30 November 2023

Moving apart – diverging approaches to broad functional antibody claims in Europe and the US

Functional antibody patent claims, in which antibodies are defined on the basis of their ability to bind to a specific target or provide a specific function, are particularly desirable because they may be used to provide a broad scope of protection encompassing an entire class of antibodies.

Recent decisions issued by the European Patent Office’s Boards of Appeal (BoA) and the U.S. Supreme Court, however, highlight the increasingly divergent approaches to the patentability of functional antibody claims in Europe and the U.S.

Whereas in Europe it is possible to obtain broad functional antibody claims, in the U.S. it is becoming increasingly difficult to obtain protection for antibodies on the basis of functional claims.

The differences in the approaches to functional claims in Europe and the U.S. can be seen as being based primarily on two related factors. The first factor is a difference in the level of competency attributed to the notional skilled person, through whose eyes the disclosure of patent applications are interpreted. In the U.S., the skilled person is considered to have a relatively low level of knowledge, with the result that patent applications require a relatively high level of disclosure in order to be considered enabling. In contrast, in Europe, the skilled person is considered to have a much higher level of knowledge, with the effect that the bar for sufficiency of disclosure of a patent specification is relatively low. A consequence of this approach, however, is that in Europe it can be more challenging to show that a claimed antibody is inventive, or non-obvious, than in the U.S., although functional antibody claims may be considered inventive if the function is surprising or advantageous.

The second factor is the significance placed on the degree of burden faced by the skilled person having to undertake potentially large numbers of experiments to produce other antibodies having the claimed function beyond those exemplified in the specification. In the U.S., this requirement presents a significant barrier to patentability, whereas in Europe it is not considered to be an undue burden provided the experiments required are routine.

Recent decisions from the U.S. Supreme Court (Amgen v Sanofi 2023) and the EPO Boards of Appeal (T0835/21) highlight these distinct differences in the approaches taken by the USPTO and EPO to the patentability of broad functional antibody claims.

The U.S. approach
The U.S. Supreme Court, in Amgen v Sanofi, has recently held that Amgen’s claims directed to a class of antibodies defined on the basis of their target and function were invalid for lack of enablement. This result confirmed a longstanding precedent in the U.S. that “If a patent claims an entire class of processes, machines, manufactures, or compositions of matter, the patent specification must enable a person skilled in the art to make and use the entire class”.

The case broadly relates to anti-PCSK9 antibodies that reduce levels of low-density lipoprotein (LDL) cholesterol, often termed “bad” cholesterol. PCSK9 is a naturally occurring protein which impairs the body’s mechanism for removing LDL cholesterol from the bloodstream. Targeting and inhibiting PCSK9, therefore, provides a potential therapeutic strategy for treating patients with high LDL cholesterol. Both Amgen and Sanofi have successfully developed and marketed competing anti-PCSK9 monoclonal antibody therapies: Repatha® (Evolocumab, Amgen) v Praluent® (Alirocumab, Sanofi and Regeneron collaboration).

In 2014, Amgen sought patent protection for antibodies that (i) bind to specific amino acid residues on PCSK9, and (ii) block PCSK9 from binding to LDL receptors. After which, Amgen sued Sanofi for infringement. In reply, Sanofi argued that the Amgen patent claims were invalid for failing to meet the “enablement” requirement (35 U.S. Code § 112). In particular, Sanofi argued that Amgen sought to claim exclusive use of “millions more antibodies than the company had taught scientists to make”.

Amgen’s patent discloses 26 exemplary antibodies identified by their amino acid sequence that performed the two claimed functions, and the patent also describes two experimental approaches which the skilled person could use to arrive at other antibodies that would also have the desired functions. Firstly, the “roadmap” approach was a method of trial-and-error which involves starting with an assortment of antibodies, positively selecting antibodies based on (a) whether the antibodies bind to the desired epitope, and (b) if so, whether the antibodies demonstrate the desired blocking function. Secondly, the “conservative substitution” approach involved starting with antibodies known to work, then introducing amino acid substitutions and testing the resulting antibodies for the claimed functions.

The Supreme Court concluded that the claims encompass a “vast” number of additional antibodies that are not disclosed in the patent. The Court also concluded that the two experimental approaches amount to “little more than two research assignments” which forced scientists to conduct “painstaking experimentation” to find functional antibodies. That is, these methods do not enable the skilled person to make and use the entire class of antibodies, but rather leave the skilled person to “random trial-and-error discovery”.

The European approach
The situation in Europe is completely different. In contrast to the U.S. Supreme Court decision in Amgen v Sanofi, in a recent Board of Appeal (BoA) decision (T 0835/21), the EPO has confirmed that it is possible to obtain broad functional claims with minimal data in the application as filed, at least in principle.

The case relates to antibodies that bind to low-density-lipoprotein receptor-related protein 6 polypeptide (LRP6) and their use in cancer. Claim 1 is directed to a monoclonal antibody or antigen-binding fragment thereof that (i) specifically binds to a 300 amino acid domain of human LRP6, and (ii) is capable of antagonizing the Wnt signalling pathway, and inhibits Wnt3- and Wnt3a-specific signalling activity.

The BoA addressed the question of whether a broad functional epitope claim was sufficiently disclosed in the application as filed. Article 83 EPC requires that the application “shall disclose the invention in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art”. The BoA confirmed that the test for sufficiency for the antibody in question is whether the skilled person is able to prepare the claimed antibodies. The Appellant argued that the application as filed did not provide any information relating to the structure or binding epitope of the claimed antibodies, and only disclosed two examples of antibodies that were alleged to have the claimed functional features.

Interestingly, the BoA acknowledged that the application did not disclose a reproducible example but indicated that an application is not required to contain a reproducible example in order to meet the sufficiency requirement. This indicates the extent to which the EPO is willing to supplement the patent disclosure with the skilled person’s common general knowledge for the purposes of establishing sufficiency of disclosure.

The Appellant also argued that every antibody that bound to the correct epitope would have to be screened for Wnt3- and Wnt3a-specific inhibition, which would amount to a research project based solely on trial-and-error, thereby placing an undue burden on the skilled person.

However, the BoA disagreed, and highlighted that the preparation of a monoclonal antibody that binds to a known target (i.e. a defined epitope) is a routine task for the skilled person, and methods for screening antibodies for Wnt3- and Wnt3a-specific inhibition would also have been known to the skilled person. The BoA stated that “it may be tedious to screen candidate antibodies binding to the propeller 3 domain of LRP6 for inhibition of WNT3- and Wnt3a-specific signalling activity, but this does not necessarily amount to an undue burden if the screening results in the desired product”. Thus, in contrast to the situation in the U.S., in Europe extensive additional experimentation may not amount to an undue burden on the skilled person.

In Europe, the “sufficiency” requirement at the EPO is a relatively low bar. The skilled person is able to meet the threshold for sufficiency provided the methods for screening and testing functional properties of a claimed product are routine in the art and/or part of the skilled person’s common general knowledge.

However, since the EPO also considers that it is routine for the skilled person to produce new antibodies to a known target, in order to establish an inventive step, Applicants must demonstrate that there is a surprising technical effect associated with the claimed antibodies.

Message to applicants
As evidenced by these recent Decisions, Applicants face increasingly distinct and sometimes conflicting challenges when attempting to protect antibody inventions across different jurisdictions, presenting particular challenges when drafting patent specifications.

In support of functional antibody claims, Applicants should aim to include in the specification as many different examples of the claimed antibodies as possible, and evidence that the antibodies meet the functional requirements. Ideally, the example antibodies should be as diverse as possible, highlighting the importance of consistent features, such as specific amino acid residues, that are conserved across the various examples, and/or not present in non-working examples. Experimental data relating to the interaction of the antibody with the target epitope, or residues of the antibody involved in binding the antigen, is likely be very helpful to support the validity and inventive step of the claimed antibodies, in all jurisdictions. In Europe specifically, these data would make it possible to claim not only the amino acids of the antibody’s CDRs that bind to the target antigen, but also those residues constituting the target epitope, and thereby potentially other antibodies binding to the same target.

Antibody patent applications should, therefore be drafted in such a way that they provide the possibility of achieving the broadest available scope of protection in different territories, including broad functional claims in Europe.

If you would like more information about patenting antibodies, please contact our specialist Antibody Team, who would be happy to assist. We have considerable experience in drafting and prosecuting antibody patent applications, and also in proceedings before the European Patent Office Opposition Divisions and Boards of Appeal concerning opposed antibody patents. Please also let us know if you would like to receive our regular antibody newsletter.