Leveraging intellectual property as bifunctional protein degraders enter clinical trials

Targeted protein degraders such as proteolysis targeting chimeras (PROTACs) have been a significant development in the therapeutics space. These heterobifunctional molecules bind to an E3 ubiquitin ligase and a target protein of interest and induce the selective degradation of this protein through the ubiquitin-proteasome system. Research on these protein degraders is creating a market for a new therapeutic modality, with early entrants leveraging their intellectual property to receive funding and transitioning to clinical trials. With multiple players in the field, this space is particularly active with partnerships and collaborations, recent ones being collaboration of Astellas with Cullgen in June and PeptiDream in July 2023. This is an excellent area to showcase the impact of active IP management.

The promise of solving many drawbacks associated with small-molecule inhibitors makes bifunctional protein degraders suitable candidates for research and commercialisation. Unsurprisingly, the endeavour to develop and refine this new technology has seen continuous and focused efforts by both industry and academia. The last few years have also seen an increasing number of bifunctional protein degraders undergoing clinical studies, with cancer as a prominent indication. By the end of the decade, we expect to see these transformative therapeutics gaining FDA approval and addressing critical patient needs.

Patent landscape evaluation

To understand this growing trend and compare it with associated patent activity, we performed a patent landscape analysis from January 2013 to July 2023 in international patent applications (covered by the Patent Cooperation Treaty). Evaluating such activity provides critical insight to address key IP management decisions. 

Further, a study of two key players’ US patents was also carried out. The search was limited to PROTACs and bifunctional degrader terms (protein degraders). Close to 622 INPADOC patent families were identified as relevant to the search, which were further analysed and classified into innovations related to specific therapeutic and diagnostic use. We also conducted an assignee analysis, classifying the patents according to their origin (eg, industries, governments, universities, non-profit research institutes and individuals/inventors). As indicated in Figure 1, the yearly filing analysis shows that activity has grown remarkably in the last few years, with around 92% of inventions directed towards therapeutical use and around 80% of the families including protein degraders to specific target proteins. The possibility of targeting previously undruggable protein targets – particularly with implications in oncology – and the associated increase in clinical studies could be partially responsible for this momentum.

*Filing activity not completely represented as patent applications are published 18 months from the application’s priority date 

The assignee analysis indicates a similar patenting trend in the industry and universities or non-profits, with around 53% of the assignees being from the industry and about 1% being individual inventors. Some of the active assignees include Arvinas, BeiGene, C4 Therapeutics, Dana-Farber Cancer Institute, the University of Michigan and the University of Dundee.

To better understand the patent filing trend and compare it with ongoing clinical trials, protein degrader clinical study data was collated from recent publications, “Protein degraders enter the clinic - a new approach to cancer therapy”, published in February 2023 in Nature Reviews Clinical Oncology, “Targeted protein degrader development for cancer: advances, challenges, and opportunities”, published in May 2023 in Trends in pharmacological sciences and “Clinical Translation of Targeted Protein Degraders”, published in July 2023 in Clinical pharmacology and therapeutics by industrial and academic researchers. Clinical studies have been initiated for more than 20 protein degraders, many of which are in trial phases one and two. Androgen receptors (AR), estrogen receptors (ER), Bruton’s tyrosine kinases (BTK) and bromodomain-containing 9 (BRD9) are some proteins of interest for cancer-related clinical studies, while those addressing autoimmune diseases include IL-1 receptor-associated kinase 4 (IRAK4) and BTK as the targets.

Further, a comparative analysis of the INPADOC families’ claims of the active assignees and the protein degraders undergoing clinical trials indicated an overlap between their protein targets, the E3 ubiquitin ligase being used and the indications being addressed. Some of the protein targets that emerged from this analysis were BTK, AR, ER and BRD9 proteins. Protein degraders for the targets AR and ER are being clinically developed by Arvinas, BeiGene’s degraders target BTK and C4 Therapeutics is involved in targeting BRD9 and epidermal growth factor receptors. Cereblon also emerged as one of the E3 ubiquitin ligases commonly associated with protein degraders in the landscape analysis of the active assignees.

On the therapeutic front, Figure 2 classifies the INPADOC families into different indications: cancer, neurodegenerative diseases, autoimmune diseases and other therapies (Figure 2). Cancer emerged as one of the most researched indications within this group, with an overwhelming 89% of inventions mentioning it. Protein degraders also found application as therapeutics for autoimmune and neurodegenerative diseases. While the last couple of years have shown an encouraging trend with an increase in patent filings in this space, these indications were largely mentioned in the claims along with cancer. The majority of patent families that were primarily directed towards cancer specified the type of cancer being addressed (eg, prostate cancer or breast cancer). Further, around 30% of the patent families mentioned cereblon as the E3 ubiquitin ligase in their claims, as highlighted in Figure 3.

As seen in Figure 1, the yearly analysis from 2013 to 2023 showed a significant growth in patent filings, which was bolstered by a parallel increase in cancer focus and continued growth in the neurodegenerative and autoimmune disease space. Approximately 45% of the patent families in the neurodegenerative space and 80% of the autoimmune disease patent families mentioned specific targets for the protein degraders. Cereblon was also included as the E3 ubiquitin ligase in 36% of inventions related to either neurodegenerative or autoimmune diseases.     

A promising future

While challenges remain to be addressed both at the preclinical and clinical front in this developing field, the progress is encouraging. Arvinas’s oncology pipeline indicates a phase-three study involving protein degraders ARV-471 (for breast cancer) and phase-two studies involving protein degraders ARV-110 and ARV-766 (for prostate cancer). The pipeline also depicts research being conducted in the neurodegenerative space, with the investigational new drug application expected to be initiated for leucine rich repeat kinase 2 in 2023.

While innovations for protein degraders addressing oncological indications are the most prominent, the landscape analysis reveals a growing focus on neurodegenerative and autoimmune diseases. Research around protein degraders continues to be active and promises to have a wider application in therapeutics, even beyond these indications. Some of the momentum in this space could be attributed to the availability of high-quality ligands for specific protein targets. This leaves open the possibility of novel research into designing ligands for the protein targets and the specific protein degraders. Considering these trends, we expect to see a sustained growth in patent filings in this area in the foreseeable future.

IP management lessons

It appears that the field of protein degraders is at an inflection point, with more degraders entering the clinical space. Evaluating the associated patent activity will play a critical role in the ability to identify the research, as well as opportunities for licensing and partnerships. A crucial consideration in such initiatives is the alignment of an organisation’s patent filing strategy with the timing and nature of the external collaborations. Conversely, studying the patents or patent applications and combining this with a specific company’s filing trends would provide insight into their research direction, IP management strategy and potential commercialisation prospects. Companies such as Arvinas have demonstrated an ability to successfully leverage their portfolios to enter into collaborations and multi-year licences and receive royalties.

A closer look at two key players

Arvinas

Founded in 2013, Arvinas has partnered with Genentech, Pfizer and Bayer. It also initiated a joint venture with Bayer in agriculture – Oerth Bio. The claims of the company’s US patents indicate that it appears to largely focus its protein degraders on specific targets. While cancer is a prominent indication, other indications were also included, such as Kennedy’s disease and endometriosis. Genetic diseases such as cardiofaciocutaneous syndrome, neurofibromatosis type 1, Costello syndrome and Noonan syndrome were also mentioned.

C4 Therapeutics

C4 Therapeutics was founded in 2015 and has entered into strategic collaborations with Roche, Biogen and Betta pharmaceuticals. Its US patents mostly focus on using degrons in their protein degraders and list multiple target proteins in their claims. Some of the indications include:

• prostate cancer;
• breast cancer;
• testicular cancer;
• colon cancer;
• melanoma;
• solid tumour;
• hematological cancer;
• multiple myeloma;
• leukemia;
• lymphoma; and
• sarcoma.

Cereblon binders are another area of focus for the company.

By developing their own proprietary platform and scientific strategy, these companies have built valuable patent portfolios and successful collaborations. With active research in this space and the availability of resources and expertise from large pharmaceutical companies, the future of protein degraders looks encouraging and promises a faster turnaround from bench to bedside.