Practical Guide to Claiming Small Molecules with Functional Language

Patent claims reciting compounds where at least one group of a compound genus is defined by its function are common. For example, familiar claim terms such as “chelating moiety,” “linker,” and “binding moiety” describe a particular group by what it does rather than by describing its chemical structure. However, in view of the requirements of written description and enablement under 35 USC § 112, is this a wise practice?

This type of functional claim language is common throughout many different technology areas, perhaps most notably in claiming antibodies. Amgen Inc. v. Sanofi, 598 U.S. 594 (2023). However, it is also relevant to claiming small molecule drugs and diagnostic agents. One class of small molecules of recent prevalence, which practitioners tend to claim in this manner, are heterobifunctional compounds. Heterobifunctional compounds—compounds designed to bind and/or act upon two or more biologically important molecules at the same time, bringing them in close proximity to interact—have become increasingly important in drug discovery in recent years. Their purposeful design is creating new paradigms for therapeutics that may effectively modulate previously undruggable targets, or improve the therapeutic potential of existing drugs.

PROTAC Compounds

The advent of the increased interest in heterobifunctional compounds can be traced in large part to the emergence of proteolysis targeting chimera (PROTAC) compounds. PROTACs are a class of heterobifunctional compounds that bind to and bring together a target protein and an E3 ligase protein. E3 ligase proteins serve to recruit ubiquitin, a protein present in all eukaryotic cells that plays a key role in marking unneeded or damaged proteins for degradation. In particular, the E3 ligase promotes ubiquitination and degradation of the target protein through cellular machinery called the proteasome. PROTACs, and this form of targeted protein degradation, first came on the scene in the early 2000s, primarily out of Craig Crews’ lab at Yale University. Subsequently, many companies and research institutions have either formed or begun drug discovery programs focusing heavily on PROTAC technology. In turn, PROTAC technology has been highly influential in inspiring other classes of heterobifunctional compounds employing the use of acronyms in their names, including OMNITAC, RIPTAC, CLIPTAC, HEMTAC, LYTAC, MADTAC, RIBOTAC, and AUTAC.

As a result of the increase in heterobifunctional drug discovery programs, there has been a corresponding increase in patent application filings claiming these types of compounds, particularly as these programs produce PROTACS entering clinical trials. The most advanced of these programs is Arvinas’ and Pfizer’s vepdegestrant (ARV-471), which was recently evaluated in Phase 3 clinical trials for treatment of metastatic breast cancer.

As an example of a patent claim that defines the claimed compound entirely in functional terms, claim 1 of Arvinas’ US 10,946,017 recites: “A bifunctional compound comprising the chemical structure: TBM-L-ULM, wherein: TBM is a TBK1 binding moiety; L is a bond or a chemical linker that covalently couples the TBM and the ULM; and ULM is an E3 ubiquitin ligase binding moiety.”

Written Description 

Many practitioners familiar with the prosecution of claims using language defining compounds in functional terms can attest to the inconsistent treatment the USPTO gives to such claims. Under Section 112, written description and enablement rejections abound in the prosecution of some applications, while other applications seem to be less scrutinized by USPTO examiners. Due in large part to their nascency, patent claims directed to heterobifunctional compounds such as PROTACs have not been the subject of appellate review and have been involved in limited cases in front of the USPTO’s Patent Trial and Appeal Board (PTAB). Thus, the case law is limited with respect to Section 112 issues for these types of compounds. However, practitioners can consult an extensive body of jurisprudence dealing with written description and enablement issues related to functional claim language in related technologies for guidance.

Regarding written description, MPEP § 2162 states that “the patentee must disclose sufficient information to demonstrate that the inventor had possession of the invention at the time of filing.” In addition, the Court of Appeals for the Federal Circuit has made clear that written description of a genus of compounds requires “either a representative number of species falling within the scope of the genus or structural features common to members of the genus so that one of skill in the art [could] ‘visualize or recognize’ the members of the genus.” Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010). Moreover, how the written description requirement can be satisfied “varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.” Id at 1351.

Accordingly, after Ariad, courts have not prescribed a required number of species that must be disclosed to adequately support a genus claim. For example, in 2017, while relying heavily on Ariad, the Federal District Court for the Eastern District of Texas held, and the Federal Circuit affirmed, that disclosure of four specific compounds and two compound classes in an application, in a mature field where hundreds of such compounds had already been discovered, was enough to satisfy written description for a method of treatment claim reciting the use of “selective PDE5 inhibitors.” Erfindergemeinschaft UroPep GbR v. Eli Lilly & Co., 276 F. Supp. 3d 629, 646 (E.D. Tex. 2017), aff’d, 739 Fed. Appx. 643 (Fed. Cir. 2018) (unpublished).

Despite this application of Ariad and there being no bright line rule requiring a certain number of species to satisfy written description, practitioners would be wise to disclose significant numbers of species when attempting to claim compounds in functional terms. Importantly, a “significant number” of species is a function of the breadth of what is being functionally claimed and provides a basis for the scope of what a patent applicant is ultimately entitled to claim.

Enablement

Distinct from the written description requirement is the enablement requirement. MPEP § 2164 states that “[t]he information contained in the disclosure of an application must be sufficient to inform those skilled in the relevant art how to both make and use the claimed invention.” The Supreme Court recently provided guidance on functional claiming in the context of antibodies. Amgen Inc., 598 U.S. at 612-616. In Amgen, the Court held that the challenged claims, which recited antibodies that (1) bind to specific amino acid residues on PCSK9 and (2) block PCSK9 from binding, were not enabled despite the disclosure in the specification of 26 such functional antibodies, plus two methods to identify more. Id at 614. In doing so, the Court reasoned that “[i]f a patent claims an entire class of processes, machines, manufactures, or compositions of matter, the patent’s specification must enable a person skilled in the art to make and use the entire class.” Id. at 610.

Although small molecules are not antibodies, the Amgen decision may provide clues as to how courts will treat functionally-claimed small molecules. In particular, the Court stated that “the more a party claims, the broader the monopoly it demands, the more it must enable,” although a patent specification need not describe “with particularity how to make and use every single embodiment within a claimed class.” Id. at 610-611.

In fact, courts have begun applying Amgen in small molecule-related cases. For example, last year the Federal District Court for the District of Delaware relied on Amgen to hold that claims reciting methods of treating non-small cell lung cancer with “a unit dosage of an irreversible EGFR inhibitor” were invalid for failing to meet the enablement requirement under Section 112. Wyeth LLC v. Astrazeneca Pharmaceuticals LP, No. 21 C 1338, 2024 WL 3823006 (D. Del. Aug. 14, 2024). However, this case is currently under appeal at the Federal Circuit.

As with the written description requirement, courts have not prescribed a required number of species that must be prepared and tested to adequately enable a genus claim. However, practitioners would be wise to also disclose significant numbers of compounds with the described utility and their associated biological activities when attempting to claim in functional terms. Again, a “significant number” is a function of the breadth of what is being functionally claimed.

Post-Grant Proceedings

In what may be rightly seen as a warning shot to applicants and owners of patents claiming small molecules in functional terms, Kymera challenged US 10,849,980, owned by Dana-Farber Cancer Institute, in a post grant review (PGR) proceeding. The ’980 patent issued with claims reciting a genus of PROTACs that comprised a “Targeting Ligand” that “is a moiety that binds to a Target Protein,” with the claim further specifying that “the Target Protein is a mediator of abnormal cellular proliferation.” After an examination at the USPTO in which no rejections under Section 112 were raised, Petitioner Kymera asserted in its PGR petition that all claims lacked written description and enablement, arguing that “[i]ndependent claim 1 is effectively limitless, encompassing targeting ligands that bind to any target protein that is a ‘mediator of abnormal cellular proliferation in a host in need thereof,’” but that “[t]he ’980 patent’s working examples, however, provide only twenty-seven degraders, having only nine different targeting ligands, that bind only six protein targets. Notably, none of these degraders falls within the scope of [the] claims.” Kymera Therapeutics Inc., Petitioner, v. Dana-Farber Cancer Institute Inc., Patent Owner., 2021 WL 3811920 , at *16 (P.T.A.B. Aug. 24, 2021). Importantly, no dependent claims defined “targeting ligand” structurally. Citing Ariad, Kymera further asserted that “[t]he ’980 patent provides little more than an invitation to experiment with the claimed target proteins to determine whether they are amenable to degradation by a degrader falling within the scope of the claim.” Id at p. 20. In response to the petition, Dana-Farber statutorily disclaimed the claims of the ’980 patent and the PGR proceedings were not instituted. Kymera Therapeutics Inc. v. Dana-Farber Cancer Institute Inc., 2022 WL 683201 (P.T.A.B. Mar. 2, 2022).

Conclusion

As demonstrated here, it is possible to prosecute and possibly obtain issued genus claims that define aspects of compounds such as small molecule drugs in functional terms. It may even be beneficial for the applicant to do so based on their needs and goals. For example, an applicant may want to announce their presence in a nascent field where there is little prior art, or an applicant may want to include broad claims in functional terms for defensive purposes. However, in order to successfully obtain or defend claims reciting functionally claimed compounds, a significant number of varied species that are representative of the full scope of the claims and support the functionally-claimed genus should be included in the disclosure to the extent possible. Absent such support, the USPTO and patent challengers, similar to Kymera, may attack claims reciting functionally-defined small molecules in an effort to expose them as being inadequately described and enabled. Of course, there is no set number of species that must be disclosed to support a genus claim and the amount of disclosure required will vary based on the scope of the claim, as well as the nascency or maturity of a particular field. But, importantly, dependent claims defining the functionally-claimed elements in structural terms should always be considered for inclusion as fallback positions should claims reciting functional language be jeopardized. In all cases, the applicant should always have clear goals and needs in mind when employing this claiming tactic.