CAR T-Cell therapy, a new biologic therapy, is taking off. As companies continue to develop this new and promising therapy, patent litigation inevitably follows.
CAR T-Cell therapy can be thought of as turbo-charging a patient’s own T-cells to treat cancer. At a high level, CAR T-Cell therapy works as follows: (1) a patient’s own T-cells are extracted and shipped to a laboratory, (2) scientists genetically engineer the T-cells to express a chimeric antigen receptor (CAR) that will recognize a specific antigen (specific protein target, e.g., CD19) residing on the surface of target cancer cells, (3) the genetically modified T-cells are then expanded to a large batch, and (4) infused back into the patient so that they can hunt down and attack their targets.
So far, the FDA has only approved two products in this area: Novartis’ tisagenlecleucel (Kymriah®) for the treatment of relapsed/refractory Acute Lymphocytic Leukemia (ALL) and relapsed/refractory Diffuse Large B-Cell Lymphoma (DLBCL) indications, and Kite Pharma’s axicabtagene ciloleucel (Yescarta®) for the treatment of certain relapsed/refractory large B-Cell non-Hodgkin lymphoma (NHL). DLBCL is the most common NHL. Both biologic products target the CD19 protein and were granted priority review and breakthrough therapy designation before receiving approval in 2017. In the clinic, Kymriah® showed an overall response rate (ORR) and a minimal residual disease (MRD)-response rate of 83% in ALL patients (ELIANA study), and an ORR of 50% and complete response (CR) rate of 32% in DLBCL patients (JULIET study). Yescarta® produced an ORR of 72% in DLBCL patients with a CR rate of 51% (ZUMA-1 study) (see FDA overview here). While the efficacy of these biologics is impressive, the cost of personalized medicine is high. Although CAR T-Cell therapy is supposed to be a one-time cure, a single dose of Yescarta® or Kymriah® for DLBCL costs $373,000. A single treatment of Kymriah® for ALL runs about $475,000.
Researchers and the medical community clearly see CAR T-Cell therapy as a new frontier for cancer treatment, and big pharma has jumped in. For example, Gilead spent $11.9B to acquire Kite and its cell-therapy pipeline just weeks prior to the FDA’s approval of Yescarta® in 2017. Celgene acquired Juno Therapeutics and its CAR T-Cell project, lisocabtagene maraleucel (“liso-cel”), for $9B in 2018. Even after the sales of the first generation CAR T-Cell products proved slower than expected, companies continue to invest in CAR T-Cell therapy. Last year, BMS announced a deal to buy Celgene and its acquired liso-cel project, for $74B. This may have been driven at least in part by the promising results of liso-cel studies for relapsed/refractory CLL/SLL (TRANSCEND CLL 004 study) and DLBCL (PILOT study), which were presented at last year’s American Society of Hematology (ASH) annual meeting. This year, BMS announced that the FDA has accepted the liso-cel BLA for its large B-cell lymphoma indication and granted priority review. Kite also recently announced that the FDA has accepted its BLA and granted priority review for another anti-CD19 product (similar to Yescarta® but made through a different manufacturing process) for the treatment of relapsed/refractory mantle cell lymphoma. It has been estimated that there are hundreds of ongoing clinical trials evaluating other CAR T-Cell therapies. Some of the next-generation products under development include allogenic off-the-shelf therapies, engineered molecular switches, and products that target solid tumors.
The activity in the CAR T-Cell therapy space combined with the financial stakes involved will undoubtedly lead to a multitude of patent disputes. Indeed, there have already been a number of high-stakes disputes. Immediately after the approval of Yescarta®, Kite (Gilead) was sued for patent infringement by Sloan Kettering, the owner of U.S. Patent No. 7,446,190, and Juno Therapeutics (Celgene/BMS), the exclusive licensee. The PTAB previously upheld the validity of the ’190 Patent in an earlier IPR proceeding brought by Kite. Last December a jury awarded Sloan Kettering and Juno Therapeutics an up-front payment of $585 million and a 27.6% running royalty on Yescarta® revenues through trial, which comes in at a grand total of $752M. Novartis was also involved in a lawsuit with Juno Therapeutics over infringement of a different patent licensed by Juno back in 2014 (St. Jude’s U.S. Patent No. 8,399,645). In that case Juno and Novartis ended up settling, with Novartis agreeing to pay $12.25M plus milestone payments and royalties on future sales of certain CAR T-Cell products. Last year Cabaret Biotech filed a declaratory judgment complaint against Kite to enforce a license agreement, seeking a declaration that Cabaret’s patent (U.S. Patent No. 7,741,465) is not invalid. According to the complaint, Yescarta® is an embodiment of the licensed patent.