Targeted protein degradation represents a revolutionary therapeutic approach and is rapidly gaining momentum in drug development. Unlike traditional small-molecule therapeutics that often modulate or inhibit protein activity, this emerging modality seeks to hijack a cell's natural protein degradation pathways to eliminate disease-causing proteins entirely. By inducing protein-protein interactions in a catalytic manner, targeted protein degraders offer compelling advantages over conventional small molecules.
In this article we focus on recent developments in two key classes of targeted protein degraders, PROTACs and molecular glues, and consider key patentability requirements for these paradigm-shifting compounds.
Understanding targeted protein degradation
The underlying concept of targeted protein degradation is that, if a protein of interest (POI), such as a disease-causing protein, can be brought into proximity with natural protein-degradation mechanisms within a cell, degradation of the POI can be induced.1
The most commonly exploited pathway is the ubiquitin-proteasome system (UPS), a post-translational modification pathway involving a number of enzymes, including substrate-specific ubiquitin ligase enzyme E3. Through repeated cycles of this pathway, proteins are poly-ubiquitinated, marking them for degradation by the proteasome. While cereblon is the most frequently recruited E3 ligase for targeted protein degradation, research into degradation via the von Hippel-Lindau, cIAP, and MDM2 E3 ligases is also underway.2
PROTACs and molecular glues: Similarities and differences
Two primary technologies have emerged to target the UPS: proteolysis targeting chimeras (PROTACs) and molecular glues.1 Both strategies work by facilitating formation of a stable ternary complex in which the POI and E3 ligase are held in close proximity to each other, thereby inducing poly-ubiquitination of the POI and subsequently, proteasomal degradation.
The catalytic nature of these approaches is particularly powerful. After degradation of the POI, the PROTAC or glue molecule is released and can facilitate degradation of further POI molecules. This catalytic activity provides significant advantages over traditional small-molecule inhibitors. For example, some PROTAC compounds have demonstrated more pronounced and longer lasting disruption of protein function than conventional small molecule inhibitors.3
PROTACs are heterobifunctional compounds comprising three distinct components: (1) a moiety targeting the POI; (2) a linking group and (3) an E3 ubiquitin ligase recruiting moiety. In contrast, molecular glues are generally monomeric compounds that lack the characteristic linker moiety found in PROTACs.
Clinical progress
PROTACs were first reported in 20014 and have since garnered significant interest, becoming the best known class of targeted protein degrader compounds. Whilst there are currently no PROTACs approved for clinical use, at least 25 compounds have entered clinical trials, for example, compounds developed by Arvinas, Bristol Myers Squibb, BeiGene, C4 Therapeutics, Cullgen, Kymera Therapeutics, Pfizer and Sanofi, amongst others.2,5
The PROTAC compound leading the clinical advancement is Vepdegestrant (ARV-471), developed by Arvinas and Pfizer for oral treatment of advanced or metastatic breast cancer. Currently in Phase III clinical trials, Vepdegestrant received FDA fast track designation in February 20246,7 and may become the first approved PROTAC therapeutic.
In contrast, the molecular glues thalidomide, lenalidomide and pomalidomide are approved for treatment of multiple myeloma. These compounds function by “gluing” together the cereblon domain of the E3 ligase complex and immune cell transcription factors, such as IKZF1/3, to facilitate degradation. Building on this, several molecular glues are in clinical development and many incorporate thalidomide or thalidomide-analogue moieties to target cereblon.
Strategic patentability considerations
As with many pharmaceutical products, there are a number of strategic points to bear in mind when seeking patent protection in Europe. Research in the PROTAC or glue space often focuses on one portion of the molecule, for example, the warhead that is designed to target a POI. Thus, it may be desirable to draft claims that retain generic scope around other portions of the molecule by employing broad terms as such as “targeting moiety”, “linker”, “therapeutic moiety”, or “warhead”.
Whilst the EPO notoriously raises clarity objections to functional terms, there is recent case law suggesting there may be scope to rely on these functional terms in some situations. T 2260/19 concerned PROTAC compounds for use in treating glioma, and clarity objections relating to use of the terms “targeting/seeker moiety”, “therapeutic moiety” and “linker moiety” to define portions of the claimed compounds were considered. The Board held that “the person skilled in the art is capable of identifying, in a given molecule, (1) the therapeutic moiety (a drug useful in treating glioma) and (2) any linker moiety linking the therapeutic moiety to the tetrahydropyridine targeting moiety” because they considered that “the therapeutic moiety is defined implicitly by the therapeutic indication of claim 1 since it must be a drug which is useful in treating glioma”. Interestingly, they also commented that “while generic, [the term DNA-damaging agent] does not lack clarity […] DNA-damaging agents are widely used in cancer chemotherapy and the term is well-established in the art.”
Nevertheless, compounds should also be defined structurally in the application as filed, and appropriate fallback positions included.
When it comes to inventive step at the EPO, as always, experimental data showing a technical effect is key. Data demonstrating the ability to bind to the target POI and intended proteasomal target will likely be crucial. Preferably, data should be included at filing, but this is not always possible. Options are available for post-filing data in Europe, and this involves additional considerations on a case‑by‑case basis. If you would like to read more about post-filing data at the EPO, see our article here.
It is also important to bear in mind that the technical effect should be demonstrated across the full scope of the claims. This is particularly relevant in the field of PROTACs and molecular glues, where genus claims are often drafted relatively broadly.
Our team brings extensive experience in advising clients on patent matters related to PROTACs, molecular glues and targeted protein degradation, and supporting clients throughout all stages of clinical trial candidate development. Please get in touch with Anna Chamberlain, Ben Heller or your usual Kilburn & Strode advisor if you have any questions.
1. Zhao, L., Zhao, J., Zhong, K. et al., Sig Transduct Target Ther, 2022, 7, 113.
2. Vicente, A.T.S., Moura, S.P.S.P. & Salvador, J.A.R., Commun. Chem., 2025, 8, 218.
3. Pal, P., Zhang, P., Poddar, S.K., Zheng, G., Expert Opin Ther Pat. 2022, 32(9),1003.
4. Sakamoto, K.M., Kim, K.B., Kumagai, A., Mercurio. F., Crews, C.M., Deshaies, R.J., Proc. Natl. Acad. Sci. U.S.A., 2001, 98, 15, 8554.
5. Liu, Z., Hu, M., Yang, Y., Du, C., Zhou, H., Liu, C., Chen, Y., Fan, L., Ma, H., Gong, Y., Xie, Y., Mol. Biomed., 2022, 3, 1, 46.
6. https://ir.arvinas.com/news-releases/news-release-details/arvinas-and-pfizer-announce-positive-topline-results-phase-3
7. https://www.pfizer.com/news/announcements/arvinas-and-pfizers-vepdegestrant-arv-471-receives-fda-fast-track-designation
8. https://ir.c4therapeutics.com/news-releases/news-release-details/c4-therapeutics-present-data-ongoing-phase-12-trial-cemsidomide