Perspectives:

Transformation of the CAR-T patent landscape

It’s 30 years since Zelig Eshhar and colleagues at the Weizmann Institute of Science in Israel first described chimeric antigen receptors (CARs). But only over the last decade has biomedical research really focused on the potential of CAR-T cells to create medicines. This is clearly shown in the graph below which demonstrates a rapid increase in the number of scientific publications describing CAR-T related research since 2008 (Figure 1). What’s even more interesting is that the number of patent filings with CAR-T related claims has not, as might be expected in many fields, lagged behind but has actually closely mirrored the rise in the number of scientific publications. This clearly shows that the healthcare industry has realized the commercial potential of this work and moved quickly in an attempt to capitalise on it.

In fact, in 2016, the number of CAR-T related patent filings actually exceeded the number of scientific research papers published on the topic, and this trend has continued, further emphasising the scientific community’s strong belief in the commercial potential of CAR-T drugs. And this isn’t just blind faith. A combination of high-value acquisitions and FDA approvals has demonstrated both that pharmaceutical companies see CAR-T as the future, and that the regulators are also convinced. The first-in-class CAR-T drug to gain FDA approval was Novartis’ Kymriah in 2017, for B-cell acute lymphoblastic leukemia. Shortly after, Kite Pharma’s drug, Yescarta, was approved as a 3^rd line treatment for relapsed or refractory large B-cell lymphoma, and at around the same time, Gilead acquired the company for almost $12 billion. The following year Celgene acquired Juno Therapeutics for the sum of ~$9 billion (Figure 2).

Patent protection for CAR-T products can take several different forms. Patent filings may be made to protect specific CAR construct designs, for the application of CAR-T drugs for particular disease (cancer) indications, and in the form of specific antigen binding sequences incorporated into the CARs. Many companies have filings describing proprietary CAR sequences which may include sequence modifications in any element of the construct design including the target binder, the transmembrane domain, the co-stimulation or activation domains. The next big challenge in the sector will be effectively applying CAR-T cell therapy to solid tumors. And technological advances are being made which researchers hope will surmount barriers to success in this area.

Although still classed as an emerging technology, the IP landscape in CAR-T is becoming increasingly crowded and this will inevitably lead to narrower claims being granted (if any) in many cases. In fact the validity of some of the earlier CAR-T patents has already been called into question, with challengers suggesting that they didn’t diverge far enough from the original patent application submitted by Eshhar and colleagues (see ‘CAR-T in the Courts’). In a similar vein, another broad ranging patent (from Celyad) which protects an approach for generating T cell receptor (TCR) deficient CAR-T cells suitable for allogeneic use has been the subject of at least one patent challenge. The creation of ‘off-the-shelf’ CAR-T drugs will be a significant advancement towards widening patient access, therefore challenges like this are unsurprising. Given the enormous curative, and therefore commercial potential of CAR-T drugs, expect to see a rise in the number of patent litigation cases as more CAR-T therapies are approved.

That’s not to say broad applications can’t be approved, but they’re going to have to be pretty special. Here at TC BioPharm (TCB), we think we’ve got something pretty special. Our technology uses the atypical gamma delta T (GDT) cell as the CAR delivery vehicle, which is in stark contrast to conventional alpha beta T cell approaches. That’s because the gamma delta T cell receptor is compatible with an allogeneic cell therapy and does not need to be knocked out. Not only that, the GD TCR is crucial for the drug’s efficacy which is further augmented by inclusion of a Co-Stim CAR-T. It’s this unique receptor design in conjunction with the GD TCR that provides a proprietary mechanism which has allowed TCB to file for patent protection on the Co-stim CAR-T platform, applicable to multiple targets and indications. It goes without saying that companies who manage to obtain a broad patent in this promising field will be in an enviable commercial position.

An informative analysis of the evolving CAR-T patent landscape can be found in Jürgens and Clarke’s “Evolution of CAR T-cell immunotherapy in terms of patenting activity” (Nature Biotechnology, 2019, 37, 370–376).

SOURCES

1. CAR-T in the Courts: https://www.genengnews.com/insights/car-t-in-the-courts/
2. “Celyad responds to misleading statements on its patent relating to allogeneic human primary T-Cells that are engineered to be TCR-deficient and express a CAR”: https://www.celyad.com/en/news/celyad-responds-to-misleading-statements-on-its-patent-relating-to-allogeneic-human-primary-t-cells-that-are-engineered-to-be-tcr-deficient-and-express-a-car
3. “Evolution of CAR T-cell immunotherapy in terms of patenting activity” (Nature Biotechnology, 2019, 37, 370–376).
4. ‘190 patent, Krause and Finney papers / patents?https://www.markmanadvisors.com/blog/2018/5/30/can-kite-pharma-reverse-its-ipr-loss-challening-junos-car-t-patent
5. CAR-T cell race article (new scientist 2015) https://www.the-scientist.com/bio-business/the-car-t-cell-race-35701