specific for soluble amyloid beta peptide protofibrils and uses thereof", derives from European patent application No. 05 753 672.4 which was filed as an international application under the PCT and published as WO 2005/123775 (the application as filed or the application).
Claim 1 as granted reads as follows:
"1. An antibody or fragment thereof that binds both wild type Abeta42 protofibrils and Abeta42 arc protofibrils and with low Abeta42 monomer cross-reactivity, wherein said antibody or fragment thereof is obtainable by use of Abeta42Arc or Abeta42wt protofibrils with greater than 95% purity for immunisation and screening."
II. The patent was originally opposed on the grounds in Article 100(a) EPC, in relation to novelty (Article 54 EPC) and inventive step (Article 56 EPC), and in Article 100(b) EPC. After expiry of the opposition period, a new ground for opposition (Article 100(c) EPC) was raised by the opponent. The opponent submitted inter alia that the features "with low Abeta42 monomer cross-reactivity" and "obtainable by use of Abeta42Arc or Abeta42wt protofibrils with greater than 95% purity for immunisation and screening" in claim 1 as granted related to subject-matter which extended beyond the content of the application as filed.
III. The opposition division revoked the patent, deciding that the ground for opposition under Article 100(c) EPC was admitted into the proceedings; that the subject-matter of claim 1 of the set of claims of the main request (claims as granted) did not meet the requirements of Article 123(2) EPC because the application did not disclose an antibody "with low Abeta42 monomer cross-reactivity"; that auxiliary requests 1
to 6 did not comply with the requirements of Article 123(2) EPC for the same reasons as the main request; that claim 1 of the set of claims of auxiliary request 7 lacked clarity (Article 84 EPC) and that auxiliary request 8 was not admitted into the opposition proceedings.
IV. With the statement of grounds of appeal, the appellant filed sets of claims of a main request (claims as granted) and of auxiliary requests 1 to 7. They also filed an amended description which, together with the set of claims of auxiliary request 1, constituted auxiliary request 1A. The appellant submitted arguments regarding the basis in the application as filed for the feature "with low Abeta42 monomer cross-reactivity". As regards the other objections raised by the opponent pursuant to Article 100(c) EPC during the opposition proceedings and decided in the appellant's favour by the opposition division they submitted that, in accordance with the doctrine of prohibition of reformatio in peius, the board was not required to decide upon them. They also requested that the board set aside the opposition division's decision to admit the ground for opposition under Article 100(c) EPC into the proceedings.
V. The opponent is the respondent in these appeal proceedings. In their reply to the appellant's statement of grounds of appeal they agreed with the opposition division's decision that the feature "with low Abeta42 monomer cross-reactivity" represented added subject-matter. Furthermore, they maintained their objections under Article 100(c) EPC against the subject-matter of claim 1 of the main request regarding inter alia the definition of the antibody by the process feature "obtainable by (...)".
VI. In response to the respondent's reply to the statement of grounds of appeal, the appellant filed a declaration of one of the inventors (document D57) to confirm that the lack of binding of the exemplified antibody to Abeta40 monomers in the patent was indicative of a lack of binding to Abeta42 monomers.
VII. The board appointed oral proceedings as requested by the parties, and issued a communication pursuant to Article 15(1) RPBA 2007, in which it noted, inter alia, that is was of the preliminary opinion that the opposition division exercised its discretion under Article 114(2) EPC according to the right principles when admitting Article 100(c) EPC as a late-filed ground of opposition (see point 11 of the communication) and that the doctrine of prohibition of reformatio in peius did not apply to the present case (see point 12 of the communication). Furthermore, as regards the subject-matter of claim 1 of the main request, it was stated that "[a]t present, the board tends to agree with the respondent that an antibody that has low cross-reactivity to only one of the Abeta monomers is not disclosed on page 13 of the application as filed" (see point 13); that "[t]he board is inclined to agree with the respondent that the skilled person reading the application as filed as a whole would understand that anti-Abeta protofibril antibodies of the invention bind to Abeta1-42 protofibrils and Abeta1-40 protofibrils, both wild type and arc" (see point 17 of the communication), that "the claimed antibody results from a selection of features for which the application appears to provide no basis" (see point 20 of the communication) and that "the board is inclined to agree with the respondent that there is no disclosure in the application as filed that the use of Abeta42Arc or Abeta42wt protofibrils with greater than 95% purity for immunisation and screening would allow the generation of antibodies as defined in claim 1" (see point 21).
VIII. In response, the appellant provided arguments, inter alia, as to why they disagreed with the preliminary opinion set out in point 21 of the board's communication. Furthermore, they withdrew pending auxiliary requests 2, 3, 5 and 7; maintained pending auxiliary requests 4 and 6, with auxiliary request 6 re-numbered as auxiliary request 5. They also filed sets of claims of new auxiliary requests 2 and 3.
Claim 1 of new auxiliary request 2 reads as follows:
"1. An antibody or fragment thereof that binds both wild type Abeta42 protofibrils and Abeta42 arc protofibrils and with low Abeta40 and Abeta42 monomer cross-reactivity, wherein said antibody or fragment thereof is obtainable by use of Abeta42Arc or Abeta42wt protofibrils with greater than 95% purity for immunisation and screening."
Claim 1 of new auxiliary request 3 reads as follows:
"1. An antibody or fragment thereof that binds both wild type Abeta42 protofibrils and Abeta42 arc protofibrils but does not bind to Abeta fibrils and with low Abeta40 and Abeta42 monomer cross-reactivity, wherein said antibody or fragment thereof is obtainable by use of Abeta42Arc or Abeta42wt protofibrils with greater than 95% purity for immunisation and screening."
IX. In response to the board's communication, the respondent requested inter alia that document D57 not be admitted into the appeal proceedings.
X. At the oral proceedings before the board, the appellant withdrew the request to set aside the decision of the opposition division to admit the ground for opposition under Article 100(c) EPC into the proceedings. The appellant filed a new auxiliary request 1 and withdrew former auxiliary requests 1, 1A, 2 and 3. Auxiliary requests 4 and 5 were renumbered 2 and 3 and were maintained in the event new auxiliary request 1 was admitted into the proceedings and the case was remitted to the opposition division for further prosecution on the basis of new auxiliary request 1. As the appellant in its final requests no longer relied on a declaration by one of the inventors (document D57), no decision was taken on the admission of this document.
Claim 1 of auxiliary request 1 reads as follows (additions and deletions with respect to claim 1 as granted are indicated by underline and strikethrough, respectively):
"1. An antibody or fragment thereof that binds both wild type Abeta42/40 protofibrils and Abeta42/40 arc protofibrils but does not bind to Abeta fibrils and with low Abeta40 and Abeta42 monomer cross-reactivity[deleted: , wherein said antibody or fragment thereof is obtainable by use of Abeta42Arc or Abeta42wt protofibrils with greater than 95% purity for immunisation and screening]."
XI. At the end of the oral proceedings the Chair announced the board's decision.
XII. The appellant's arguments, submitted in writing and during the oral proceedings, are summarised as follows:
Scope of appeal
A number of added matter arguments were raised by the respondent during the opposition proceedings. The opposition division decided that none of these arguments were valid. In accordance with the doctrine of prohibition of reformatio in peius the board was not required to decide upon these points.
Main request
Amendments (Article 100(c) EPC) - claim 1
"obtainable by use of Abeta42Arc or Abeta42wt protofibrils with greater than 95% purity for immunisation and screening"
The application as filed provided a clear disclosure of pure (>95%) preparations of Abeta42wt or Abeta42Arc protofibrils that could be used as immunogens and screening agents for the purpose of obtaining antibodies capable of binding both wild type Abeta42 and Abeta42 arc protofibrils, see page 9, lines 1 to 3.
Page 7, fourth paragraph disclosed that in order to immunise and screen for conformation specific anti- protofibril antibodies, it was necessary to produce pure Abeta42arc and Abeta42 protofibrils. These protofibrils had been used as immunogens to make the exemplified antibody, thus providing a basis for combining the "obtainable by" feature with the other antibody features recited in claim 1.
An antibody having "low Abeta42 monomer cross-reactivity" was disclosed in the last line on page 13 of the application as filed, on page 16, paragraph 5 and in Example 5 (Figure 4) of the application as filed.
Low Abeta42 monomer cross-reactivity had not been demonstrated in the application for the exemplified antibody because the Abeta42 monomer did not exist in solution. However, an antibody with low binding to Abeta40 monomers inevitably had low binding to Abeta42 monomers.
Auxiliary request 1
Admittance into the appeal proceedings
It was recognised that the request was filed late but the ground for opposition under Article 100(c) EPC had also been raised late in the opposition proceedings. The request should be admitted as it addressed all the objections identified by the board with respect to the subject-matter of claim 1 of the main request. The board's findings as regards the main request could not have been foreseen by the appellant, because in the preliminary opinion, the board did not see a problem with the process feature, see point 21 of the board's communication.
Deletion of the "obtainable by" feature did not extend the scope of protection conferred beyond the scope conferred by the claims as granted. The newly added binding specificities in the claim narrowed the claim's scope. No antibody that would not have fallen within the scope of the granted claims fell within the scope of claim 1 (Article 123(3) EPC).
XIII. The arguments of the respondent, submitted in writing and during the oral proceedings, are summarised as follows:
Scope of appeal
Appellant's notion as regards the prohibition of reformatio in peius was wrong in law. The prohibition of reformatio in peius referred to situations where the patent was maintained in amended form, not where it was revoked. It was open to the respondent to re-argue matters which had already been at issue before the opposition division.
Main request
Amendments (Article 100(c) EPC) - claim 1
"obtainable by use of Abeta42Arc or Abeta42wt protofibrils with greater than 95% purity for immunisation and screening"
The only general reference to the use of Abeta42arc or Abeta42wt protofibrils with greater than 95% purity for immunisation and screening was on page 7, third full paragraph of the application. This passage referred to "conformation-specific anti-protofibrils" antibodies. It was not disclosed that by using these antigens, an antibody as defined in claim 1, i.e. an antibody that
could bind to Abeta42 and Abeta42arc protofibrils and that had a low Abeta42 monomer cross-reactivity, could be obtained. If anything, it was disclosed that conformation-specific anti-protofibril antibodies were obtained.
"Conformation-specific antibodies" were referred to in the second paragraph on page 7 as antibodies that "have the property to bind both wild type Abeta42/40 and Abeta42/40arc protofibrils".
On page 9, first paragraph, the application was silent about any cross-reactivities of the antibodies obtained.
There was no exemplified antibody that showed all the properties as defined in claim 1. For the exemplified antibody, Abeta42 monomer cross-reactivity had not been tested. It was scientifically incorrect to assume that an antibody having low binding to Abeta40 inevitably had low binding to Abeta42 monomers too. The last line on page 13 of the application as filed described desirable properties of a hypothetical antibody only. The section further referred to low cross-reactivity also with Abeta40 monomers.
Auxiliary request 1
Admittance into the appeal proceedings
This request was filed very late in the appeal proceedings without any justification. That the ground for opposition pursuant to Article 100(c) EPC was raised late in opposition proceedings did not justify filing of a new claim request at the oral proceedings before the board. That the board had found against the appellant for the higher ranking claim request was also no reason to now file a new request. The request addressed issues which had already been in the proceedings before the opposition division.
The board had issued a preliminary opinion and the appellant had had a choice what subject-matter it wanted to defend. The appellant had filed various claim requests to address the objections under
Article 100(c) EPC individually, but never in combination. The claimed combination of features had not been on file before and constituted a fresh case.
Claim 1 was also not prima facie clearly allowable.
The "obtainable by" feature in claim 1 as granted had imparted particular properties to the antibody as regards the epitope bound. Removing the process feature "obtainable by (...)" extended the scope of protection (Article 123(3) EPC). The claim now defined an entirely different antibody.
XIV. The appellant requested that the decision under appeal be set aside and the patent be maintained on the basis of the main request or, alternatively, on the basis of new auxiliary request 1, filed during oral proceedings before the board.
The respondent requested that the appeal be dismissed.
Reasons for the Decision
1. The appeal complies with Articles 106 to 108 and Rule 99 EPC and is therefore admissible.
2. An amended version of the Rules of Procedure of the Boards of Appeal (RPBA 2020) came into force on 1 January 2020. The transitional provisions are set out in Article 25 RPBA 2020. In the present case, the parties were notified of the summons to oral proceedings before 1 January 2020. Therefore, Article 13(2) RPBA 2020 does not apply to the present case and instead Article 13 RPBA 2007 shall continue to apply.
Scope of appeal
3. The appellant submitted that in accordance with the doctrine of prohibition of reformatio in peius, the board was not required to decide upon the added matter objections raised by the respondent during the opposition proceedings and decided in the appellant's favour in the decision under appeal.
4. The board notes that the rulings in Enlarged Board decisions G 9/92 and G 4/93 (both OJ EPO 1994, 875, see Order, points 1 and 2) concerning the prohibition of reformatio in peius apply to appeals lying from interlocutory decisions of the opposition divisions in which either the patent proprietor or the opponent is the sole appellant. The Enlarged Board ruled in essence that if a party is the sole appellant against an interlocutory decision maintaining a patent in amended form, the result of that decision cannot be challenged by the respondent or the board to the detriment of the sole appealing party.
5. In the present case, the patent was not maintained in amended form but revoked by the opposition division and the patent proprietor is the appellant. The situation arising from a decision to revoke a patent is legally different from the one in which the patent has been maintained by the opposition division in amended form, i.e. the case of an interlocutory decision of the opposition division, where the decision could be appealed by both the patent proprietor and the opponent. As the patent has been revoked, it is not possible for the appellant to have an worse outcome or for the opponent to appeal the decision. In this respect the rulings of decisions G 9/92 and G 4/93 are not relevant. In addition, from these decisions it cannot be inferred that any submissions of the respondent that defend the first instance decision could be ignored by the board or that arguments, that were not accepted in first instance, could not be again submitted for consideration by the board.
6. Therefore, the board concludes that it is open to the respondent on appeal to again raise the added matter objections which had already been at issue before the opposition division (see also decision T 169/93, reasons, points 2.1. to 2.6).
Main request (claims as granted)
Amendments (Article 100(c) EPC) - claim 1
7. The claim relates to an antibody which is characterised functionally by its binding properties - it "binds both wild type Abeta42 protofibrils and Abeta42 arc protofibrils, and with low Abeta42 monomer cross-reactivity" - and furthermore by the process feature "obtainable by use of Abeta42Arc or Abeta42wt protofibrils with greater than 95% purity for immunisation and screening".
8. In the decision under appeal, the opposition division decided that the subject-matter of claim 1 did not extend beyond the content of the application as filed as far as the feature "obtainable by use of Abeta42Arc or Abeta42wt protofibrils with greater than 95% purity for immunisation and screening" was concerned. This feature did not need to be limited to conformation specific antibodies (see Reasons, point 3).
"obtainable by use of Abeta42Arc or Abeta42wt protofibrils with greater than 95% purity for immunisation and screening"
9. On appeal, the appellant relied on page 7, second and third paragraphs; page 9, lines 1 to 3, page 13, last line and the exemplified antibody as providing a basis for the use of the process feature in the context of the subject-matter of claim 1 (see section XII).
10. The respondent maintained that there was no disclosure in the application as filed that the use of Abeta42Arc or Abeta42wt protofibrils with greater than 95% purity for immunisation and screening would allow the generation of antibodies as defined in claim 1, i.e. antibodies that were required to bind to Abeta42 and Abeta42arc protofibrils and to have a low Abeta42 monomer cross-reactivity.
11. According to established case law of the boards of appeal, amendments are only permitted within the limits of what a skilled person would derive directly and unambiguously, using common general knowledge, from the whole of the application as filed. After the amendment the skilled person may not be presented with new technical information (see Case Law of the Boards of Appeal of the European Patent Office, 2019, 9th edition, II.E.1.1 and II.E.1.3.1; decision G 2/10, OJ EPO 2012, 376).
12. On page 7, third full paragraph, the application discloses that "[t]o immunise and screen for conformation-specific anti-protofibril antibodies, it is necessary to produce pure Abeta42arc and Abeta42 protofibrils (>95% degree of purity)" while according to page 7, second paragraph, "conformation-specific antibodies" are "antibodies that have the property to bind both wild type Abeta42/40 and Abeta42/40arc protofibrils".
13. On page 9, lines 1 to 3, the application discloses that "the invention describes procedures to generate wild type Abeta42 and Abeta42arc protofibrils as antigens for immunization and for reagents to screen for antibodies that bind Abeta42arc and wild type Abeta42 protofibrils."
14. Examples 2 to 5 disclose that mice were injected with a wtAbeta1-42 (wtAbeta42) protofibril preparation (example 2), and hybridoma supernatants screened for antibodies that bind Abeta42 protofibrils (example 3). Hybridoma supernatant #258 showed high protofibril specificity (Figure 3). The monoclonal antibody (mAb) that was produced from the #258 hybridoma was termed mAb258. This antibody was tested for cross-reactivity and showed "no binding to wtAPP, APPswe or APPswe-arc nor to wtAbeta40 monomer" (Example 4) and "little or no cross-reactivity towards wtAbeta40 monomers or wtAbeta42 fibrils" (Example 5). In the fifth paragraph on page 16 it is also stated that "mAb 258 bound wtAbeta42 protofibrils and slightly less Abeta42arc protofibrils. No binding was observed to wtAbeta40 monomers."
15. It is evident from points 12 to 14 that the application as filed does not explicitly convey any technical information to the skilled person as regards the cross-reactivity to the Abeta42 monomer of antibodies obtained by the use of Abeta42Arc or Abeta42wt protofibrils for immunisation and screening.
16. In the board's judgement, the skilled person would not necessarily deduce a certain binding behaviour for Abeta42 monomers based on the data (see point 14) provided for the Abeta40 monomers. Abeta40 and Abeta42 are two distinct molecules, the Abeta42 molecule having two additional amino acids at the C-terminus compared to Abeta40 (see page 2, lines 5 to 7, of the application as filed). The additional amino acids present in Abeta42 provide additional sequential and conformational epitopes. Indeed, according to the application as filed, each molecular form has a "unique structural conformation" (see page 2, lines 22 to 25). The appellant's argument that an antibody with low binding to Abeta40 monomers inevitably has low binding to Abeta42 monomers is thus not found persuasive.
17. Furthermore, accepting for the appellant's benefit that page 13, last line, discloses an anti Abeta42 protofibril antibody with low Abeta42 monomer cross-reactivity, the board notes that the passage also requires the antibody to have "low Abeta1-40 monomer cross-reactivity" and more importantly, it does not disclose how such an antibody is obtained.
18. Given that "low Abeta42 monomer cross-reactivity" is a feature of the claimed antibody, the appellant's argument that low Abeta42 monomer cross-reactivity had not been demonstrated in the application for the exemplified antibody because the Abeta42 monomer did not exist in solution misses the point. By defining the claimed antibody as having "low Abeta42 monomer cross-reactivity" the person skilled in the art is presented with new technical information for the reasons set out in points 15 to 17 above.
19. The board concludes that the skilled person cannot directly and unambiguously derive, from the application as filed as a whole and using common general knowledge, that an antibody that "binds both wild type Abeta42 protofibrils and Abeta42 arc protofibrils, and with low Abeta42 monomer cross-reactivity" is "obtainable by use of Abeta42Arc or Abeta42wt protofibrils with greater than 95% purity for immunisation and screening".
20. Therefore, the subject-matter of claim 1 of the main request extends beyond the content of the application as filed and the ground for opposition under Article 100(c) EPC prejudices the maintenance of the patent as granted.
Auxiliary request 1
Admittance into the appeal proceedings
21. This request was filed during the oral proceedings after the board had expressed its view that the subject-matter of claim 1 of the main request and of all auxiliary requests extended beyond the content of the application as filed.
22. Claim 1 of auxiliary request 1 has been amended vis-à-vis claim 1 of the main request (claims as granted) by further defining the antibody by its binding properties as "an antibody that binds both wild type Abeta42/40 protofibrils and Abeta42/40 arc protofibrils but does not bind to Abeta fibrils and with low Abeta40 and Abeta42 monomer cross-reactivity" while the process feature "obtainable by use of Abeta42Arc or Abeta42wt protofibrils with greater than 95% purity for immunisation and screening" was deleted (see section X).
23. The respondent objected to the admission of this request into the appeal proceedings (see section XIII) while the appellant submitted that the request should be admitted (see section XII).
24. The board noted that the combination of features now claimed had not been claimed before and thus represented an amendment to appellant's case. Pursuant to Article 13(1) RPBA 2007, an amendment to a party's case after it has filed its grounds of appeal or reply may be admitted and considered at the board's discretion. The board, when exercising its discretion, shall consider, inter alia, the complexity of the new subject matter submitted, the current state of the proceedings and the need for procedural economy.
25. In the board's judgement, the fact that the ground for opposition under Article 100(c) EPC was raised late in the opposition proceedings is not a justification for addressing the objections at such a late stage of the appeal proceedings. The appellant was aware that the respondent maintained these objections on appeal since they were contained in the respondent's response to the statement of grounds of appeal (see section V). However, no fall-back positions were filed at that time (see point VI). In response to the board's communication, the appellant filed two auxiliary requests (see section VIII). Neither one of these addressed all the respondent's objections pursuant to Article 100(c) EPC in combination and both of these requests recited the process feature "obtainable by (...)" which feature was removed for the first time in auxiliary request 1.
26. The filing of the auxiliary request was a reaction to the board's finding that claim 1 of the main request did not meet the requirements of Article 123(2) EPC. Objectively, this finding could however not be considered unforeseeable or unexpected, given that it was in line with the board's preliminary opinion set out in its communication issued pursuant to
Article 15(1) RPBA (see section VII). In particular, the appellant's submission that in point 21 of the board's communication no problem had been identified as regards the process feature was untenable, given (i) the explicit statement in the board's communication as regards the subject-matter of claim 1 of the main request that "the board is inclined to agree with the respondent that there is no disclosure in the application as filed that the use of Abeta42Arc or Abeta42wt protofibrils with greater than 95% purity for immunisation and screening would allow the generation of antibodies as defined in claim 1" and considering that (ii) the appellant in its response to that communication indicated that it disagreed with that preliminary opinion. Thus, auxiliary request 1 which aims at addressing the issue by deleting the process feature could and should have been filed earlier.
27. The board further considered that it was not immediately apparent that the suggested amendments resulted in a clearly allowable claim that did not give rise to new objections, at least as far as the requirements of Article 123(3) EPC are concerned for the following reasons.
28. The skilled person is aware that the immunogen used for immunisation influences the epitope recognised by the antibody. It is therefore at least questionable that an antibody "that binds both wild type Abeta42/40 protofibrils and Abeta42/40 arc protofibrils but does not bind to Abeta fibrils and with low Abeta40 and Abeta42 monomer cross-reactivity" will bind to the same epitope as an antibody "that binds both wild type Abeta42 protofibrils and Abeta42 arc protofibrils, and with low Abeta42 monomer cross-reactivity, wherein said antibody is obtainable by use of Abeta42Arc or Abeta42wt protofibrils with greater than 95% purity for immunisation and screening". Thus, it was not immediately apparent to the board that all antibodies encompassed by claim 1 of auxiliary request 1 were within the scope of the granted claims (Article 123(3) EPC). Thus, admitting the request at this stage of the proceedings, would not have been in keeping with the principle of procedural economy.
29. Accordingly, the board, exercising its discretion pursuant to Article 13(1) RPBA 2007, decided not to admit this request into the appeal proceedings.
Order
For these reasons it is decided that:
The appeal is dismissed.