Date: 17 December 2020
Conventional antibodies are large, Y-shaped proteins naturally produced by plasma B-cells and composed of two identical light chains and two identical heavy chains, both containing variable and constant domains. They may exist as single molecules or e.g. in the case of IgM as pentamers or dimers in the case of IgA. Antibodies are designed by nature to bind specifically to antigen targets via the antigen binding region which contains complementarity-determining regions (CDRs) present in the fragment antigen binding (Fab) variable region.
Patenting of antibodies presents significant challenges, in particular relating to how the novel antibody is to be clearly defined. Moreover, rapid and extensive development, in a field that is now quite crowded, has led EPO examiners to assume that the person skilled in the art has quite extensive knowledge of routine techniques for improving such properties as affinity or immune response. This often leads to challenges in presenting a convincing case for inventive step.
The November 2020 Guidelines for Examination at the European Patent Office have a new section encapsulating some of the office practice that has become established in this field.
The new Guidelines discuss different ways in which an antibody may be defined in patent claims. Thus, conventional antibodies, recombinant antibody derivatives or new antibody formats can be defined by their own structure (amino acid sequences), by nucleic acid sequences encoding the antibody or by reference to the target antigen. If defining by the target antigen, it is often necessary to define further functional features. Combinations of functional and structural features can be used and indeed are often necessary. The new Guidelines include comments on each of these approaches and also on defining by the production process, the epitope or the hybridoma producing the antibody.
When defining a conventional antibody by its structure, the EPO has adopted a practice of requiring at least six Complementary Defining Regions (CDRs). Normally this calls for three CDRs of each of the variable domains of the light and the heavy chains that are responsible for binding to the antigen. This already-adopted practice is set out in the new Guidelines. If the claim has fewer than 6 CDRs, it will, under the new guidelines, be objected to under Article 84 EPC because it lacks an essential technical feature. Exceptions are possible if it is experimentally shown that one or more of the 6 CDRs do not interact with the target epitope or if the claim concerns a specific antibody format or variant allowing for epitope recognition by fewer CDRs.
CDRs when not defined by their specific sequence must be defined according to a numbering scheme for example chosen from that of Kabat, Chothia or IMGT.
An antibody can be functionally defined by the antigen to which it binds, as long as the antigen is clearly defined in the claims. If the antigen is defined by a protein sequence, no sequence variability and no open language (e.g. an antigen comprising…) is permitted.
An antibody can also be defined by its ability to bind to a well-defined antigen or a portion thereof in combination with a negative feature as for example: “Antibody binding to antigen X and not binding to antigen Y”.
Claims directed to antibodies that are further characterised by further properties of the antibodies such as binding affinity, neutralising properties, induction of apoptosis, internalisation of receptors, inhibition or activation of receptors are already addressed in the Case Law of the Boards of Appeal. See, e.g. T0299/86 and T1300/05). The Guidelines emphasis the burden of proving any unusual parameters to ensure they do not disguise a lack of novelty and the need for an enabling disclosure across the whole scope claimed, and whether a functional definition allows the skilled person to clearly determine the limits of the claim.
Product-by-process definitions, though possible, are disfavoured. They are susceptible to lack of clarity if there may be variants that could render the scope of the resultant antibodies unclear.
An antibody may be defined also by its epitope, i.e. the antigenic determinant of a molecule, especially the specific portion or part of an antigen to which an antibody binds which may represent linear or conformational binding sites. Epitopes may, for example, be formed by protein or peptide sequences or parts thereof forming conformational binding sites, by hormones, by oligo- or polysaccharides as such or in glycoproteins (e.g. in blood group determining regions of proteins), sites on glycolipids, by lipopolysaccharides or the like. An example is the set of specific amino acids of an antigen which are specifically recognised and bound by the paratope, the binding portion of a complementary antibody.
However, since an antibody defined in this way cannot be easily compared with known antibodies binding to the same antigen the same principles as for the functional features apply.
If the epitope is a “linear epitope” (i.e. the antibody interacts e.g. with continuous amino acids on the antigen), it needs to be defined as a clearly limited fragment using closed wording (e.g. epitope consisting of). If the epitope is “non-linear” or “discontinuous” (i.e. the antibody interacts with multiple, distinct segments e.g. from the primary amino-acid sequence of the antigen), the specific amino acid residues of the epitope need to be clearly identified.
According to EPO case law and the new Guidelines, it is not enough that a claim defines a novel antibody binding to a known antigen. Techniques for finding novel antibodies are so routine that the EPO also requires a surprising technical effect to satisfy the need for inventive step. Examples of surprising technical effects might include an improved affinity, an improved therapeutic activity, a reduced toxicity or immunogenicity, a high specificity, an unexpected species cross-reactivity or a new type of antibody format with proven binding activity.
In the case of binding affinity, the structural requirements for conventional antibodies inherently reflecting this affinity must typically comprise the six CDRs and the framework regions because the framework regions also can influence the affinity.
Open structural claim language is not permitted, as it will be taken as lacking novelty over any known antibody, because existing antibodies will bind to the undefined region of the target antigen. In our experience, an exception to this principle can be argued if variability around specific epitopes is possible or specific antibody binding sites are present within an antigen.
Antibodies can be inventive if technical difficulties are overcome in producing or manufacturing the claimed antibodies, and we would add that technical difficulties in identifying the antibody may also be relevant.
The new guidelines are silent on T cell receptors (TCRs), These represent a special class of antigen binding molecules similar to antibodies. Due to their specific binding properties, especially soluble derivatives of TCRs may also fulfil patentability requirements in a way comparable to antibodies.
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