For decades, small-molecule drug discovery was built around a straightforward principle: identify a protein’s active site, design a compound that binds to it, and inhibit its biological function. This occupancy-based approach underpinned many of modern medicine’s most successful therapies, including kinase inhibitors for cancer and statins for cardiovascular disease. However, its effectiveness depends on one critical requirement: the target protein must contain a well-defined binding pocket capable of accommodating a small molecule. That structural constraint ultimately limited the range of proteins that conventional drug discovery could effectively target.
Most disease-relevant proteins do not meet this requirement. Depending on the analysis, up to 85% of the human proteome has historically been classified as “undruggable” because proteins such as transcription factors, scaffolding proteins, and those involved in protein-protein interactions, including KRAS, lack the well-defined binding pockets that conventional small molecules require. As a result, many disease-driving biological pathways remained beyond the reach of traditional drug discovery despite their therapeutic relevance.
That shift from direct inhibition to functional modulation is transforming drug design while accelerating investment, scientific research, and patent activity, creating an intellectual property landscape that differs significantly from traditional small-molecule drug discovery.
The patent landscape for undruggable targets
Global patent activity for drug conjugates and therapeutic antibodies rose from 26,245 filings in 2015 to a peak of 34,559 in 2021, reflecting sustained development of antibody-based approaches to targeted drug delivery. The dataset covers A61K 47/68, A61K 31/, A61P 35/00, and C07K 16/, encompassing drug-antibody conjugates, therapeutic agents, antineoplastic therapies, and immunoglobulins. These classifications capture technologies such as antibody-drug conjugates (ADCs), which link therapeutic payloads to antibodies to target specific cells and address targets that conventional small-molecule drugs may struggle to reach.
Patent filings rose sharply through 2021, coinciding with record biotechnology financing. U.S. biotech venture financing reached $26.2 billion in 2021, according to EY, while broader estimates that include additional life-sciences financing place the figure higher. The subsequent deterioration in biotech markets was reflected in the XBI biotechnology index, which fell about 61% from its February 2021 peak through 2023. This funding cycle likely contributed to elevated patent activity, although patent filings can lag research investment by a year or more.
Activity remained elevated at 33,422 filings in 2022 and 30,779 in 2023, before falling to 18,473 in 2024 and 11,270 in 2025. The decline does not necessarily indicate an equivalent reduction in innovation, as recent applications can take time to enter and progress through the patent system.
Conversations with Julie Carlisle
To explore how these shifts are playing out in practice, we spoke with Julie Carlisle, Partner, and European Patent Attorney at Mewburn Ellis. She shares her perspective on how targeted protein degradation and related modalities are reshaping IP strategy in the life sciences.
Q1. Why were so many important biological targets historically considered “undruggable”?
A: Conventional small-molecule drugs generally work by binding into a well-defined pocket on a protein and altering its activity. Many biologically important proteins do not possess such pockets, or are involved in large protein-protein interactions that are difficult to disrupt using traditional approaches. As a result, a significant proportion of disease-relevant targets were long considered inaccessible to conventional drug discovery.
The term “undruggable” has been used to describe these targets. However, that term might actually be a little misleading. It does not imply that a target is unimportant or cannot influence disease. Rather, it means that the target is difficult to modulate using the types of drug molecules which were traditionally available to researchers.
What has changed over the past decade is not the biology of the targets, but the toolkit available to scientists. Rather than simply inhibiting a protein’s activity, newer therapeutic modalities can induce degradation, alter localisation, stabilise interactions or otherwise manipulate biological pathways in ways that were previously impossible. The practical meaning of “undruggable” is therefore becoming increasingly narrow as new technologies continue to emerge.
Q2. Beyond PROTACs and molecular glues, which emerging modalities show the greatest promise?
A:Several emerging modalities are particularly interesting because they extend targeted degradation concepts beyond the intracellular protein targets that have been the primary focus so far.
LYTACs have attracted considerable attention because they may enable degradation of extracellular and membrane-bound proteins, significantly expanding the range of potential therapeutic targets. Similarly, RIBOTACs are exploring selective degradation of disease-associated RNA molecules, opening up opportunities that lie beyond the proteome altogether.
I am also watching developments in AUTACs, PhosTACs and related approaches with interest. While some of these technologies remain relatively early stage, collectively they demonstrate that the field is moving from a single therapeutic concept to an increasingly diverse toolbox of modalities capable of manipulating biological function in highly specific ways.
From an intellectual property perspective, this diversification is particularly significant because each new modality has the potential to generate valuable platform technologies capable of supporting multiple therapeutic programmes.
Q3. Have you observed any notable patent prosecution trends among the major innovators in this field?
A: One clear trend is the increasing emphasis on experimental evidence.
Patent offices are often looking carefully at whether broad therapeutic concepts have been demonstrated across the full scope of the claims being sought. This is particularly relevant where applicants are attempting to secure protection for platform technologies capable of addressing numerous targets.
As the field matures, I think we are also seeing drafting and prosecution strategies becoming more sophisticated, with applicants building layered patent portfolios that combine broad platform protection with target-specific and product-specific filings.
There is also increasing recognition that a robust patent portfolio may include claims directed not only to compounds themselves, but also to mechanisms of action, methods of identifying suitable molecules, combinations, biomarkers and patient-selection approaches.
Q4. Over the next five to ten years, how do you expect patent strategies for targeted therapeutics to evolve as the science continues to mature?
A: I expect patent portfolios to become increasingly multi-layered. Early entrants understandably focused on establishing ownership of foundational platform technologies. However, as the science matures, competitive advantage is likely to depend increasingly on specific molecular architectures, new target classes, patient-selection strategies, manufacturing innovations and clinical applications.
The evolution of molecular-glue technologies provides a useful example. As compounds move through clinical development and generate increasing amounts of biological and clinical data, patent strategies are likely to extend well beyond protection of the core compound itself. In the case of molecular glues, for example. innovators could seek protection around mechanisms of ternary-complex formation, resistance pathways, biomarker strategies, next-generation molecules and combination therapies.
Freedom-to-operate considerations will also become increasingly important. As more organisations enter the field, companies will need not only strong proprietary protection, but also a clear strategy for navigating an increasingly crowded and interconnected patent landscape.
Q5. Have you observed any changes in the types of organisations leading innovation, for example large pharmaceutical companies versus biotech startups or universities?
A: Some of the most important breakthroughs in this area have originated from biotechnology companies and academic institutions rather than traditional large pharmaceutical organisations.
Smaller companies are often well positioned to pursue novel scientific approaches and tolerate higher levels of technical risk. Large pharmaceutical companies, meanwhile, bring development expertise, manufacturing capability and commercial scale.
The result has been a highly collaborative ecosystem in which licensing transactions, strategic partnerships and acquisitions play a central role in translating scientific innovation into commercial products. In many cases, the most successful programmes reflect a combination of entrepreneurial scientific innovation and the resources needed to progress therapies through late-stage development and commercialisation.
Q6. Do you think we’ll eventually stop referring to these proteins as “undruggable”, or will there always be biological targets that remain beyond our reach?
A: I suspect the term will gradually become less useful.
Time and again, proteins once considered undruggable have become tractable as new technologies emerge. The history of drug discovery is full of examples where supposedly impossible targets became accessible following advances in chemistry, biology or engineering.
That does not mean every target will become easy. Biology is extraordinarily complex, and there will always be proteins that challenge the limits of current technology. However, the boundary between druggable and undruggable is continually shifting. Increasingly, the key question is not whether a target can be modulated at all, but which technology is best suited to achieving the desired biological effect.
In that sense, “undruggable” may ultimately come to be seen less as a fixed category and more as a temporary description of the current state of scientific capability.
From small molecules to targeted therapeutics
Conventional small-molecule inhibition is constrained by protein structure. It relies on the presence of a well-defined binding pocket capable of accommodating a drug-like compound with sufficient affinity and selectivity, a feature that many transcription factors, scaffolding proteins, and other disease-relevant proteins do not possess. Even when such binding sites exist, therapeutic activity depends on maintaining sufficient drug concentrations because inhibition persists only while the molecule remains bound to its target. As drug levels decline and the compound dissociates, the target protein resumes its normal biological function.
Targeted protein degradation overcomes these limitations by changing how therapeutic molecules interact with disease-relevant proteins. Rather than continuously blocking protein activity, PROTACs recruit the cell’s own protein disposal machinery to eliminate the target. By bringing a target protein together with an E3 ubiquitin ligase, they trigger ubiquitination and subsequent degradation by the proteasome. Because this process is catalytic, a single PROTAC molecule can degrade multiple copies of the same protein, enabling durable effects at lower drug exposure. Molecular glues achieve a similar outcome by stabilizing interactions between target proteins and E3 ligases without the bifunctional structure of conventional PROTACs.
While PROTACs attracted much of the early attention, molecular glues have emerged as an equally powerful approach, says Julie Carlisle. Unlike conventional inhibitors, they can induce or stabilize interactions between proteins that would not normally occur, “effectively allowing researchers to reprogram cellular machinery to achieve a desired biological outcome,” she explains, opening up an entirely different way of thinking about targets once dismissed as inaccessible. Revolution Medicines’ daraxonrasib illustrates how quickly the field is moving: the molecular glue promotes formation of a ternary complex involving cyclophilin A and active RAS proteins, and is now delivering clinically meaningful activity against one of oncology’s most historically difficult target classes, evidence, Carlisle says, of how far the field has progressed against targets once considered quintessentially undruggable.
The next generation of therapeutic modalities extends this approach beyond intracellular proteins. LYTACs, AUTACs, and RIBOTACs apply targeted degradation to extracellular proteins, organelles, and RNA, respectively. Meanwhile, PhosTACs and SUMOTACs modify protein activity by recruiting enzymes that alter post-translational modifications rather than degrading the target protein itself.
Intellectual property in an increasingly complex therapeutic landscape
Heterobifunctional and other functional-control modalities are also reshaping pharmaceutical patent strategies. Unlike conventional small molecules, which are typically protected as single compounds targeting one protein, PROTACs combine multiple functional components, including a target-binding ligand, a linker, and an E3 ligase recruiter. This modular architecture allows companies to pursue protection not only for individual therapeutic molecules but also for broader platform technologies, such as linker chemistries, E3 ligands, and screening methods that can support multiple drug candidates. While these platform patents offer broader commercial potential, they also face greater scrutiny because of their wider claim scope and more demanding enablement requirements.
That shift is also changing how companies organize R&D itself, says Carlisle. Where pharmaceutical research was historically built around individual biological targets, companies are increasingly investing in technologies that can be applied across multiple targets and disease areas, building expertise, data, and IP around a platform rather than a single candidate. Revolution Medicines is a case in point: daraxonrasib draws attention not only as a promising therapeutic in its own right, but because it validates a broader molecular-glue approach to RAS-driven cancers. As Carlisle puts it, the commercial value of such platforms increasingly resides “not only in the individual molecule, but also in the underlying scientific framework” that opens up an entire class of targets, which is why, in her view, IP considerations are now being built into R&D planning much earlier than they were with traditional small-molecule programmes.
Protecting these multi-component therapeutics also introduces new patenting challenges. Patent claims must distinguish not only the individual components, such as the target-binding ligand and E3 recruiter, but also the specific combination that enables the therapeutic mechanism. At the same time, patent offices increasingly expect experimental evidence demonstrating functional activity rather than structural novelty alone. As a result, companies must generate stronger supporting data earlier in development to secure broad and defensible patent protection.
The growing complexity of these therapeutic platforms is also reshaping patent portfolio management. A single degrader or conjugate program may incorporate innovations spanning small molecules, biologics, RNA-targeting technologies, and delivery systems, all of which have traditionally been managed as separate intellectual property categories. As these technologies increasingly converge within a single therapeutic platform, companies are adopting more integrated patent strategies that consider the entire technology stack rather than individual components alone.
Carlisle sees this playing out at the level of claim strategy too: innovators are now seeking protection across multiple layers at once, platform technologies, molecular constructs, target-specific applications, methods of treatment, manufacturing processes, and biomarker strategies, creating dense, overlapping patent landscapes where freedom-to-operate becomes as important as the underlying science. The result, she notes, is that patent strategy has become a genuinely multidisciplinary exercise, requiring close, ongoing interaction between scientists, patent attorneys, business teams, and regulatory specialists.
Freedom-to-operate and licensing in crowded platform landscapes
Because many components of heterobifunctional therapeutics are already covered by existing patents, commercial success increasingly depends not only on scientific innovation but also on freedom-to-operate. Companies must demonstrate that new therapeutic platforms can be developed, manufactured, and commercialized without infringing existing intellectual property, making patent strategy an increasingly important consideration from the earliest stages of drug development.
The concentration of intellectual property around key platform technologies illustrates this challenge. Although more than 600 human E3 ligases have been identified, most PROTAC development has focused on a small number of ligases, particularly CRBN and VHL, creating densely patented technology areas. Similar patterns have emerged in linker chemistry and antibody-drug conjugate (ADC) payload technologies, where foundational patents are concentrated among early innovators. As a result, scientific novelty alone is no longer sufficient. Companies must also demonstrate freedom-to-operate, making patent access and licensing increasingly important to the commercial development of next-generation therapeutics.
As a result, freedom-to-operate analysis is increasingly being integrated into the earliest stages of drug development rather than treated as a final legal review. Access to key platform technologies, including E3 ligands, linker chemistries, and conjugation methods, has become a strategic advantage alongside scientific innovation. In many cases, commercial success depends not only on developing a novel therapeutic approach but also on securing the intellectual property needed to bring it to market.
This increasingly complex intellectual property landscape is also reshaping collaboration across the pharmaceutical industry. Licensing and partnership agreements are becoming strategic tools for securing access to critical platform technologies rather than simply expanding product portfolios. As patent ownership becomes more fragmented across targeted degradation and conjugate therapeutics, access to complementary intellectual property is increasingly essential for advancing new therapies from discovery through commercialization.
Major filers and key jurisdictions
Corporate assignees dominate patent activity in drug conjugates and therapeutic antibodies. Hoffmann-La Roche ranks first globally, followed by Novartis, Bristol Myers Squibb, and Regeneron Pharmaceuticals, while Genentech, Amgen, Incyte, Janssen Biotech, and AstraZeneca also hold substantial portfolios. The University of Texas is the only academic institution among the ten largest assignees, indicating that although academic research remains an important source of therapeutic innovation, the patent landscape is primarily led by pharmaceutical and biotechnology companies.
China is the largest patent jurisdiction by a significant margin, followed by the United States and the European Patent Office, with Japan and South Korea also representing major filing markets. The distribution reflects the commercial importance of securing intellectual property protection across the world’s largest pharmaceutical markets and research ecosystems.
Pending applications make up a substantial share of activity in several major jurisdictions, particularly China and Europe. This indicates that the patent landscape remains active and continues to expand as applications progress through examination, potentially increasing the number and scope of enforceable rights surrounding drug conjugates and therapeutic antibodies.
What’s ahead
The evolution of targeted therapeutics reflects more than an expansion of what can be considered druggable. Rather than simply designing molecules to inhibit protein activity, researchers are increasingly developing therapies that control protein fate and function through mechanisms such as degradation, stabilization, relocalization, and post-translational modification. This broader therapeutic toolkit is expanding the range of biological targets that can be addressed while reshaping both drug discovery strategies and the intellectual property landscape surrounding these emerging technologies.
This shift in therapeutic design is also reshaping intellectual property strategies. Unlike conventional small molecules, heterobifunctional and other multi-component therapeutics often combine multiple patented technologies within a single platform. As a result, freedom-to-operate and licensing have become strategic considerations throughout the drug development process, influencing not only how companies protect innovation but also which therapeutic approaches are commercially viable.
Success in this next phase will depend on IP strategies built for that reality: platform-level thinking rather than target-by-target patenting, FTO analysis built into early discovery rather than bolted on before filing, and licensing treated as core infrastructure rather than opportunistic dealmaking. Science has moved from inhibiting proteins to controlling their fate by other means. The IP strategies protecting that science need to make the same move.
OUR FEATURED GUEST
JULIE CARLISLE
Partner and European Patent Attorney, Mewburn Ellis
Julie is a partner and European patent attorney specialising in pharmaceutical patent work, with a particular focus on complex and contentious matters before the EPO.
Her practice centers on protecting and defending commercially important pharmaceutical inventions, including late stage clinical candidates and approved drug products.