The EPO Guidelines 2024 G.II.6.1.3 explicitly allow an antibody to be claimed by reference to its epitope, i.e. the structurally defined part of the antigen that it specifically binds to. However, decision T2552/22 issued by Board 3.3.04 highlights the importance of precisely defining the epitope for this type of claim. The decision also nicely demonstrates the EPOs current approach to assessing inventive step for antibody related claims.
Overview
The patent at issue, European patent 2 905 030, relates to human monoclonal antibodies that bind to lymphocyte activation gene-3 (LAG-3). Claim 1 of the Main Request was an ‘epitope claim’ defining the antibody by target plus epitope:
An isolated human monoclonal antibody, or an antigen-binding portion thereof, which binds human Lymphocyte-activation gene 3 (LAG-3) and binds an epitope of human LAG-3 comprising the amino acid sequence of SEQ ID NO: 77.
Auxiliary Requests further defined the antibody by a series of functional features.
Key to the appeal was the meaning of the epitope definition in the claim. The patent demonstrated that antibody 25F7 specifically bound to SEQ ID NO: 77 and that antibody 25F7 had improved properties (as evidenced by increased IL-2 production) compared to prior art mouse monoclonal antibody 17B4. This was also supported by post-published data directly comparing antibody 25F7 to prior art antibody 17B4.
The opponent had argued that antibody 17B4 bound an epitope that comprised the amino acid sequence of SEQ ID NO: 77. However, the Board found the evidence presented by the patentee convincing that this was not the case. The patentee argued that this improvement was linked to all antibodies binding SEQ ID NO: 77 and thus was seen across the scope of the claim.
Also disclosed in the patent was antibody 8B7 but there was a question over whether, like 25F7, this antibody also performed better than 17B4. It was therefore critical whether 8B7 fell with the scope of the claim. If it was within the scope of the claim but didn’t perform better than 17B4, then the effect alleged for the claimed antibodies would not be achieved over the whole scope claimed.
It was stated in paragraph [0241] that "the 25E3, 25F7 and 8B7 antibodies bind to different although closely located epitopes within human LAG-3". However, it was only apparently during the oral proceedings that the patentee advanced this as part of an argument that 8B7 was not an embodiment of the claimed subject-matter because this antibody did not bind an epitope "comprising the amino acid sequence of SEQ ID NO: 77". In contrast to this the Board noted that, in the submission made in its reply to the appeal, the patentee had asked for comparative data on 8B7 with 17B4, thereby being understood to have taken the view that 8B7 falls under the claim.
The Board’s finding on the meaning of the epitope definition was decisive for how the objective technical problem was defined
The Board’s comments regarding the meaning of the term “epitope” are important for those drafting in this field. Specifically, the determination, and thus meaning, of an "epitope" of a particular antibody depends on the assay method used and the parameters with which the assay is carried out:
The board recalls that the term "epitope", as understood by the skilled person at the relevant date of the patent, does not refer to an exact amino acid sequence or a specific number of amino acids in a protein target which together form the epitope. Rather the determination of an "epitope" of a particular antibody depends on the assay method used and the parameters with which the assay is carried out. Different assays can, as also pointed out by the opponent, measure different properties of an epitope, e.g. functional or structural ones, and thus result in different amino acids being included or not included as part of an epitope for a given antibody on a given target. Examples of functional assays are e.g. peptide mapping (see patent, Example 3) or alanine scanning, examples of structural assays as provided by the opponent during oral proceedings are e.g. cryo-electron microscopy, X-ray crystallography or hydrogen deuterium exchange (HDX) combined with mass spectrometry (MS). (Reasons 4)
The Board decided that since neither the method of determining the epitope nor the extent of binding were defined in the claim, the broadest technically sensible interpretation of the term "epitope" had to be adopted which is that the epitope bound by the reference antibody comprises the sequence with SEQ ID NO: 77. The Board further concluded that antibody 87B binds to an epitope comprising the amino acid sequence of SEQ ID NO: 77 and was thus an embodiment of the claimed subject-matter.
The further experimental data submitted with the opponent's statement of grounds of appeal directly compared antibodies 25F7, 8B7 and 17B4 in the same assay and revealed that antibody 25F7 shows improved activity compared to prior art antibody 17B4, while antibody 8B7 does not. Accordingly, the Board found that the patentee had not provided any evidence beyond that for antibody 25F7 to establish a link between the epitope defined in the claim and the alleged improved activity. The effect achieved for antibody 25F7 was therefore not taken into account in formulating the objective technical problem, which thus was formulated as the provision of alternative human monoclonal antibodies binding to human LAG-3 protein.
The claimed subject matter was found to be obvious
Starting from the closest prior art and aiming to provide alternative antibodies specifically binding to human LAG-3 protein, the Board found lack of inventive step on the basis that:
- The skilled person would have chosen the extra loop as an antigen for raising antibodies
- the closest prior art provides a “straightforward method” for generating antibodies against epitopes in the extra loop
- following this “routine path of antibody generation”, the skilled person would have arrived at the claimed subject-matter.
The Board also considered that the skilled person had a reasonable expectation of success to obtain such alternative antibodies and disagreed with the opposition division reasoning that "[a]ttainement of the same effect by binding to a different epitope could already have been surprising and sufficient for the claimed antibodies to qualify as a non-obvious alternative"[1].
Comment
When drafting an antibody related application, there is a possible squeeze for ‘epitope’ claims between data included in the patent application to support such a claim under sufficiency and the scope that might be desired to distinguish from prior art antibodies. For example, epitope binding based on competition assays which characterise a novel antibody as competing for the ‘same’ epitope as a prior art antibody might be viewed as showing that the antibodies bind the ‘same’ epitope if there is no further characterisation of the epitope. An ‘epitope’ claim in this case might be sufficient, but not novel if a prior art antibody also competes for binding with the reference antibody. Alternatively, if taking the position that determining if an antibody binds the same ‘true’ epitope as the reference antibody requires a more refined technique such as X-ray crystallography, the patentee runs the risk of the claim not being sufficient because the skilled person cannot prepare antibodies across the scope of the claim without undue burden if this data is not included in the patent.
Careful consideration therefore should be given at the time of drafting to the method or parameters to be used when determining the epitope of the reference antibody, as well as what "binding" means. In the present case, failure to do this meant that the same issues under inventive step applied even when the patent claim was amended to recite the VH and VL sequences of the reference antibody.
The Board’s finding on the meaning of the epitope definition was decisive for how the objective technical problem was defined. Once the Board had redefined the objective technical problem as the provision of alternative antibodies, their finding of lack of inventive step was consistent with the current EPO Guidelines stating that:
“Arriving at alternative antibodies exclusively by applying techniques known in the art is considered to be obvious to the skilled person.” [2]
Although not relevant to the claim in the present case, even if the claimed antibodies had been defined structurally by an amino acid sequence, this would not have changed the outcome under the EPO’s current approach to inventive step for antibody related inventions unless limited to an antibody showing a surprising technical effect. This is because the EPO currently takes the position that:
“The fact that the structure of an antibody, i.e. its amino acid sequence, is not predictable is not a reason for considering the antibody as non-obvious.” [3]
In the present case, the reference antibody 25F7 per se (which the patentee argued stimulates antigen specific T cell response more efficiently and thus did show a surprising technical effect) had already been claimed by reference to the VH and VL sequences in parent patent EP 2 320 940. The surprising technical effect allowed the objective technical problem to be defined as providing an improved human monoclonal anti-LAG-3 antibody and the solution claimed could be acknowledged as inventive.
[1] Point 19.3.2 of the decision under appeal
[2] EPO Guidelines 2024 G.II.6.2
[3] EPO Guidelines 2024 G.II.6.2
