17 Mar 2016

T 2220/14 - Sufficiency and inventors

Key points:

  • A document describing the difficulties that the inventors had in getting the invention to work, is not relevant for Article 83 EPC because that article requires that patent application discloses the invention in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art. This is a notional figure, not a real person. 
EPO T 2220/14 - [C] - link


Reasons for the Decision

23. Respondent I submitted document (169) to support its case under Article 83 EPC. Article 83 EPC requires that a European patent application shall disclose the invention in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art. Such a requirement needs to be fulfilled at the date of filing of the application. The "person skilled in the art" is a notional figure, not a real person. Document (169) is written from memory by one of the inventors. It describes in an informal way the difficulties that the inventors had in getting the invention to work. The respondents seem to be suggesting that document (169) is relevant to Article 83 EPC upon the basis that if the inventors had problems putting the invention into effect, then this is evidence that the "person skilled in the art" would have such problems. The board is not convinced by this argument. The key issue is the disclosure of the European patent application and how the notional skilled person would understand this disclosure. A document describing what the inventors did in order to make their invention, even if such a document did not suffer from the weaknesses of document (169) enumerated above, would not assist on this point. The board therefore finds that document (169) lacks relevance as regards sufficiency of disclosure and the board therefore declines to admit document (169) into the proceedings.
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Confidentiality of documents (169) to (172)
29. At this point it is also convenient to consider the question of whether, as requested by the appellant, to maintain documents (169), (171) and (172) as confidential, which means that they will not be stored in the publicly accessible part of the EPO's file.
30. Respondent I requested that document (169) be maintained as confidential in its letter of 8 September 2015. None of the other parties have opposed this request, respondent II has remarked, however, that it does not consider itself bound by any confidentiality obligations arising from the English litigation to which it is not a party.
31. Document (171) was filed on 1 October 2015 by respondent II without any request that this document be kept confidential. The appellant in its 12 October 2015 letter, requests that document (171) be treated as regards confidentiality in the same way as document (169).
32. Document (172) was filed by the Appellant on 12 October 2015 with a request that it be kept confidential.
33. None of these documents have been admitted into the proceedings, the board therefore sees no good reason not to maintain the confidentiality of these documents, given that requests to this effect have been filed by the appellant, and respondent I. The board notes that no party has made any positive case that these documents should be placed on the publicly accessible part of the file. The board therefore directs that these documents are not to be made publicly accessible.
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Article 83 EPC - Sufficiency of disclosure
55. In the decision under appeal, the opposition division did not decide on the objections raised by the opponents under Article 83 EPC. However, it expressed the view - as obiter dictum - that, as regarded the seventh auxiliary request then on file, the requirement of sufficiency of disclosure was fulfilled.
56. Having considered the objections raised by the respondents in appeal proceedings and the evidence on file, the board sees no reason to doubt that the invention as claimed in claims 1, 5 and 6 is disclosed in the application as filed in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art, as required by Article 83 EPC.
57. It is a well-established principle in the case law of the boards of appeal that, for the disclosure of an invention to be sufficiently clear and complete within the meaning of Article 83 EPC, the skilled person, on the basis of the information provided in the application itself, supplemented by the common general knowledge at the filing date (or the priority date, if applicable), must be able to carry out the invention without undue burden of experimentation or inventive skill (see e.g. decisions T 694/92 OJ EPO 1997, 408 and T 612/92 of 28 February 1996).
58. The assessment of sufficiency of a disclosure has to be conducted in each case on its own merits, and it depends on the correlation of the facts of the case to certain general parameters, e.g. the amount of reliable technical details disclosed in the application, the time when the disclosure was presented to the public and the corresponding common general knowledge, as well as the character of the technical field and the average amount of effort necessary to put into practice a certain written disclosure in that technical field (see decision T 158/91 of 30 July 1991, point 2.3 of the reasons; and T 639/95 of 21 January 1998).
59. In the present case, the notional person skilled in the art for the purpose of assessing sufficiency of disclosure must be regarded as being a team of specialists with knowledge and capabilities in the fields of genetic engineering, immunology and mouse embryology and genetics, and in particular ample experience in the fields of bacterial homologous recombination, targeted recombination in eukaryotic cells and generation of transgenic mice from embryonic stem cells containing xenogeneic, in particular human DNA, these techniques being - undisputedly - well-established at the priority date. The team would have a good knowledge of the genetic structure of the murine and human immunoglobulin gene loci.
60. Since the technical field to which the present invention relates is highly complex, the average amount of effort necessary to put into practice a written disclosure in this field would be rather high and involve a considerable amount of trial and error.
61. As regards the disclosure content of the application as filed, the board does not share the respondents' view that the pertinent disclosure for the purpose of assessing sufficiency of disclosure is restricted to Example 3. Rather, it is the technical content of the application as a whole, which relates to methods of modifying eukaryotic cells that can be applied to modify any endogenous gene or chromosomal locus, which is to be considered. In Example 3 the methods of the invention are exemplified for the modification of specific loci, but when trying to carry out the invention - which, in the board's view, cannot be equated to repeating Example 3 - the skilled person would resort to the entire technical information provided in the application as filed.
62. In their pleadings at the oral proceedings, the respondents based their objection of lack of sufficient disclosure mainly on documents (126) and (127), two scientific articles co-authored by the inventors and published in 2014. In the respondents' view, document (127), in particular Figure 1 was a clear evidence that a person skilled in the art could not have carried out the invention applying the technical teachings contained in Example 3 of the application as filed.
63. The board disagrees with this view. First, the fact that the approach followed by the appellant itself to humanize the mouse heavy chain variable gene as described in document (127) differs from the approach suggested in Example 3 of the application as filed does not necessarily mean that the latter cannot be carried out without an undue burden of experimentation and/or inventive skills. The respondents have not presented convincing evidence that this would be the case, their main argument being that Example 3 is a "prophetic" example. However, there is no requirement in the EPC that, either at the priority or filing date, the applicant must have carried out the claimed invention. The requirement of Article 83 EPC is that a person skilled the art, following the teachings in the application as filed supplemented with his/her common general knowledge and with a reasonable amount of experimentation, including some trial and error, would be able to carry out the invention as claimed at the relevant date.
64. Second, the board observes that the approach followed in document (127), in which a total 2.6 Mb of the murine heavy chain variable region gene locus was replaced by 1 Mb of the human orthologous locus, does in fact make use of the methods disclosed in the application as filed. The board is persuaded that any required modifications could be devised by a person skilled in the art at the relevant date using his/her common general knowledge with a reasonable amount of trial and error, but without applying any inventive skills. In fact, this approach makes use of the targeted integration/deletion of large cloned genomic fragments in murine ES cells by homologous recombination using LTVECs as described in detail in the application as filed (the so-called VelociGene method referenced as (7); see page 3, left-hand column, first full paragraph of document (127)). Applying this method, a 144 kb fragment of human immunoglobulin DNA containing 3 VH, all 27 DH, and 9 JH was inserted using about 75 kb of mouse homology arms (Figure 1B, step A). Concomitantly, 16.6 kb of the mouse sequence were deleted. The fact that this transgene still contains murine V gene segments which may be involved in rearrangement and give rise to antibodies which contain, at least in part, a murine variable region is, in the board's view, not prejudicial to Article 83 EPC. The presence of 3 VH ensures that antibodies containing (entirely) human variable regions and mouse constant regions are produced.
65. The approach in document (127) also makes use of a quantitative assay to detect modification of allele, which is designated MOA in the application as filed (see step d) in present claim 1) and LONA ("loss-of-native-allele") in document (127) (see page 3, left-hand column, lines 19 to 24). The board does not share the respondents' view that the MOA step would not work if orthologous human sequences were inserted without concomitant deletion of the corresponding murine sequences. First, the board does not construe the wording "to replace" in step c) of the method of claim 1 as meaning that all murine V, D and J gene segments must be deleted concomitantly with the insertion of the human segments. As apparent from document (127), it is not necessary to delete all the murine sequences to be replaced by the corresponding human sequences. Deletion of as little as 16.6 kb murine sequence is sufficient to detect a modification of allele, i.e. a loss of murine sequences at the site where the human sequences are inserted.
66. The approach described in document (127) also makes use of site-specific recombination, in particular the loxP/Cre tool disclosed in Example 3 of the application as filed to insert further human V gene segments and delete murine sequences (see Figure 1B, step B and LTVEC1 and LTVEC2 in Example 3 of the application). According to document (127) (see Figure 1C, steps D to H), insertion of additional V gene segments was achieved by several rounds of sequential targeting by homologous recombination. This has also been described in the application as filed (see passage from page 11, line 17 to page 12, line 2 and claims 8 and 9). It has not been disputed that, at the priority date, there was information available in the art that would allow a person skilled in the art to design suitable homology arms for inserting in a sequential fashion fragments of the human DNA containing additional V gene segments, without applying any inventive skills.
67. Concerning the homology arms, the sole argument put forward by the respondents was that the 5' end of the murine immunoglobulin variable region locus was not conclusively known at the priority date and that, therefore, the skilled person could not have created LTVEC2. To support their objection, the respondents relied on documents (116) and (121). Document (116) is a statement filed by the present appellant which includes allegations as to the lack of information on the genomic fragment to be used as 5' homology arm in Example VII of document (1).
68. In the board's view, these allegations are without merit. Although the 5' end of the murine heavy chain variable region locus was fully characterized only in 2006 (see document (121)), at the relevant date BAC libraries of the murine immunoglobulin genes were available. Hence, a person skilled in the art could have found by, e.g., chromosome walking with the aid of the technical information provided in document (120) a suitable DNA fragment containing the 5' end of the locus for use as a homology arm. In the board's view, this would not have required an undue amount of experimentation, because a detailed mapping as reported in document (121) was not required.
69. The respondents based a further objection under Article 83 EPC on documents (93) and (94), arguing that, at the relevant date, only deletions of up to approximately 30 kb had been achieved. Deleting 200-300 kb of the murine locus, as suggested in Figure 4A of the application as filed, would have been impossible, because the capacity of BAC vectors was limited. The respondents relied also on document (127) in which the appellant admitted that only 114 kb of the proximal end of the human heavy chain locus had been inserted, and 16.6 kb of the mouse sequence deleted. The board is of the view that this evidence is not conclusive. First, the relatively "poor" gene targeting results reported in documents (93) and (94) were achieved with "conventional" gene targeting techniques, eventually adding a site-specific recombination step, but not with vectors containing large homology arms, as in the application. Second, as apparent from document (114) the capacity of a BAC vector is about 300 kb; thus, the "theoretical" disclosure in Figure 4A of the application is not called in question. Thirdly, the board holds that, if the skilled person trying to carry out the invention with the guidance provided in the application as filed would have failed to replace 200-300 kb of the murine sequence by the human sequence, the next logical step would have been to try again with a shorter DNA fragment. The skilled person would not have thought that it was absolutely necessary to use a fragment of 200-300 kb to insert the human J, D, and at least some V gene segments into the murine locus and concomitantly would have deleted at least part of the murine sequence in order to be able to detect modification of allele (MOA), as taught in the application.
70. With respect to the transgene with 144 kb of human immunoglobulin sequence described in document (127) (see page 3, left-hand column, first full paragraph), the respondents disputed that 3 VH would be sufficient for producing hybrid antibodies. The evidence in Appendix A1 of document (46) (see "Velocimmune 3hVH:137 mVK"), which has not been plausibly questioned, shows that this objection is not justified.
71. Finally, the respondents pointed to the passage on page 4, right-hand column, second full paragraph of document (127) and argued that the skilled person trying to carry out the invention would have been confronted with unexpected fertility problems of the transgenic mice, and would have found no guidance in the application as filed to solve this problem. In the board's view, this difficulty cannot be seen as insurmountable because, as the appellant plausibly argued, only male mice were affected and fertility was only reduced, rather than the mice being rendered infertile.
72. Summarizing the above, the board has no reason to doubt that the invention as claimed in claims 1, 5 and 6 is sufficiently disclosed as required by Article 83 EPC.

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