Both the patent proprietor and the opponents appealed the decision of the Opposition Division maintaining the opposed patent in amended form.
The claims on file were directed at a particular humanized antibody, or fragment thereof.
The Board found the main request on file to violate A 123(2) and the first auxiliary request to lack clarity because of the expression “a light chain framework sequence substantially identical to a native human light chain framework”.
The decision contains some interesting paragraphs dealing with the sufficiency of disclosure of auxiliary request 2:
A 83
[43] The patent discloses in SEQ ID Nos. 11 and 12 (describing sequences of the variable and constant regions for the heavy and light chain of the humanized antibody) the sequence of a specific humanized antibody having CDR sequences as recited in claim 1 and modified human framework sequences. In particular, the framework sequences of the heavy chain variable region framework according to SEQ ID No. 12 are derived from the human germline VH segment DP53 and J segment JH4 with amino acid substitutions according to the Queen procedure (see paragraph [0040] of the patent). The light chain variable chain framework according to SEQ ID No. 11 originates from the human germline Vkappa segments DPK18 and J segment Jkappa1 with amino acid substitutions according to the Queen procedure […]. This exemplified humanized antibody is the one denoted as “Hu266” (see paragraph [0112] of the patent).
[44] The patent moreover discloses in SEQ ID Nos. 7 and 8 […] positions labelled as “XAA” which denote potential sites of variation of the sequence of the specifically disclosed Hu266 antibody. More precisely, ten and eight sites, respectively, for modification in the light and heavy chain variable regions are listed in SEQ ID Nos. 7 and 8 with two to three and two to four, respectively, possible amino acid substitutions at each of those sites.
[45] Thus, the patent discloses not only one, but many examples. The opponent does not contest that the skilled person is able to obtain Hu266 and its disclosed derivatives.
[46] The opponent’s argument however is that, because the framework sequences are defined in claim 1 as framework sequences from a human immunoglobulin light or heavy chain, this claim does not only encompass the specifically disclosed antibody Hu266 and its disclosed derivatives, but also humanized antibodies with framework sequences unrelated to the exemplified one.
[47] According to the opponent these variants (in the following “variants at issue”) cannot be obtained when following the disclosure in the patent. The reason is in the opponent’s view that the only method for the preparation of humanized antibodies disclosed in the patent is that developed by Queen et al. This method requires knowledge of the sequence of the non-human donor antibody from which the CDRs are derived. However, the sequence of, in the present case, the mouse donor antibody Mu266, is not disclosed in the patent (nor in the prior art) and there is no disclosure either in the patent or in the prior art of how humanized antibodies could be obtained without knowledge of the sequence of non-human donor antibody. Thus, the opponent concludes that the disclosure in the patent, even when taking into account common general knowledge, does not enable the skilled person to carry out the invention over its whole claimed scope and therefore, the requirements of A 83 are not fulfilled.
Burden of proof
[48] The opponent has suggested that in a case such as the present where neither the patent nor the prior art expressly disclose how to obtain particular embodiment of the claim, it should not be for the opponent to prove that the variants at issue cannot be obtained, but rather the burden should be on the patentee to prove that the variants at issue can be obtained.
To support its view the opponent refers to decisions T 792/00 and T 397/02 and argues that the patentees have not provided evidence that the invention is enabled with respect to the variants at issue.
[49] The board in T 792/00 [9] alludes to the general rule that
“he who asserts something positive has the burden of proof”
and concludes thus that
“if a patentee asserts that an example in a patent works as stated, and an opponent denies this, it is up to the patentee to provide proof. However, if the example contains a complete experimental protocol and the patentee affirms that the results reported have been obtained, a Board is likely to accept that the patentee has done enough to shift the burden of proof to the opponent to provide a repeat of the experiment to show that it does not, in fact, work as stated. Finally, however, the board must be satisfied, considering all the evidence, that the example works as stated.”
[50] The board in decision T 792/00 considered that the burden of proof was on the patentee because (i) the claimed invention went against a prevailing technical opinion and (ii) the patent contained only an example which was expressly labelled as a hypothetical experimental protocol.
[51] In the case underlying decision T 397/02 the board emphasized that the invention did not consist in adapting an already known method to make it simpler or more efficient, but the claimed method was conceptually different from the approach taught in the prior art (see point 12 of the reasons). There was one example, but it was not suited to show that the claimed subject-matter was enabled (see point [7] of the reasons), i.e. an example was in principle absent. As is apparent from points [13] to [16] of the decision, the board in that case considered that these were circumstances where the proprietor had to demonstrate that the claimed invention worked because, since it was not convinced of the patentee’s arguments that the invention worked, it denied sufficiency of disclosure.
[52] The circumstances of the present case are different from those dealt with in decisions T 792/00 and T 397/02 insofar as the concept of and methods for humanization are known and can, from a technical point of view, be applied to each antibody donor-acceptor pair, i.e. also to a humanized donor-human acceptor pair […]. The opponent’s submission that there is no disclosure that any-one has applied the known method to this particular situation does not necessarily establish that there was a prevailing opinion that this could not be done. In addition, the patentees submit that there was no obstacle.
[53] In the present board’s view, the situation in the case at issue here rather coincides with the situation mentioned by the board in T 792/00 [10] – a situation which was considered not to be present in case T 792/00:
“[I]n the special situation where an opponent accepts that the invention can be carried out as stated in the examples, but alleges that there are other circumstances where something falling under the claim cannot be carried out, then Boards of Appeal would normally expect the opponent to provide concrete evidence of this (cf. Latin legal tag “Qui excipit, probare debet, quod excipitur” : he who raises an objection should prove it)”.
[54] In conclusion, in the board’s view, in the present case it is the opponent who should prove that the variants at issue cannot be made.
Enablement
[55] It is established case law that the disclosure of a European patent is only considered as sufficient in the sense of A 83 if the skilled person is able to obtain substantially all embodiments falling in the ambit of the claim (for example, decisions T 409/91 and T 435/91).
[56] Yet, the concept of “sufficiency of disclosure over the whole scope of the claim” does not mean that, for a disclosure to be considered as sufficient, it has to be demonstrated that each and every conceivable embodiment of a claim can be obtained.
[57] This is explicitly acknowledged in decision G 1/03. The Enlarged Board of Appeal states in point [2.5.2] of the reasons that if a claim comprises “non-working” embodiments this may have different consequences with regard to the fulfilment of the requirements of A 83, depending on the circumstances. There may be situations where the specification contains sufficient information on the relevant criteria for finding appropriate alternatives (“variants”) over the claimed range with reasonable effort. Under these circumstances the non-availability of certain variants encompassed by the claim at the priority date is considered immaterial for the sufficiency of disclosure.
[58] An example where this was not so is the case underlying decision T 601/05. In that case the board found that a whole class of compounds falling under the terms of a claim - antibodies binding with a high affinity to TNF alpha - could not be produced on the basis of the teaching in the patent and/or the common general knowledge and that the class concerned was the very class which was particularly aimed at by the scientific community. Moreover, also the single example disclosed in the patent was an antibody which did not have high affinity (see points [24] to [44] of this decision).
[59] The present situation differs however from that in case T 601/05 in that the present patent describes quite a number of appropriate alternatives and in that the allegedly non-obtainable variants are “hypothetical” variants.
[60] Taking into account the above mentioned case law and in view of the number of examples given the patent, the board comes to the conclusion that the requirements of A 83 are fulfilled.
[61] Since most of the parties’ arguments in relation to sufficiency of disclosure dealt with the question of whether or not the variants at issue, humanized antibodies with framework sequences unrelated to the exemplified one, could be made, the board has nevertheless considered the situation that the present case was one where the requirements of A 83 could be considered as fulfilled only if there was evidence that the variants at issue could be made. Starting from this assumption, the board agrees with the opponent that these variants cannot be obtained by following the “classical” Queen-procedure disclosed in the patent, because this procedure requires knowledge of the non-human donor sequence.
[62] However, this finding would be irrelevant for sufficiency of disclosure as long as the skilled person knows other ways of making the variants at issue. It is established case law that the skilled person may use his/her common general knowledge when it comes to carrying out an invention.
[63] Thus, the question is whether or not there is any other way available to the skilled person by which the variants at issue could be made. The board can only come to the conclusion that the requirements of A 83 are not fulfilled, if it is convinced that there is not a single method for obtaining the variants at issue.
[64] The opponent argues that the variants at issue cannot be made by, for example, a) a modified Queen procedure, i.e. by applying the Queen-technology to humanized antibody Hu266 as the donor antibody or b) by random site-directed mutagenesis or c) by reconstruction of the mouse sequence and subsequent application of the Queen method.
[65] It is established case law that an objection of lack of sufficiency of disclosure only succeeds, if there are serious doubts that claimed subject-matter is enabled, and these doubts are supported by verifiable facts.
[66] As for example to method a) above, the opponent submits that screening the database of human germline immunoglobulin sequences for sequences with highest identity - this is a central step of the Queen procedure - with the sequence of the humanized Hu266 would result in the provision of sequences with an identity that was much lower than that which would result if the database was screened with the sequence of the mouse parent antibody. It appears that the opponent’s implicit conclusion is that the identity is in fact so low that the framework would not be suitable to properly support the specific CDRs from the mouse parent antibody Mu266 and that therefore an antibody constructed with these low-identity frameworks would not have a useful affinity and may even have lost the binding specificity.
[67] The opponent – who has the burden of proof, see points [48] to [57] above – has not provided, for example, tangible evidence that homology-screening with the humanized antibody Hu266 would result in finding only framework regions with a sequence identity that was lower in relation to the original mouse antibody framework sequence than the identity of sequences that would be found if screening was made with the parent antibody Mu266. Even if this was assumed to be so, there is also no evidence that the retrieved sequence, even if it had a lower identity, would not properly three-dimensionally position the specific CDRs of the Mu266 antibody.
[68] It appears that there have been cases where the grafting of CDRs to framework sequences which were not selected on the basis of sequence identity resulted in functional humanized antibodies. It is reported in, for example, document D7 on page 4285, in the middle of the second column and document D18B page 70, in the middle of the first column, that simple transplantation of CDRs without changes to framework residues resulted in antibodies with the expected specificity and affinity:
“In some cases, transplanting hypervariable loops from rodent antibodies into human frameworks is sufficient to transfer high antigen binding affinity (16, 18) whereas in other cases it has been necessary to also replace one (17) or several (20) framework region (FR) residues.”; “[a]lthough CDR grafting was successful in some cases [10,11], [...]”.
[69] Evidence allowing the verification of alleged facts may vary in nature according to each case, i.e. experimental data are certainly not always necessary as a means of proof. However, in the present case, as in particular shown by the observations in point [67] above, without such experimental data the board cannot verify the facts alleged by the opponent.
[70] Thus, the board is not convinced that the variants at issue cannot be obtained by a “modified” Queen procedure or the procedures referred to in documents D7 or D8.
[71] The opponent has relied on decisions T 792/00 and T 397/02 to support its case. However, in both cases sufficiency of disclosure was denied because not a single embodiment could be obtained on the basis of the disclosure in the patent and even less on the disclosure in the prior art. Thus, these cases do not help in the present situation where the question of the obtainability of a particular embodiment is at stake.
[72] Thus, even assuming that the present case was one where the requirements of A 83 could be considered as fulfilled only if there was evidence that the variants at issue could be made, the board would come to the conclusion that no case of lack of sufficiency of disclosure has been made.
[73] The requirements of A 83 are fulfilled.
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