T 1251/16 (Unstructured recombinant polymers/AMUNIX) 06-05-2021

1. The appeal is admissible.

2. As announced by letters dated 23 March 2021 and 16 April 2021, the respondent was not represented at oral proceedings. In accordance with Rule 115(2) EPC, if a party duly summoned to oral proceedings does not appear as summoned, the proceedings may continue without that party. As stipulated by Article 15(3) RPBA, the board is not obliged to delay any step in the proceedings, including its decision, by reason only of the absence at the oral proceedings of any party duly summoned that may then be treated as relying on its written case.

3. Main request, Article 100(c)/123(2) EPC

3.1 In accordance with Article 123(2) EPC, the European patent application or the European patent must not be amended in such a way that it contains subject-matter which extends beyond the content of the application as filed. The "gold standard" for assessing compliance with Article 123(2) EPC is that any amendment to the parts of a European patent application or European patent relating to the disclosure may only be made within the limits of what the skilled person would have derived directly and unambiguously, using the common general knowledge available at the date of filing, from the whole of these documents as filed.

3.2 Claim 9 as granted reads as follows:

"9. The method of claim 1, wherein said URP contains only 3, 4, 5, or 6 different types of amino acids selected from the group consisting of glycine (G), aspartate (D), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P)."

3.3 The board agrees with the conclusions of the opposition division that claim 9 of the main request adds subject-matter contrary to the requirements of Article 123(2) EPC. In particular, there is no basis for the feature "wherein the URP contains only 3, 4, 5, or 6 different amino acids selected from the group consisting of ... [GADSTEP]".

3.4 The appellant indicated paragraph [0121] "in combination with the rest of the application" or possibly paragraph [0113] of the application as filed as constituting a basis for this feature. The relevant passage in paragraph [0121] reads "URPs or the repeats inside URPs often contain only 1, 2, 3, 4, 5 or 6 different types of amino acids". It does not refer to any group of amino acids from which to select the different types of amino acids, and it is therefore interpreted as referring to any possible amino acid. Paragraph [0113], on the other hand, discloses that "Where desired, URPs can be designed to contain (...) sometimes only a few types of amino acid, e.g., two to five types of amino acids (e.g., selected from G, E, D, S, T, A and P)". This passage, while referring to the GADSTEP group, only envisages the use of two to five, rather than three to six (as in the claim), types of amino acids from this group. Hence, the two passages do not provide an adequate basis for the disputed feature.

3.5 While the board agrees with the appellant's argument that literal support is not necessarily required for the purposes of Article 123(2) EPC, this does not mean that different passages of the originally filed documents can be freely combined to come up with a teaching that is not unambiguously derivable from the application as filed.

3.6 The appellant further argued that the application was focused on the use of URPs comprising amino acids of the GADSTEP group and that therefore the skilled person would have read any general statements such as the one in paragraph [0121] within this context. The board agrees that URPs comprising GADSTEP amino acids are frequently mentioned in the application but so are other types of URPs, such as glycine-rich URPs (e.g. paragraph [0111] and following), URPs containing non-glycine residues (paragraph [0118] and following) and URPs derived from human sequences (paragraph [0122] and following). Accordingly, the disclosure of paragraph [0121] referring to URPs comprising only one to six different types of amino acids would not have been implicitly interpreted as meaning one to six different amino acids of the GADSTEP group.

3.7 The board thus comes to the conclusion that claim 9 of the main request adds subject-matter contrary to Article 123(2) EPC. The main request is thus not allowable.

3.8 On page 5 of the letter of reply to the grounds of appeal, the respondent stated that it maintained its objections for added subject-matter also in relation to claims of the main request other than claim 9. These objections were decided upon in the appealed decision, the opposition division having come to the conclusion that they were not valid. Hence, if the respondent still wanted to rely on these objections in appeal, it should have submitted its arguments why the opposition division was wrong in this respect. In the absence of any such arguments, the board sees no reason to deviate from the conclusions of the opposition division. Hence, the board considers that the other claims of the main request fulfil the requirements of Article 123(2) EPC.

4. Auxiliary request 1, Article 83 EPC

4.1 Claim 1 of auxiliary request 1 is directed to a method of increasing the serum half-life of a protein, comprising fusing this protein with one or more URPs, the URP being further defined by a number of structural and functional features as follows (for the exact wording of the claim, see section I): it comprises at least about 200 contiguous amino acids; the sum of glycine (G), aspartate (D), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) residues contained in the URP constitutes more than about 80% of the total amino acids of the URP; at least 50% of the amino acids of the URP are not present in secondary structure as determined by the CF algorithm; it is substantially incapable of non-specific binding to a serum protein; and it has a Tepitope score equal to or less than -4.

4.2 Being a method claim, the purpose of the method, which is increasing the serum half-life of a protein, is a limiting feature of the claim. Hence, only embodiments that achieve this effect are part of the claim. For the purposes of sufficiency of disclosure, the application must thus provide an enabling disclosure of the URPs as claimed and must also show or at least render it plausible that use of these URPs in a method as claimed achieves the effect of increasing the serum half-life of a protein.

4.3 In the board's view, the patent fulfils both conditions. It discloses how to produce URPs with the features as claimed, and it also describes the technical basis for the half-life extension of a protein when using a URP as claimed, thus rendering it plausible that such a URP can be successfully used in a method for increasing serum protein half-life as claimed. Post-published data in documents D32 and D33 confirm that this effect is achieved for two fusion proteins comprising pharmaceutical proteins and a URP according to the invention.

4.4 The respondent argued that preparing a URP according to the definition in the claims was not enabled by the disclosure in the patent because the skilled person would not have been able to unequivocally identify whether something was a URP according to the invention. In view of parameters which were ill-defined, it would be essentially arbitrary whether a particular embodiment would fall within or outside the scope of the claims. In particular, the features of items (b) and (c), namely "at least 50% of the amino acids of the URP are not present in secondary structure as determined by Chou-Fasman algorithm", "URP is substantially incapable of non-specific binding to a serum protein" and "URP has a Tepitope score equal to or less than -4", were considered to be such ill-defined parameters.

4.5 First, the board notes that any URPs that do not achieve the technical effect will not be encompassed by the claim, as explained above. Moreover, the respondent has not provided any evidence of any such embodiment. Second, the URPs as claimed are already structurally defined as having at least 200 amino acids, of which more than 80% should be of the GADSTEP group. Accordingly, the skilled person would have already known that, for a URP of 200 amino acids, at least 160 of them should be selected from G, A, D, S, T, E or P and would only have had to decide on the remaining 40 or less amino acids and on the order of the amino acids in the sequence. As further explained below, the board considers that, with the teaching of the patent, the skilled person could have made the necessary decisions to produce the URPs according to the invention without undue burden.

4.6 The skilled person would have known from the patent application (e.g. paragraph [0075]) that the term "unstructured recombinant polymer" (URP) refers to amino acid sequences that share commonality with denatured peptide sequences, i.e. peptide sequences in "denatured conformation" or "unfolded conformation". This is defined in the preceding paragraph as referring to a state of a peptide in solution that is characterised by a large conformational freedom of the peptide backbone. Paragraph [0075] further teaches that URP sequences lack a defined tertiary structure and have limited or no secondary structure as detected by, e.g. the CF algorithm. Paragraph [0102], which again defines the URPs as comprising "amino acid sequences that typically share commonality with denatured peptide sequences under physiological conditions", goes on to teach that "A variety of methods have been established in the art to ascertain the second and tertiary structures of a given polypeptide", these methods including CD spectroscopy and "computer programs or algorithms such as the Chou-Fasman algorithm (Chou, P. Y., et al. (1974) Biochemistry, 13: 222-45)", the cited reference being document D2 in the proceedings. The algorithm is able to predict, for a given URP sequence, "whether there exists some or no secondary structure at all".

4.7 The following paragraph (paragraph [0103]) then teaches that "The subject URPs can be sequences with low immunogenicity" and that "Low immunogenicity can be a direct result of the conformational flexibility of URP sequences", preferred URPs being "designed to avoid formation of conformational epitopes". Possible sequences with low immunogenicity can be "sequences having a low tendency to adapt compactly folded conformations in aqueous solution" and "low immunogenicity can be achieved by choosing sequences that resist antigen processing in antigen presenting cells, choosing sequences that do not bind MHC well and/or by choosing sequences that are derived from human sequences". Paragraph [0125] further teaches how to design URP sequences that are "substantially free of epitopes recognized by human T cells" by synthesising "a series of semi-random sequences with amino acid compositions that favor denatured, unstructured conformations and evaluate these sequences for the presence of human T cell epitopes and whether they are human sequences" by using known assays. One possible approach is "to design URP sequences that result in low scores using epitope prediction algorithms like TEPITOPE (Stumiolo, T., et al. (1999) Nat Biotechnol, 17: 555- 61 [document D18 in the proceedings])".

4.8 Paragraph [0100] further teaches that the URP should be designed to minimise interaction with (i.e. binding to) serum proteins, including antibodies. It states that "Different URP designs can be screened for serum protein binding by ELISA, immobilizing the serum proteins and then adding the URP, incubating, washing and then detecting the amount of bound URP". Two approaches are further disclosed, and the patent then states that "Using these approaches we have designed our URPs to show very low levels of binding to serum proteins".

4.9 Paragraph [0108] provides specific teaching concerning the preferred amino acids to be used in the construction of URPs. It refers to the predominance of hydrophilic amino acids such as glycine, serine, aspartate, glutamate, lysine, arginine and threonine (GADSTEP) and teaches that tryptophan, phenylalanine, tyrosine, leucine, isoleucine, valine and methionine are "Hydrophobic residues that are less favored in construction of URPs". It also teaches in paragraph [0109] that "As a result of their amino acid composition, URP sequences have a low tendency to form aggregates in aqueous formulations and the fusion of URP sequences to other proteins or peptides tends to enhance their solubility and reduce their tendency to form aggregates, which is a separate mechanism to reduce immunogenicity". Paragraph [0110] then teaches that "URP sequences can be designed to avoid certain amino acids that confer undesirable properties to the protein. For instance, one can design URP sequences to contain few or none of the following amino acids: cysteine (to avoid disulfide formation and oxidation), methionine (to avoid oxidation), asparagine and glutamine (to avoid desamidation)".

4.10 Hence, the patent application provides detailed teaching on how to obtain URPs suitable for use in the method as claimed. It also makes clear that the functional properties of the claimed URPs derive from their structural features. Hence, while these functional features may not be very clearly defined in the claims, this would not have hindered the skilled person from carrying out the invention without undue burden.

4.11 The board agrees with the respondent that the feature "at least 50% of the amino acids of the URP are not present in secondary structure as determined by Chou-Fasman (CF) algorithm" is unclear. In fact, it is common general knowledge, evidenced by, for example, D65, that all amino acids in a protein are part of a secondary structure since they all contribute to the protein backbone chain and thus to the spatial arrangement, independent of them being part of a highly ordered secondary structure, such as helices or sheets, or of non-ordered secondary structures such as random coils or unstructured loops. This definition is also in agreement with the patent's disclosure in paragraphs [0077] and [0100], referring to "unstructured loops" and "random coil structures", respectively. The implementation of the CF algorithm, described in D2, also does not exclude coils as secondary structure, as extensively argued by the respondent. According to this definition of secondary structure, all amino acids of a URP will be found to be present in "secondary structure" and the percentage of amino acids not in secondary structure according to the CF algorithm would always be 0. It is also true, as argued by the respondent on basis of documents D55, D56 and D61, that the CF scores can change drastically depending on whether some secondary structure types (e.g. beta turns) are taken into account.

4.12 While the above is true, the board considers that the skilled person would still have been in a position to decide what URPs were according to the claim. It follows from the definition itself of URPs (given in the patent, for instance, in paragraphs [0075] and [0102], see above) that these should have a "denatured conformation" or "unfolded conformation" and that this is what is meant by having little or no secondary structure. It would therefore have been immediately obvious to the skilled person reading the patent application that the URPs according to the invention should have few to no highly ordered structures such as helices and sheets and rather have more unordered structures such as random coil. The skilled person would thus have known how to apply the CF algorithm accordingly, i.e. which secondary structures should be taken into account to end up with a URP with "unstructured conformation".

4.13 The respondent also argued that it was not clear how the Tepitope score was to be calculated and that there were major inconsistencies as shown for instance in D42, D58 and D60. Moreover, it was not apparent how the score should be evaluated for a whole peptide of 200 amino acids since the algorithm was in fact designed for 9mers within a peptide. The board agrees that there might be a lack of clarity as to how the Tepitope score is to be calculated but again considers that the disclosure of the patent application would have put the skilled person in a position to be able to determine which URPs were part of the invention. As mentioned above, the patent application teaches (paragraph [0125]) how to design URP sequences that are "substantially free of epitopes recognized by human T cells" and that these sequences can be evaluated for the presence of human T cell epitopes by using known assays such as the Tepitope disclosed in D18. It would also have been clear for the skilled person that, when calculating the Tepitope score for larger peptides, it would be important that none of the 9mers within the peptide had a score over -4; anything else would not make sense in the context of the patent. The post-published document D63 moreover confirms that URPs meeting the Tepitope criteria of the claims could be readily provided by following the teaching of the specification. For these purposes, it is irrelevant that it is not clear what specific "Tepitope software" tool was used in D63 because the claim is also not limited to any specific tool being used.

4.14 Finally, while the feature "substantially incapable of non-specific binding to a serum protein" may be unclear, the patent application again teaches what is meant by such a feature and how to test it (paragraph [0100], see above). Similarly, the respondent's objection concerning the "serum half-life" feature is also not convincing. It is true that different methods of assessing serum half-life can be used which may lead to different results. However, since the claim requires only that there is an increase in serum half-life, it is not relevant what the absolute values are and whether they differ according to the method used.

4.15 The board thus comes to the conclusion that claim 1 of the auxiliary request fulfils the requirements of Article 83 EPC.

5. Admission of documents

Documents D46 to D51, D53 and D54

5.1 All these documents were submitted during the proceedings before the opposition division, and the opposition division decided not to admit them into the proceedings. In the appeal proceedings, the respondent requested that documents D46 to D51 be admitted into the proceedings, while the appellant requested that the decision of the opposition division not to admit documents D46 to D51 be confirmed. The appellant also appears to have contested the decision of the opposition division not to admit D53 and D54.

5.2 In the communication pursuant to Article 15(1) RPBA, the board gave its preliminary opinion that it did not see any reason to deviate from the decision of the opposition division not to admit documents D46 to D51 into the proceedings. It noted that the appellant had not relied on D53 or D54 in its submissions and that there was therefore no apparent reason to rule on the admission of these documents.

5.3 The parties have not provided any further arguments concerning the admission of these documents. Hence, the board sees no reason to overrule the decision of the opposition division not to admit these documents into the proceedings. Documents D46 to D51, D53 and D54 are therefore not admitted into the proceedings.

Documents D62 to D78

5.4 Documents D62 to D78 have all been submitted during appeal proceedings: D62 and D63 by the appellant with the statement of grounds of appeal; D64 to D76 by the respondent with the reply to the grounds of appeal; and D77 and D78 by the appellant and the respondent, respectively, in further letters. The appellant requested that new documents D64, D65 and D67 to D76 not be admitted.

5.5 In the communication pursuant to Article 15(1) RPBA, the board gave its preliminary opinion that it was inclined to admit documents D62 and D63 into the proceedings and that it was not apparent why documents D64 to D76 should be admitted into the proceedings.

5.6 There have been no further arguments from the parties concerning the admission of these documents. Since documents D62 and D63 were filed with the statement of grounds of appeal and the respondent did not object to their admission, the board decided to use its discretion pursuant to Article 12(4) RPBA to admit them into the proceedings. As to the further documents, the following is noted.

5.6.1 D65 is an extract of a physical chemistry textbook providing a definition of secondary structure. The board sees no reason not to admit a document which is simply evidence of the common general knowledge at the relevant date. Hence, document D65 was admitted into the proceedings.

5.6.2 The appellant had no objections against the admission of document D66, which consisted of an official communication of the USPTO concerning the proceedings to which declaration D30 related. The board therefore also decided to admit this document into the proceedings.

5.6.3 The remaining documents have not been considered relevant for the present decision. They consisted of the well-known UKHL Kirin-Amgen vs. Hoechst Marion Roussel decision (D64); CF scores for different proteins (D67 to D69) and for randomly generated "URPs" (D70) as well as a summary of D70 results (D71); a second declaration of Professor Sternberg (D72); Tepitope for the first set of sequences from D30, exhibit 2 (D73) and for the first 200mer GADSTEP sequence of D63 (D74); two prior art scientific publications where Tepitope has been used (D75 and D76); an answer to an enquiry to the providers of the IEDB Tepitope server (D77); and a letter from the patentee submitted during the examination proceedings of the case at issue (D78). The board found it appropriate not to decide on the admission of these documents in view of the decision to remit the case for further prosecution (see below).

6. Remittal for further prosecution

6.1 Under Article 111(1) EPC, the boards, following examination on the allowability of the appeal, must decide on the appeal and may either exercise any power within the competence of the department which was responsible for the appealed decision or remit the case to that department for further prosecution. The boards may remit a case for further prosecution if essential questions regarding the patentability of the claimed subject-matter have not yet been examined by the department responsible for the appealed decision and their handling in appeal would imply a significant burden.

6.2 In the present case, the opposition division reached a decision on Article 123(2) and 83 EPC but did not discuss, let alone decide on, any other of the remaining opponents' objections, namely under Articles 54 and 56 EPC. Both parties were of the opinion that the case should be remitted to the department of first instance for discussion of these issues. The board considers that an exhaustive analysis of these aspects would imply a burden which makes it appropriate to remit the case to the department of first instance for further prosecution.