Therapeutic antibodies are among the most widely used and valuable drug classes worldwide. Treatment of diseases in the fields of oncology and immunology currently dominate the therapeutic antibody market.
The first monoclonal antibodies approved for human use were IgG isotype antibodies targeting a single antigen. At the time of writing, this remains the most commonly used therapeutic antibody format. However, as the field’s innovation has continued at high pace, different antibody formats have been conceived and developed, enabling improvement and expansion of the more traditional IgG antibody repertoire. These advances include antibodies capable of binding different epitopes/antigens simultaneously. For example, certain bispecific antibodies have recently gained traction in oncology because they enable the recruitment of particularly potent cytotoxic T cells directly to cancer cells for efficient cancer cell lysis, something which is not possible with antibodies targeting a single antigen. More and more of these multispecific antibodies, in various molecular formats, are being approved for therapeutic use every year, reflecting the advantages they deliver for patient care. This changing landscape is reflected in the patents and applications before the EPO. Applicants for these molecules must, as for normal antibodies, be cognisant of the EPO’s already developed views on antibodies to achieve commercially useful protection of these particularly high value biologic products.
Familiar challenges and beyond
When pursuing claims to a multispecific antibody at the EPO, applicants may face objections on the basis of alternative multispecific antibodies (i.e., known antibodies binding the same combination of targets) in the prior art. Such an objection would not be dissimilar to the objections applicants will recognise when pursuing claims to a monospecific antibody in the face of prior art disclosing a monospecific antibody targeting the same antigen.
Although novelty may be achieved by virtue of the different sequences of one or more of the multispecific antibody binding arms, inventive step becomes a challenge because the EPO can assert that the claimed multispecific antibody is simply an arbitrary (and thus obvious) alternative to those in the art. In contrast to some other jurisdictions, there is no application of “structural non-obviousness” at the EPO. That is, the EPO does not consider antibody claims to be inventive based solely on the fact that an antibody sequence is structurally distinct to those in the prior art. As noted by the Board of Appeal in T735/00, it is expected that the skilled person can arrive at alternative antibodies using routine methods and techniques well-known in the art. This rationale, developed over decades of consideration of monospecific antibody cases by the EPO, is now equally applied to multispecific antibodies which differ only in sequence to multispecific antibodies available in the prior art. Similar to the position in which applicants find themselves for monospecific antibody claims, they must demonstrate that either there is a surprising technical effect associated with the multispecific antibody or there was no reasonable expectation of success of obtaining multispecific antibodies having the displayed properties (Part G, Chapter II, Section 6.2 of the Guidelines for Examination 2024).
Furthermore, applicants pursuing multispecific antibody claims at the EPO may encounter prior art disclosing only monospecific antibodies binding to single antigens corresponding to those targeted by the multispecific antibody. Indeed, a common opinion of EPO examiners is that antibodies are modular structures, and that the combination of the modular binding arms of two monospecific antibodies in the prior art to generate a bispecific antibody, for example, would be entirely within the routine technical abilities of the skilled person.
Multispecificity enables creative argumentation
As noted above, in order to establish inventive step of multispecific antibody claims at the EPO, typically applicants must demonstrate that the multispecific antibody either represents an improvement over the corresponding antibodies in the prior art or was particularly challenging to generate. However, given the nature of multispecific antibodies, applicants have various arguments at their disposal beyond those available for monospecific antibodies to achieve commercially useful claims. In this way, the complexities of generating a functional, therapeutically effective, multispecific antibody can be exploited to an applicant’s benefit. The approach, of course, depends on the level of generality of claim to the multispecific antibody.
At the highest level of generality, an applicant may aim for claims defining the multispecific antibody only functionally, perhaps with respect to the antigens to which the multiple arms bind. If a multispecific antibody binding the combination of targets has not been disclosed in the prior art, and, for example, if the prior art provides reasons to doubt that it would be possible to generate an antibody capable of simultaneously binding the multiple targets, such a claim may be achievable. Indeed, the biology of the antigen(s) or locations of the epitope(s) of the multispecific antibody may provide avenues to patentability. Such arguments may have even greater weight when there are more than two binding arms.
As with monospecific antibodies, the binding arms of the multispecific antibody may be characterized by binding to novel epitopes on one of the target antigens. In the revised 2024 EPO Guidelines for Examination, the section discussing definitions of antibodies by their epitope has been deleted, and instead epitopes are discussed in relation to defining the antibody by the target antigen. In this revised section, there is less emphasis on the structural details of epitopes, but new guidance that, unless there is evidence to the contrary, prior art antibodies binding to the same antigen will be presumed to bind the same epitope. This has effectively cemented the approach taken by examiners in recent years. Despite monospecific antibody epitope claims facing tough resistance at the EPO, it is certainly conceivable, dependent upon the prior art backdrop, that identification of an epitope for one of the binding arms that imparts a particularly remarkable therapeutic activity to the multispecific antibody (e.g., by enabling appropriate orientation of a cytotoxic T cell against a cancer cell) would justify an inventive step for even broadly defined multispecific antibody claims. In this scenario, it may be that the other arms of the multispecific can be left broadly defined, e.g., by their target antigen. In other instances, such as where the efficacy of the bispecific antibody is suggested to be a consequence of the orientation of the antibody with multiple target epitopes, the epitopes of multiple binding arms may correspondingly be required. As for monospecific antibodies, examiners may not accept language relating to definition of the epitope, and can instead request that the epitope binding be defined by reciting the CDRs of the binding arms of the multispecific antibody. Irrespective, it is clear that the interplay of steric interactions between multiple target antigens and the complexity of multispecific antibody functionality provides further avenues for achieving multispecific antibody claims beyond those available for monospecific antibodies, where even CDR defined claims are becoming more challenging to achieve.
Limitation of the claims to define the binding affinity of one or more arms of the multispecific antibody can represent a further avenue to patentability. For example, high affinity binding to a target cell may be important to ensure the multispecific antibody adequately targets and remains bound to the cell of interest, while a lower affinity of the arm targeting a cytotoxic T cell, for example, may avoid off-target effects. Such activity may be captured by exploiting functional claim language while defining the antibody binding arms only by CDR sequences or, as often requested by EPO examiners, by reciting the full variable domain sequences. Furthermore, if a combination of affinity and avidity is key to the technical effect of the multispecific antibody, claims capturing multispecific antibodies with multivalent binding to the antigen, or binding multiple antigens on the same target cell, may in some cases be argued to be inventive by improving immune targeting.
Structural definition beyond the variable domains also provides opportunity for applicants to seek to exploit properties of the constant domain of a full-length multispecific antibody to argue inventive step. Although particular Fc domain mutations in the context of cytotoxic bispecific antibodies, for instance to avoid unwanted recruitment of further effector cell functionality, can be considered by the EPO to be well-established, certain effector functionality of the Fc domain may be key for therapeutic activity of a multispecific antibody, as is often the case for trispecific antibodies. The combination of technical effects imparted by each structural feature of a full-length multispecific antibody may synergise to enable inventive step arguments even in the event that picture claims are facing resistance during examination.
Beyond this, there is further innovation in the field of ever more complex and creative molecular formats, driving the applications of multispecific antibodies far beyond those of their monospecific counterparts. In T0921/17, for example, it was successfully argued that the use of a shared light chain on both arms of the claimed bispecific IgG format antibody was not obvious, despite the prior art providing alternative bispecific antibodies to the same targets. As such, a particularly new, unconventional, or challenging multispecific structure might also lend support to arguments that the claimed multispecific antibody is inventive.
Accordingly, applicants have a broad variety of contextually dependent arguments in favour of inventive step of multispecific antibodies at each level of structural definition, thanks to the complex functionality of these molecules.
Bringing things together: defining an inventive multispecific antibody
In summary, the EPO’s typical approach in the absence of evidence otherwise, is that multispecific antibodies are obvious if the prior art discloses multispecific antibodies to the same targets, irrespective of the complexity of their format. Nonetheless, the added complexity afforded by these non-conventional formats compared to their monospecific counterparts allows for greater creativity of argumentation during prosecution.
As ever at the EPO, providing data demonstrating an advantageous and unexpected technical effect can be of assistance. However, even if appropriate comparative data demonstrating an improvement over the prior art is not available at the time of filing, an applicant may be able to rely on post-published data to establish a technical effect for inventive step. Of course, in this instance, the applicant must still demonstrate that the technical effect is encompassed by the technical teaching and embodied by the originally disclosed invention, in line with G2/21.
Finally, the breadth of multispecific antibody claims must be commensurate with the contribution of the application, and examiners may be unwilling to grant a patent if they consider the structural definition of the multispecific antibody to be too broad to achieve the alleged technical effect across the scope of the claims. Further structural or functional limitation may therefore be required.
At Carpmaels & Ransford, our patent attorneys regularly handle cases protecting blockbuster brand‑name antibodies. Our qualified experts are very familiar with this subject area, working with a range of clients at the forefront of modern antibody technology. We are well-equipped to handle any complexities that these new technologies generate during patent drafting, prosecution, opposition, and litigation. Please contact the team for further information.
