The EPO has now published their revised Guidelines for Examination 2021 which contain new sections detailing EPO practice in relation to antibodies for the first time, entering into force on 1 March 2021.
The content of this new section of the Guidelines is in line with our recent experience in the antibody field and appears to follow on from recent internal guidance circulated amongst EPO Examiners. This new material covers a number of points that we have seen regularly raised during examination of antibody claims before the EPO, but that had not previously been formalised.
The introduction of this section to the Guidelines is however of significant benefit in helping to ensure consistency of practice at the EPO and in informing the drafting process for antibody-related inventions. It also serves to complement the existing sections of the EPO’s Case Law of the Boards of Appeal regarding sufficiency of disclosure in relation to antibodies, as well as the broader sections relating to inventions in the biotechnology field more generally.
What do the new Guidelines say?
The new section of the Guidelines deals mainly with the clarity of how antibodies are defined in claims, and the potential consequences of this definition for whether the claimed antibodies are considered to be novel over known antibodies. Further guidance on what is considered to be inventive in the antibody field is also provided.
Defining antibodies by antibody structure only:
The new Guidelines set out that a conventional antibody (having both heavy and light chain variable domains) needs to be defined by at least its six CDRs to meet the requirements of Article 84 EPC “in order to be uniquely defined by its structure only and have its characteristic binding specificity” according to the EPO. In addition, if the claim refers to CDR sequences within a longer sequence (e.g. a heavy or light chain variable domain sequence) then the CDRs must be defined according to a particular numbering scheme. Defining an antibody by fewer than six CDRs will lead to objections under Article 84 EPC as lacking an essential technical feature unless the applicant can show that one or more of the CDRs do not interact with the target epitope or that the antibody format allows epitope recognition with fewer than six CDRs.
Defining antibodies by target antigen:
The new Guidelines still permit antibodies to be functionally defined by the antigen they bind to (e.g. “an antibody binding to X”, “an anti-X antibody”, or “an antibody binding to antigen X consisting of the sequence defined by SEQ ID NO: Y”). However the antigen definition must use closed, specific language that does not allow for sequence variability, otherwise the claimed antibodies will be considered to lack novelty because existing antibodies may also bind to the undefined region of the target antigen.
Defining antibodies by target antigen and further functional features:
Claims defining antibodies by further functional features (such as binding affinity, neutralising properties, induction of apoptosis, internalisation of receptors, inhibition or activation of receptors) in addition to defining the antigen it binds to may also be permitted. However, the Guidelines set out a number of potential novelty issues that may arise with antibodies defined in this way. Firstly, if antibodies directed to the same antigen are disclosed in the art and the protocol used to obtain the prior art antibodies leads to antibodies having the claimed properties, then the EPO will assume that the prior art antibody inherently displays the same functional properties as the claimed antibody. The claimed antibody will therefore be considered to lack novelty. Secondly, if the antibody is defined by so-called “unusual parameters”, these may also be considered to disguise a lack of novelty. In both of these cases, the EPO places the onus on the applicant to demonstrate that the claimed antibodies are different to those of the prior art.
Finally, the Guidelines also state that for antibodies defined only by functional features, it must be considered whether the application provides an enabling disclosure across the whole scope of the claim and whether this definition permits the skilled person to clearly determine the limits of the claim scope. However, no further detail on this point is provided in the new Guidelines and so it remains unclear precisely what functional language will be considered acceptable.
The particular language used to describe functional features can often prompt objections from EPO Examiners, so applicants will still need to consider carefully what language they use to define an antibody’s functional properties and how these may be measured. Careful drafting will therefore be needed for functional features, including disclosure of how these properties may be tested experimentally.
Defining antibodies by functional and structural features:
The new Guidelines also confirm that antibodies may still be defined by a combination of functional properties and structural features, including structural features allowing for some sequence variability (for example both variable domains or CDRs with less than 100% sequence identity) if combined with a “clear functional feature”. Clearly, the issues noted above regarding functional features need to be considered here too.
Defining antibodies by production process:
Antibodies may also still be defined by their production process, for example by an immunisation protocol with a well-characterised antigen, although the Guidelines caution that immunisation by an antigen comprising a sequence having less than 100% identity to a defined sequence would lack clarity under Article 84 EPC since the use of variants renders the scope of the antibodies obtained by the immunisation process unclear.
Defining antibodies by the epitope:
Antibodies may also be defined by the epitope, although the EPO applies the same principles here as for functional features since such antibodies cannot easily be compared with known antibodies binding to the same antigen.
For “linear” epitopes where the antibody interacts with continuous amino acids on the antigen, the epitope must be defined as a clearly limited fragment using closed wording such as “an epitope consisting of ...”. For “non-linear” or “discontinuous” epitopes where the antibody interacts with multiple, distinct segments of the antigen amino acid sequence, the specific amino acid residues of the epitope must be clearly identified and the method used for determining the epitope must also be indicated in the claim. In parallel, the application as filed must provide an enabling disclosure that would allow the skilled person to determine whether or not further antibodies also bind this discontinuous epitope. Finally, the application must also enable the production of further antibodies binding to the same discontinuous epitope without undue burden. The EPO has therefore placed the onus squarely on the applicant to demonstrate that antibodies defined by a particular epitope can be readily distinguished from other known antibodies.
Although not specifically mentioned in the new Guidelines, this new guidance could also lead to EPO Examiners citing this section as additional reasoning for objections to “same epitope” claims. Similarly, the new Guidelines also contain no mention of claims that define antibodies by competition with another reference antibody. Such claims are frequently objected to by EPO Examiners and so further guidance on this point in these new Guidelines would have been useful to applicants.
Defining antibodies by hybridoma:
Antibodies may also be defined by the hybridoma cell which produces them, as long as this has been deposited and meets the standard requirements for deposited biological materials.
Inventive step of antibody claims:
The final section of the new Guidelines sets out the EPO’s current approach to inventive step with antibody claims.
As has been the EPO’s approach for some time, a claimed antibody which is new but binds to a known antigen will not be considered to be inventive unless a surprising technical effect is shown in the application. Examples of such effects compared to known antibodies include improved affinity, improved therapeutic activity, reduced toxicity or immunogenicity, unexpected species cross-reactivity or a new type of antibody format with proven binding affinity.
The Guidelines also set out that if an improved property versus prior art antibodies is relied on for inventive step, the main characteristics of the method for determining the property must also be indicated in the claim or by reference to the description. It is also noted that if the surprising technical effect involves the binding affinity, the EPO considers that because the framework regions can also influence the affinity of an antibody the claim should reflect these structural requirements and recite the six CDRs and the framework regions.
The Guidelines also confirm existing EPO practice that inventive step is not acknowledged solely on the basis that a novel antibody binding to the same antigen as known antibodies is structurally different. The EPO considers it obvious for the skilled person to arrive at alternative antibodies binding to the same antigen using techniques that are routine in the art, and the fact that the structure of these new antibodies is not predictable is not enough to consider these antibodies to be non-obvious.
Although no further guidance is provided specifically in relation to determining the closest prior art document for assessing inventive step of antibody claims, the new Guidelines appear to align with typical objections seen in this field where the claimed antibodies are considered not to be inventive on the basis that they are mere alternatives to prior art antibodies binding the same target.
Finally, the Guidelines also set out that antibodies may also be considered inventive if there are technical difficulties in producing or manufacturing the claimed antibodies, as long as this is demonstrated in the application.
Applicants therefore need to consider carefully whether they can demonstrate the required surprising technical effect from the data in the application as filed.
Whilst its content is perhaps not surprising, the fact that the EPO’s approach to antibody claims has now been formalised in these new Guidelines should be helpful to applicants in this field. It provides further clarity in terms of the potential claim scope that applicants may be able to achieve at the EPO. It will also be helpful when considering how to define new antibodies at the drafting stage to ensure that sufficient language is included to adequately distinguish the invention over the prior art, particularly where functional features or more atypical language is used to define the antibodies. Because of the EPO’s strict approach to priority, applicants will also need to ensure that antibody-related priority applications are also drafted with the new Guidelines in mind. It should also help to provide consistency of approach between different EPO Examiners in this field where previously this has not always been the case. This may be particularly useful for applicants who have experienced EPO Examiners taking a stricter approach than others regarding antibody subject matter. In such circumstances, applicants will now be able to point to concrete guidance in this area to counter any overly strict approach.