T 2697/16 (Antibody production/CHUGAI SEIYAKU KABUSHIKI KAISHA) 10-02-2021

Reasons for the Decision

Admission of document (39) into the appeal proceedings

1. Document (39) is a review article concerning the definition of the term "vector". According to the appellant, the filing of this document was a direct response to a discussion under Articles 84 and 123(2) EPC that took place for the first time at the oral proceedings before the opposition division. However, in the statement of grounds of appeal, document (39) was cited only in the context of Articles 84 and 83 EPC for illustrating the common general knowledge of a skilled person, in particular that "there are several other kinds of vectors beside circular plasmids". This fact has never been contested neither at first instance nor in appeal proceedings and it is well-known in the art.

2. The relevance of document (39) is thus limited to appellant's objections raised under Articles 83 and 84 EPC, in particular when these objections relate to the term "vector". However, the objection raised under Article 83 EPC was not admitted into the proceedings by the opposition division and the admissibility of the objection under Article 84 EPC is questioned by the respondent (with reference to decision G 3/14, OJ EPO 2015, A102). Therefore, in the communication pursuant to Article 15 RPBA 2020 (hereafter the boards communication), the board informed the parties that the admission of document (39) into the appeal proceedings would be considered only if any of the appellant's objections raised under these two articles were admitted into the appeal proceedings. In that communication, the parties were also informed that, in the board's opinion, none of these objections could be admitted into the appeal proceedings.

3. Since the board has no reason to deviate from its provisional opinion as regards the non-admission of appellant's objections raised under Articles 83 and 84 EPC (infra), there is no need for the board to consider the admission of document (39) into the appeal proceedings.

Admission of the ground for opposition under

Article 100(b) EPC (Article 83 EPC) into the appeal

proceedings

4. The opposition division considered the ground for opposition under Article 100(b) EPC not to be substantiated in the notice of opposition and thus, to be a fresh ground. After consideration of the parties' arguments, the opposition division decided that this fresh ground of opposition was not relevant and thus, it was not admitted into the proceedings (cf. page 10, point 7 et seq. of the decision under appeal).

5. As stated by the respondent with reference to decision G 10/91 (supra), fresh grounds for opposition may be considered in appeal proceedings only with the patent proprietor's approval. In the present case, this approval is lacking.

6. Therefore, as stated in its communication, the board understands appellant's request to admit the objection raised under Article 83 EPC into the appeal proceedings to be a request for the board to review the opposition division's discretionary decision not to admit the ground for opposition under Article 100(b) EPC into the proceedings. The criteria for such review are set out in the case law and require the board to assess whether the opposition division exercised its discretion in accordance with the wrong principles or in an unreasonable way (cf. "Case Law of the Boards of Appeal of the EPO", 9th edition 2019, V.A.3.5.1.b), 1198, and V.A.3.5.5, 1205).

7. In the board's communication, the parties were also informed that, in the light of the facts of the present case and the reasons given in the decision under appeal, the board was of the opinion that the opposition division exercised its discretion neither in an unreasonable way nor according to the wrong principles. In the board's view, appellant's arguments submitted in appeal on this issue neither indicated nor supported that this was the case. This was not contested at the oral proceedings before the board.

8. Therefore, the board saw no reason to deviate from its provisional opinion and decided not to admit the fresh ground for opposition (Article 100(b) EPC/Article 83 EPC) into the appeal proceedings.

Main request

9. The main request is identical to the auxiliary request 1 upheld by the opposition division and underlying the decision under appeal. Thus, the main request already forms part of the appeal proceedings.

Article 84 EPC

10. Claim 1 defines the vector used in the method of producing an IgG1 antibody as comprising several expression units, wherein these units are further defined as consisting of a promoter, an exogenous DNA encoding either the heavy chain of the antibody or the light chain of the antibody (or a fragment thereof), and a polyA signal. The term "consisting" used in the definition of these expression units has a clear and accepted meaning in the case law which, as acknowledged by the opposition division, excludes the presence in these units of components other than those explicitly mentioned in the claim (cf. "Case Law", supra, II.A.6.2, 308, and II.E.1.15, 499). The comment made by the opposition division in the decision under appeal regarding the possible presence of small sequences joining the three components of these units mentioned in claim 1, reflects only what is already known by a person skilled in the relevant technical field. It neither changes the definition of these expression units and the components of these units as defined in claim 1 nor does it go beyond what a skilled person would normally understand to fall within such a definition.

11. The vector used in the method of claim 1 is first defined as "comprising" one copy of a DNA encoding a heavy chain of the antibody (or a fragment thereof) and two or more copies of a DNA encoding the light chain of the antibody (or a fragment thereof). Although the term "comprising" is used, the board considers this definition to require the vector to have only a single (one) copy of a DNA encoding the heavy chain of the antibody and clearly excluding vectors with more than one copy of a DNA encoding the heavy chain. In this context, the term "comprising" allows the presence of other components within the vector (such as promoters, signal sequences, etc.) but not variations or changes in the specific amount or proportion defined in the claim for the DNA encoding the (one) heavy chain and the DNA encoding the (two or more) light chain. Otherwise, the term "comprising" would render this relation completely meaningless and superfluous. This interpretation extends to, and necessarily limits and constrains also, the further definition of the vector as "comprising" an expression unit with an exogenous DNA encoding the heavy chain of the antibody and two or more expression units with a DNA encoding the light chain of the antibody. The presence in the vector of further expression units with an exogenous DNA encoding the heavy chain of the antibody is therefore clearly excluded from the scope of claim 1.

12. Whilst appellant's first objection under Article 84 EPC arises from a comment made by the opposition division in the decision under appeal, this is not the case for the second objection concerning the ratio of DNA sequences encoding the heavy chain and the light chain of the antibody in the vector. Indeed, as acknowledged by the appellant at oral proceedings before the board, this objection was originally raised at first instance under Article 123(2) EPC, not under Article 84 EPC (cf. page 3, point 3.1.3 of appellant's submissions dated 5 August 2016 at first instance). However, there is no evidence in the Minutes of the oral proceedings before the opposition division and in the decision under appeal that the appellant further pursued this objection under Article 123(2) EPC at the oral proceedings at first instance. There is no decision of the opposition division thereupon, neither under Article 123(2) EPC nor under Article 84 EPC. In any case, in view of the presence in the granted claims of the term "vector comprising", the examination of such objection under Article 84 EPC is more than questionable (infra). Be that as it may, the board, as stated above, does not consider this objection to be relevant since the term in the context of claim 1 does not allow for more than one (single) DNA sequence encoding the heavy chain of the antibody.

13. As regards appellant's objections arising from the definition of the vectors in the claims not being limited to the (sole) linear vectors exemplified in the patent, in particular for claims 8 and 9 which require the (animal) cell to stably express the antibody but without any limitation to linear vectors, the board observes that this limitation was already not present in the vectors mentioned in the granted claims, in particular claims 9 and 10 as granted. Claims 8 and 9 of the main request, apart from the correction of their claim dependencies and the addition of the term "animal" in claim 9, are literally identical to claims 9 and 10 as granted. Thus, appellant's objections under Article 84 EPC do not arise from an amendment of the granted claims. In line with decision G 3/14 (supra) which states that the claims of an amended patent may be examined for compliance with the requirements of Article 84 EPC only when, and then only to the extent that, the amendment introduces non-compliance with this article, appellant's objections based upon the term and definition of "vector" cannot be examined by the board.

14. Thus, the main request fulfils the requirements of Article 84 EPC.

Article 100(c) EPC; Article 123(2)EPC

15. The appellant argued that there is no basis in the patent application for embodiments comprising more than one copy of a DNA encoding a heavy chain or a fragment thereof of the antibody.

15.1 These embodiments are also the basis of an objection raised by the appellant for an objection of lack of clarity. The substance and merits of this objection have been assessed by the board under Article 84 EPC above and considered not to be relevant. In the board's view, the claims of the main request are clearly limited to a method using vectors which have only one (single) copy of a DNA encoding the heavy chain of the antibody and, correspondingly, only one (single) expression unit with an exogenous DNA encoding such a heavy chain. Since appellant's embodiments upon which the objection raised under Article 123(2) EPC is based do not fall within the scope of the claims of the main request, the appellant's objection is not relevant.

16. The appellant argued that there is no basis in the patent application for vectors or expression units other than the (sole) exemplified circular plasmids. According to the appellant, the absence of such a limitation represented an unallowable intermediate generalisation lacking any basis in the patent application. Moreover, the appellant also argued that, according to the patent application, linear vectors were necessary for obtaining (animal) cells that stably express the antibody. There was no basis in the patent application for a generalisation to cells obtained by using vectors other than linear vectors and thus, claims 8 and 9 of the main request contravened Article 123(2) EPC.

16.1 Without entering into the merits of these objections, the board, in its communication, informed the parties that these objections had never been raised under Article 123(2) EPC at first instance. Neither the decision under appeal, the Minutes of the oral proceedings at first instance nor the parties' submissions filed in preparation of those proceedings indicated that these objections were ever discussed at first instance. Thus, these were new objections under Article 123(2) EPC not raised at first instance.

16.2 In view thereof, the board also indicated in its communication that the question arose why these objections could not have been raised at an earlier stage of the proceedings. The parties' attention was drawn to Article 12(4) RPBA 2007 (in conjunction with Article 25(2) RPBA 2020) and the board stated that these objections could be admitted into the appeal proceedings only at the board's discretion. In view of the submissions on file, indeed, the lack of any reasons for explaining the introduction of these objections at this late stage of the proceedings, the parties were informed that the board was minded not to admit them into the appeal proceedings.

16.3 At the oral proceedings before the board, both parties referred to their written submissions and made no further submissions. In view thereof, the board saw no reason to deviate from its provisional opinion and therefore, in the exercise of its discretion, did not admit these objections into the proceedings.

17. The appellant further argued that there was no basis in the patent application for a generalisation of the specific components or elements of the expression units and vectors other than those exemplified in the patent application, such as the promoter, signal sequences, etc. and, more particularly, for orientations within the vector of the expression unit with the exogenous DNA encoding the heavy chain of the antibody and the expression units with the exogenous DNA encoding the light chain of the antibody.

17.1 In the board's communication, the parties were informed that it agreed with the findings of the opposition division on this issue. The examples of the patent application instruct the skilled person how to construct the vectors with the expression units suitable for use in the method of claim 1. Although these vectors are exemplified with specific elements, such as the CAG promoter, mouse beta globin polyA, etc., and used for the production of specific antibodies, namely anti-human glypican-3 and anti-human IL6R, a skilled person would recognise these specific elements as not essential and being replaceable by known alternatives, such as those mentioned in the description of the patent application and referred to by the respondent in response to the statement of grounds of appeal.

17.2 In line with the case law which acknowledges that an intermediate generalisation may be justified if the extracted elements or features are recognised as being not inextricably linked with other (exemplified) elements or features (cf. "Case Law", supra, II.E.1.9, 482), the board considers the appellant's objection not to be relevant. The same applies also to the orientation of the expression units within the vector. As stated in its communication, the board sees no reason to deviate from the findings of the opposition division as regards this issue.

18. Therefore, the main request does not contravene Article 123(2) EPC.

Article 123(3) EPC

19. Appellant's objection under this article was raised against claims 6 and 7 of the main request. The appellant argued that, contrary to granted claims 7 and 8, they covered not only (first generation) cells "into which the vector has been introduced", but also (second generation) cells ("a cell which has a vector") wherein the vector was present due to cell duplication, and not by introduction.

19.1 In the board's communication, the parties' attention was drawn to the case law stating that, for the purpose of Article 123(3) EPC, it is the totality of the claims before the amendment in comparison with the totality of the claims after the amendment that has to be considered, i.e. it is necessary to assess the whole scope of the claims before and after the amendments (cf. "Case Law", supra, II.E.2.2, 502). In the board's view, the granted claims contemplated a culture of (first generation) cells into which the vector defined in the claims had been introduced. Cell cultures are known to have several phases (lag, log, stationary, decline) in which cells are grown and divided. This is also supported by the disclosure of the patent and the exemplified subject-matter. Thus, the scope of the granted claims - in their totality - encompassed cells with properties as those identified by the appellant, namely (second generation) cells having the vector as a result of said cell culture and not by direct introduction of the vector.

In this context, the parties' attention was also drawn to the case law on product-by-process claims (cf. "Case Law", supra, II.A.7, 315 and I.C.5.2.7, 133). According thereto, features related to the method of production may be relevant for a product, such as for establishing novelty, only if they cause it to have properties different from those of the product known from the prior art and obtained by other methods. In the present case, both first and second generation cells, are characterised only by the presence of a vector as defined in the claims; no technical differences - arising directly from their method of production and rendering each of these cell types distinct - have been put forward by the appellant. Therefore, the board sees no reason to deviate from the findings of the opposition division in the decision under appeal on this issue.

20. Thus, the main request does not contravene Article 123(3) EPC.

Article 100(a) EPC; Article 54 EPC

21. The decision of the opposition division acknowledging the novelty of the subject-matter of the main request has not been contested in appeal and thus, it is not the subject of the appeal proceedings.

Article 100(a) EPC; Article 56 EPC

22. In the decision under appeal, the opposition division considered document (2) to represent the closest prior art since this document has the same purpose as the patent, namely an efficient and high yield production of IgG antibodies. Thus, the selection of this closest prior art document follows the criterion established in the case law (cf. "Case Law", supra, I.D.3, 178).

23. Document (2) discloses the (transient and stable) expression of an exogenous DNA sequence encoding a heavy chain and an exogenous DNA sequence encoding a light chain of an IgG antibody, either from two distinct expression vectors (pLNOH2 and pLNOK, respectively) or from a single (dual-gene) expression vector (pLNOH2K), wherein each exogenous DNA sequence is under control of its own specific (CMV) promoter (cf. pages 79 and 81, figures 1 and 2, respectively). Hence, document (2) discloses a vector comprising two expression units, one with an exogenous DNA sequence encoding the IgG heavy chain and one with an exogenous DNA sequence encoding the IgG light chain. The vector used in the method of claim 1 of the main request differs from this dual-gene vector by having an increased number (two or more) of expression units with an exogenous DNA sequence encoding the light chain of the IgG antibody.

24. Starting from this prior art, the respondent formulated the objective technical problem to be solved as the provision of an improved method for the production of IgG1 antibodies. This was contested by the appellant arguing that such an ambitious problem was not solved across the whole scope of the claims and thus, in line with the findings of the opposition division, the objective technical problem needed to be reformulated in less ambitious terms (cf. "Case Law", supra, I.D.4.4, 192), namely as the provision of an alternative method for the production of IgG1 antibodies.

24.1 It is known in the art that the HC:LC gene ratio is highly relevant in the production of antibodies. Indeed, both intracellular and extracellular abundance of the heavy and light chain polypeptides, even though not directly proportional to the HC:LC gene ratio, will eventually determine the yield of the antibody produced, as shown for instance in document (20). It is not contested that the examples of the patent show an improved, higher yield production of IgG1 antibody when using the exemplified vectors comprising one expression unit with an exogenous DNA sequence encoding the heavy chain and two expression units with an exogenous DNA sequence encoding the light chain of the antibody, compared with a vector such as the one disclosed in the closest prior art document (2) with only one expression unit for the heavy chain and one expression unit for the light chain of the antibody.

24.2 However, the opposition division observed that, whilst in the examples of the patent all expression units have the same promoter, this is not a limiting feature of the claims of the main request and thus, the claims encompass also vectors wherein the expression units may have different promoters, such as for instance a weak promoter for the expression units with the exogenous DNA sequence encoding the light chain of the antibody, whilst the expression unit with the exogenous DNA sequence encoding the heavy chain of the antibody may have a much stronger promoter. In that case, the intracellular and extracellular HC:LC ratio may not necessarily result in the improvement shown in the examples of the patent. This was contested by the respondent with reference to the examples of the patent and to the prior art on file which, the respondent argues, always use the same promoters for expressing both, the heavy and the light chain, in all constructs described therein. Therefore, the claims of the main request could not be read in any other way.

24.3 There is no evidence on file, and none has been put forward by the appellant, to show the effects on the level of antibody expression and production of the embodiments envisaged by the opposition division. However, the board understands respondent's argumentation not to contest these effects but to argue that, in the light of the teachings of the patent and the disclosures in the prior art, these embodiments would not be contemplated by a skilled person. In the board's view, this is a question different from that of whether or not the embodiments envisaged by the opposition division may fall within the scope of the claims. For answering this latter question, no evidence is needed.

24.4 In the board's view, it cannot be contested that the claims are not limited to vectors with expression units having all the same promoters. Although all the examples of the patent may describe such vectors, it is well established case law that, when assessing novelty and inventive step, there is no reason to use the description of the patent to interpret a broad claim more narrowly (cf. "Case Law", supra, I.C.4.8, 122, and II.A.6.3.4, 312). Thus, there is no reason for reading this restrictive feature or limitation, namely the use of the same promoter in all expression units, into the claims. Indeed, a suggestion to alter the HC:LC ratio by replacing and using a different promoter is found also in the prior art, even though it goes in a sense contrary to that referred to by the opposition division; document (20) suggests to use strong promoters - not weak ones - for expressing and increasing the amount of light chain of the antibody (cf. page 131, left-hand column, last sentence of second full paragraph). Nevertheless, this disclosure shows that the interpretation of the opposition division and thus, the specific embodiments referred to by the appellant and the opposition division, makes technical sense and is not illogical (cf. T 190/99 of 6 March 2001).

24.5 Thus, the board agrees with the findings of the opposition division and considers that the objective technical problem needs to be formulated in the terms used by the opposition division and the appellant, namely the provision of an alternative method for the production of IgG1 antibodies.

25. It remains to be assessed whether, starting from the closest prior art document (2) and the above formulated less ambitious technical problem, a skilled person would have arrived at the claimed subject-matter in an obvious manner. For carrying out this assessment, the so-called "could-would approach" followed by the opposition division is appropriate (cf. "Case Law", supra, I.D.5, 197). In this context, the appellant referred to documents (20) and (1) as leading the skilled person, when starting from document (2), to the claimed subject-matter in an obvious manner.

25.1 Although the case law defines the skilled person as being cautious and having a conservative attitude (cf. "Case Law", supra, I.D.8.1.3, 205), it also acknowledges that furthering the state of the art belongs to the normal tasks of the skilled person and that routine adaptations as well as the use of known alternatives do not go beyond what may be normally expected from a skilled person (cf. inter alia, T 1715/15 of 27 February 2020, point 18 of the Reasons, and T 688/14 of 24 July 2019, point 25.1 and the case law cited therein). Indeed, even though the method described in document (2) is said to provide a high yield of recombinant antibody, document (2) itself refers to an alternative for ensuring even higher levels of antibody expression. Thus, a skilled person would certainly be motivated by document (2) to look for possible alternatives. However, the alternative mentioned in document (2), namely the introduction of genomic introns or a genomic leader sequence (cf. page 85, left-hand column, penultimate paragraph), would not lead the skilled person to the method of claim 1, nor is there any other suggestion or indication in document (2) that would have led the skilled person thereto.

25.2 As stated above, document (20) shows that the transfected HC:LC gene ratio is not directly proportional to the intracellular level of the heavy and light chain polypeptides and that the presence of active antibody depends on both intracellular and extracellular abundance of the heavy and light polypeptides. In agreement with previous studies, document (20) acknowledges that an increased proportion or an excess of intracellular light chain polypeptide facilitates the assembly and secretion of the antibody and results thus in an improved production of the antibody (cf. inter alia, page 131, left-hand column, second full paragraph; and paragraph bridging left and right-hand columns). In line therewith, document (20) refers to advantageous expression vectors biased toward low HC:LC polypeptide ratios (<1:2) (cf. page 131, right-hand column, penultimate sentence of last full paragraph), and discloses HC:LC gene ratios falling within the HC:LC gene ratio of the vectors defined in the main request.

25.3 However, these HC:LC gene ratios are always achieved by increasing the amount of the expression vector with a (single) expression unit with an exogenous DNA sequence encoding the light chain of the antibody, not by increasing the number of exogenous DNA sequences encoding the light chain in the dual-gene expression vector disclosed in document (20) (pConk+VL and pcB72.3, respectively; see figure 1 on page 125). There is no suggestion in document (20) to modify the dual-gene expression vector in order to increase the number of the exogenous DNA sequence encoding the light chain, let alone to provide these additional exogenous DNA sequences as distinct, individual expression units within said vector. Indeed, as rightly observed by the respondent, the skilled person is taught away therefrom because document (20) already reports an excess of intracellular light chain over the heavy chain when using the dual-gene expression vector with a 1:1 HC:LC gene ratio (cf. figure 2 on page 126, and figure 6 on page 130). Moreover, as also stated above, if the suggestion made in document (20) would be followed, namely to use stronger promoters for the expression of the light chain (cf. page 131, left-hand column, last sentence of second full paragraph), this suggestion would lead the skilled person away from the vectors defined in the main request.

25.4 Likewise, it is also acknowledged in document (1) that an improved antibody expression is achieved when using two copies of an exogenous DNA sequence encoding the light chain and one copy of an exogenous DNA sequence encoding the heavy chain of the antibody (cf. page 83, first paragraph, last sentence; page 107, third paragraph, last sentence). However, the disclosure on page 83 is made after a reference to the advantageous use of the 2A and 2A-like sequences or other self-processing sequences described in document (1) which facilitate the equimolar expression of two or more polypeptides by way of a single promoter.

25.5 Although HC:LC gene ratios like those of the subject-matter of the main request are disclosed in document (1) and are described as being advantageous for antibody expression, the exogenous DNA sequences encoding the heavy chain and the light chain are always separated by intervening sequences encoding cleavage sites, preferably the self-processed cleavage sites cited on page 83 (cf. inter alia, page 9, paragraphs [00021] and [00022]; page 29, paragraphs [00095] to [00097]). These intervening sequences are described as allowing the expression of the heavy and light chain coding sequences under the transcriptional control of a single promoter, i.e. as a polyprotein from a single transcript in a host cell (cf. inter alia, page 10, paragraph [00026] and page 11, paragraph [00027]).

25.6 Although document (1) refers also to prior art disclosing the use of two promoters within a single vector (cf. page 4, paragraph [00011], and page 5, paragraph [00013]), these references are cited only for describing the disadvantages and problems associated with such a single vector when compared to the advantages of the vectors with the intervening sequences disclosed in document (1). Therefore, in the board's view, the skilled person seeking to modify the dual-gene expression vector disclosed in document (2) would not contemplate these single vectors with multiple promoters explicitly referred to in document (1) as being disadvantageous but, if anything, the use of the advantageous intervening sequences disclosed in this document. Therefore, the skilled person would also be led away from the subject-matter of the main request.

25.7 It follows from the above considerations that the claimed subject-matter is not rendered obvious by the disclosure of document (2) alone or in combination with those of either document (20) or document (1).

26. Therefore, the main request fulfils the requirements of Article 56 EPC.

Conclusion

27. Since the main request fulfils all requirements of the EPC, the appeal is to be dismissed.