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We are pleased that the comments on patentability of antibodies in Guidelines Part G, Chapter II, section 5.6 has been clarified and updated. AA Thornton’s Craig Turner discussed this with industry contacts and recommended clarifications.
The new antibody Guidelines give helpful expression and guidance concerning what is, generally speaking, the practice now being followed at the EPO in this area. New antibody formats such as heavy chain-only antibodies are specifically noted, and it is recognised that such antibodies (now more specifically referred to as an IgG) may be defined structurally by the number of CDRs required for its binding (rather than at least six CDRs). If an IgG is defined by fewer than the six sequences of its CDRs, the claim will be objected to as lacking clarity because it lacks an essential technical feature unless it is shown experimentally that one or more of the six CDRs do not interact with the target epitope. This is helpful clarification and improves on the wording of the 2021 version of the Guidelines. Detailed guidance is also provided on other ways of defining and claiming antibodies, with some useful example wording.
A specific section on inventive step of antibodies has now be provided. A novel, further antibody binding to a known antigen is considered not to involve an inventive step unless a surprising technical effect is shown or unless there was no reasonable expectation of success of obtaining antibodies having the required properties. The italicised wording is a helpful addition and again improves on the 2021 version of the Guidelines, although some may feel it is still too restrictive given that the statutory question of inventive step is simply whether the invention is obvious to one skilled in the art. Examples of surprising technical effects are given, and include improved affinity or therapeutic activity, or reduced toxicity or immunogenicity; an unexpected species cross-reactivity, or a new type of antibody format with proven binding activity. If the surprising technical effect involves the binding affinity, the structural requirements needed for this must include the required CDRs and the framework regions, since the latter can affect the binding affinity.
Also, if a novel antibody binds to the same antigen as known antibodies, inventive step is not acknowledged solely on the basis that the novel antibody is structurally different from the known antibodies. Arriving at alternative antibodies exclusively by applying techniques known in the art is considered to be obvious. Citing T605/14 and T187/04, the Guidelines state that the fact that the antibody structure i.e. the amino acid sequence, is not predictable is not a reason for considering these antibodies as non-obvious.
The new Guidelines also recognise that antibodies can nevertheless be inventive if the application overcomes technical difficulties in generating or manufacturing the claimed antibodies.
The above changes should be broadly welcomed by patent applicants, although it remains to be seen to what extent this will alter existing practice (may be very little, in fact). It is possible we could see further changes in wording around inventive step in future versions of the Guidelines.
The new Guidelines contain this revised wording
5.6.1 General remarks
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. Antibodies are designed by nature to bind specifically to antigen targets via the antigen binding region which contains complementarity-determining regions (CDRs).
Knowledge of the structure-function relationships of antibodies allows the provision of a number of derivatives for a multitude of applications. Variants of antibodies, antibody fragments, bispecific or multispecific antibodies, antibody fusion products are commonly designed and produced.
New antibody formats such as heavy-chain-only antibodies have also been developed. Compared with conventional antibodies, camelid heavy-chain-only antibodies consist of only two identical heavy chains (with variable and constant domains) and the antigen-binding region consists of a single variable domain with three CDRs.
Antibodies exist in a number of different formats. The most frequently used format is an immunoglobulin G (IgG), which is a large, Y-shaped protein composed of two identical light chains and two identical heavy chains, both containing variable and constant domains. Antibodies bind specifically to antigen targets via the antigen binding region which contains complementarity-determining regions (CDRs). In the case of an IgG, the antigen binding region consists of a heavy and light chain variable domain, each variable domain having three CDRs. Other immunoglobulin structures are also known, such as heavy-chain-only antibodies that consist of only two identical heavy chains (with variable and constant domains) and the antigen-binding region consists of a single variable domain with only three CDRs. Furthermore, knowledge of the structure-function relationships of parts of the antibody has allowed for the creation of antibody derivatives for a multitude Rule 33(1) Part G – Chapter II-48 Guidelines for Examination in the EPO March 2022 (Draft) of applications. These include antibody fragments, bispecific or multispecific antibodies and antibody fusion products.
In general, antibodies can be defined by (but are not limited to):
(a) their own structure (amino acid sequences);
(b) nucleic acid sequences encoding the antibody;
(c) reference to the target antigen;
(d) target antigen and further functional features;
(e) functional and structural features;
(f) the production process
(g) the epitope
(h) the hybridoma producing the antibody.
5.6.2 Inventive step of antibodies
The subject-matter of a claim defining a novel, further antibody binding to a known antigen does not involve an inventive step unless a surprising technical effect is shown by the application or unless there was no reasonable expectation of success of obtaining antibodies having the required properties (see also G-VII, 13). Examples of surprising technical effects when compared to known and enabled antibodies are, for example, an improved affinity, an improved therapeutic activity, a reduced toxicity or immunogenicity, an unexpected species cross-reactivity or a new type of antibody format with proven binding activity.
If inventive step of a functionally defined antibody relies on an improved property versus the enabled antibodies of the prior art, the main characteristics of the method for determining the property must also be indicated in the claim or indicated by reference to the description (F-IV, 4.11.1).
If the surprising technical effect involves the binding affinity, the structural requirements for conventional antibodies inherently reflecting this affinity must comprise the six required CDRs and the framework regions because the framework regions also can influence the affinity (T 1628/16).
If a novel antibody binds to the same antigen as known antibodies, inventive step is not acknowledged solely on the basis that the novel antibody is structurally different from the known antibodies. Arriving at alternative antibodies exclusively by applying techniques knowknown in the art is considered to be obvious to the skilled person. The fact that the structure of the thus obtained alternative antibodies, i.e. their amino acid sequences, is not predictable is not a reason for considering these antibodies as non-obvious (see T 605/14, section 24; T 187/04, section 11).
Nevertheless, antibodies can be inventive if the application overcomes technical difficulties in producing generating or manufacturing the claimed antibodies.