PROTACs reach the clinic: what the first regulatory approval means for drug discovery and the patent landscape

Just as the attention of the pharmaceutical industry appeared to have shifted over the past few years towards biologics with blockbuster potential, a new and exciting therapeutic modality has emerged that opens a new chapter for small molecule drugs - targeted protein degradation (TPD). Despite biologics growing at more than three times the rate of small molecules and commanding an ever-larger share of peak revenues, small molecules still account for the majority of approved drugs worldwide and around 58% of global pharmaceutical revenue - and their share of new annual approvals has recently been rising, reaching 64% of FDA approvals in 2024.

In early May 2026, about a decade after the pharmaceutical industry began seriously researching this new therapeutic modality, it was finally clinically validated when the FDA approved Arvinas’ vepdegestrant (Veppanu) for adults with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer following progression on at least one line of endocrine therapy. This is the first regulatory approval of a PROTAC (PROteolysis-TArgeting Chimera), a heterobifunctional protein degrader.

This milestone for PROTAC therapies matters not only for patients, but for innovators and investors. It proves that TPD can translate from compelling biology and elegant chemical design into an approved medicine. It also raises important questions for innovators about how best to protect their PROTAC assets. Patent claim drafting in this area is often complicated due to the size and structural complexity of PROTACs, along with the increasingly crowded patent landscape and partial overlap with other technologies.

What is a PROTAC?

A PROTAC is a heterobifunctional molecule with two distinct binding ends joined by a linker. One end engages the protein of interest (the target), the other recruits an E3 ubiquitin ligase. When both ends are engaged simultaneously, the resulting ternary complex brings the target into proximity with the ligase machinery, triggering ubiquitination and subsequent degradation by the proteasome – the cell’s own protein disposal system. In simple terms, it puts the target protein in the trash.

This proximity-driven mechanism is often described as ‘event-driven’ rather than ‘occupancy-driven’ pharmacology, as unlike protein inhibitors a PROTAC does not need to sit in a pocket continuously to block activity. Instead, it need only engage long enough to trigger a degradation event, after which the PROTAC can in principle be recycled to engage further target molecules. The ability of one PROTAC to degrade multiple copies of the target protein is a significant advantage compared to traditional small molecule protein inhibitors where one molecule binds to and inhibits one protein molecule.

The practical implications of this modality are significant. In broad terms, degradation offers a route to deal with proteins that are difficult to inhibit with traditional small molecules (e.g., proteins that lack tractable binding pockets) and can remove both catalytic and scaffolding functions of a target by eliminating the protein rather than merely blocking one interaction or activity.

The first approved PROTAC: vepdegestrant

The newly approved drug, vepdegestrant, is an oral oestrogen receptor (ER) degrader. It was developed by Arvinas and Pfizer. Its approval is biomarker restricted, and so treatment eligibility depends on confirmation of an ESR1 mutation in the patient by an FDA authorised test. Alongside the drug approval, the FDA also authorised Guardant360 CDx as a companion diagnostic for this biomarker.

From a strategic perspective, this dual approval (drug + diagnostic) highlights a feature we expect to see more often in the degrader space. Degraders can be designed for specific molecular contexts and can be engineered to target specific protein conformations, mutant isoforms, or disease contexts. That precision lends itself naturally to biomarker-driven development, and the vepdegestrant approval sets a precedent for how future degrader programmes are likely to be structured to reach regulatory authorisation: drug plus diagnostic, approved together, deployed in molecularly defined patient populations.

Why PROTAC patenting differs from “classic” small molecules

A typical small molecule programme often centres on one core inventive idea - a new chemical series where the structure as a whole gives rise to the potency and selectivity for a target. PROTACs, by contrast, are multi-component and purposefully engineered systems where each part serves a distinct function. Their behaviour depends on (at least) three interacting subcomponents - target binder, E3 ligase recruiter, and linker. Each of these components can represent an independent inventive contribution. 

A novel warhead that engages a previously undrugged site, a new recruiter with improved selectivity for a particular E3 ligase, a linker architecture that dramatically improves cell permeability or unlocks tissue-selective degradation – any one of these parts of a PROTAC might be patentable in its own right.

This modularity is one of the things that makes the PROTAC IP landscape so interesting and complex. In this respect, PROTAC IP strategy resembles that of other multipartite therapeutic modalities such as antibody–drug conjugates (ADCs), where patentable innovation may arise at the level of individual components or in the way those components are combined to produce a specific biological effect.

Building a PROTAC patent portfolio: key considerations

Protecting PROTACs often requires a more modular and layered approach than conventional small molecules, reflecting their bifunctional design and mechanism.

The modularity of PROTACs provide many opportunities for so-called ‘platform filings’, wherein an innovation in one component is protected in the context of an otherwise broadly defined PROTAC describing classes of target binders, E3 ligase recruiters, and linkers. This approach offers innovators a way to secure relatively broad protection and strengthen their competitive advantage.

An example is innovation in the linker, where differences in linker length, flexibility, and chemistry can meaningfully affect permeability, selectivity, and degradation efficiency. A novel linker design conferring such an advantage is a potential inventive concept in its own right and so could be claimed with in combination with a broad range of target binders and E3 ligase recruiters. 

This platform approach is typically combined with claims or subsequently-filed applications directed to more explicitly defined groups of PROTACs as well as specific, exemplified lead compounds. This strategy balances commercial breadth with defensibility. Overly broad combinations can be vulnerable if not well supported by data.

The PROTAC mode of action means that functional language in claims can play an important role. This is particularly true where the inventive contribution lies in inducing target degradation rather than inhibition. Claims framed around degradation efficiency, ternary complex formation or isoform-selective depletion can be valuable, but must be firmly anchored to experimental evidence demonstrating that the claimed structures reliably achieve those outcomes.

Further along the R&D lifecycle, medical use and indication claims – for example, targeting biomarker defined patient populations or specific resistance mechanisms – often provide important additional protection, particularly where composition claims face a crowded prior art landscape.

Freedom-to-operate: a complex landscape

Freedom to operate (FTO) analysis for PROTACs is complicated by their position at the intersection of multiple, independently protected technologies. Unlike a conventional small molecule, where risk concentrates around a single chemical scaffold, a single degrader must steer clear of prior rights relating to the target protein binder, the E3 ligase recruiter or the linker architecture.

In practice, this means that a novel PROTAC candidate can still conflict with well established prior art, for example, around widely used E3 ligases such as cereblon or VHL, or around target binding ligands repurposed from earlier inhibitor programmes. As the field expands, overlapping layers of protection are increasingly common: for example, early platform patents, followed by generation specific improvements and lead-focused filings. 

For PROTAC innovators, early and iterative FTO assessment is therefore a crucial part of overall IP strategy. Seemingly minor structural changes, such as altering linker chemistry, recruitment handles, or points of attachment, can have a material impact on infringement risk without necessarily undermining biological performance. 

Jurisdictional differences also matter as claims that present manageable risk in one territory may be more problematic in another, influencing prosecution strategy, licensing, and launch strategy.

Looking ahead: what this milestone signals

The approval of vepdegestrant is a milestone for the PROTAC modality that will accelerate both R&D investment and IP activity around degraders. As more degraders progress clinically, we expect to see a continued push towards diversification beyond familiar E3 ligases, better oral drug-like properties and tissue-specific targeting. 

While PROTACs are the most clinically advanced form of targeted protein degradation, they are not the only way to induce selective protein removal. Molecular glues, for example, achieve degradation through stabilising the interaction between a target protein and an E3 ligase, often with smaller, less obviously ‘bifunctional’ structures. Other emerging heterobifunctional modalities, including LYTACs, AUTACs, RIBOTACs and related approaches, extend the degradation concept beyond the proteasome, targeting extracellular proteins, organelles or RNA.

Each brings its own scientific opportunities and IP challenges, with corresponding questions of protection scope, claim language, sufficiency of disclosure (enablement), and freedom to operate. We will explore those modalities in future posts in this series.

This blog was co-authored by Annabel Cardno and Andrew Pitts.