10080374656_1d802535cb_bOn December 2016, another CAR-T patent fight temporarily came to the end by the issuing of the final written decision from the Patent Trial and Appeal Board (PTAB) (IPR2015-01719).  This Inter Partes Review (IPR) was initiated by Kite Pharma Inc. (“Kite”) to challenge a patent held by Memorial Sloan Kettering Cancer Center (MSKCC), relating to chimeric antigen receptors (CAR) T-cells for cancer immunotherapy (US 7,446,190). The IPR petition was filed on August 2015 and granted by the US PTAB on February 2016. After review, the PTAB determined that Kite did not show by a preponderance of the evidence that all the claims in the ‘190 patent are unpatentable.

Inter Partes Review (IPR)
Inter Partes Review (IPR) is a new post grant procedure, enacted on September 16, 2012 as part of the America Invents Act (AIA), to allow third parties to challenge the validity of US patents before the United States Patent and Trademark Office (USPTO). IPR is only based on a ground that could be raised under 35 U.S.C. §§102 or 103, and only on the basis of prior art consisting of patents or printed publications. Though any third party (a person who is not the patent owner) can initiate an IPR proceeding, the petitioner must show that there is a reasonable likelihood that they would prevail with respect to at least one claim challenged. If the IPR is instituted and not dismissed, the PTAB will issue a final decision within 1 year (extendable for good cause by up to 6 months) from the filing of the petition.

Another interesting procedural fact about IPR is the estoppel effect of IPR. This means the petitioner may not request or maintain a proceeding before the USPTO, a civil action, or the United States International Trade Commission (USITC), with respect to that claim on any ground that the petitioner raised or reasonably could have raised during the IPR.

Sloan Kettering Car-T patent US 7,446,190
The ’190 patent which is titled “Nucleic Acids Encoding Chimeric T Cell Receptors” describes engineered T cell receptors (TCR) for modifying T-lymphocytes to stimulate their immune response to specific target cells. These Chimeric TCRs are able to induce cytotoxicity on tumor cells and facilitate cancer immunotherapy. Claim 1, the only independent claim, of the ’190 patent, describes specific nucleic acids encoding TCRs formed by combining an activation signaling region (CD3z), a co-stimulatory signaling region (CD28), and a binding element for specific interaction with a selected target, in one single molecule.

PTAB decision on this IPR case
Kite challenged the patentability of the ’190 patent based on obviousness over the combination of three prior art references: Krause, Finney, and Aruffo. Krause describes a chimeric CD28 construct specific for Gd2, a molecule overexpressed on the surface of tumor cells. Finney describes chimeric receptors with co-stimulatory signaling regions of CD28 and the z –chain from the TCR complex. Aruffo reports the successful cloning of human CD28 cDNA and the sequence of CD28 cDNA. Kite offers three rationales for combining these three prior art references: (1) adding Finney’s CD3z to Krause’s chimeric TCRs with the sequence provided by Aruffo; (2) replacing Finney’s CD28 sequence with Krause’s CD28 sequence; and (3) optimizing Finney’s CD28 sequence using routine methods, with guidance from Krause and Aruffo. MSKCC does not dispute that the combination of the cited prior art references teaches each of the claim elements.  Instead, they argues that Kite has not shown sufficient reason for one with ordinary skill in the art to combine the prior art references and that one would not have expected success in doing so.

The PTAB agreed with MSKCC that there is not sufficient motivation as Kite suggested for one of ordinary skill in the art to combine the prior art references of Krause, Finney, and Aruffo. The Board found that Kite did not express evidence demonstrating the advantages of Krause’s CD28 sequence versus Finney’s CD28 sequence. Thus, there is no “apparent reason to combine the known elements in the fashion claimed by the patent at issue” (Cf. KSR, 550 U.S.). Furthermore, the Board found that the prior art actually teaches away from the replacement of Finney’s CD28 region with Krause’s CD28 sequence in a chimeric TCR, because the Krause’s CD28 sequence has a longer extracellular domain, including the MYPPPY and LDN motifs. By adding the MYPPPY motif to Finney’s dual-signaling chimeric TCR, this generates additional binding sites for CD28’s natural ligands, which enhances the rate of “off-target” binding and/or activation. This off-target activation could “induce the engineered T cells to target and kill other activated T cells, or to at least become distracted – in either case, significantly limiting any immune response initiated by the chimeric TCRs or presenting a safety risk.” (see Ex. 2022, 144-146) The Board concluded that, “at the time of the invention, the artisan of ordinary skill would have been generally concerned about off-target binding as presenting efficacy and safety risks for chimeric TCRs”. Therefore, the artisan of ordinary skill would have been discouraged to include Krause’s CD28 sequence in designing a dual-signaling chimeric TCR. In the final written decision, the PTAB upheld the patentability of all claims in the ’190 patent.

Overview of Car-T patent landscape
In 2012, the University of Pennsylvania and St. Jude Children’s Research Hospital commenced a patent challenge relating to a CAR-T patent entitled “Chimeric Receptor with 4-1BB Stimulatory Signaling Domain” (US 8,399,645). This challenge initiated from the termination of a research agreement between Dr. Dario Campana at St. Jude’s Children’s Hospital and Dr. Carl June at the University of Pennsylvania.  In 2014, when Juno licensed the ‘645 patent from St. Jude’s Children’s Hospital, this IP dispute became a controversy between Juno and Novartis, which licensed the University of Pennsylvania’s patent (US 7,638,325) to develop its cancer immunotherapy candidate CTL019. In 2015, Juno and Novartis reached a settlement. Novartis agreed to pay $12.25 million to Juno and hand over certain royalties on all future sales of CAR-T based on US market. Though the PTAB upheld all claims in the ‘190 patent, it seems to provoke another legal fight between Juno and Kite. Just three days after the Board’s decision, Juno filed an infringement lawsuit against Kite, targeting Kite’s most advanced CAR-T candidate, KTE-C19 (US 6,319,494, US 7,741,465). Meanwhile, Kite announced it is also preparing to appeal the PTAB decision.

Driven by the invaluable market profit of cancer immunotherapy, more companies and institutions, such as Cellectis, Bluebird Bio, Celgene, Pfizer, Ziopharm, Bellicum, and others have actively joined in the research and development of new CAR-T candidates. With the advance of next generation of CAR-T cell therapy for cancer, we will likely see more patent applications and challenges related to this novel technology of chimeric TCRs.

Patent Number Title Assignee Inventor
US 7,446,190 Nucleic acids encoding chimeric T cell receptors Sloan-Kettering Institute for Cancer Research


Sadelain, Michel; Brentjens, Renier; Maher, John
US 8,399,645 Chimeric receptors with 4-1BB stimulatory signaling domain


St. Jude Children’s Research Hospital, Inc. Campana, Dario; Imai, Chihaya


US 7,638,325 Activation and expansion of T-cells using an engineered multivalent signaling platform


The Trustees of the University of Pennsylvania June, Carl; Riley, James; Maus, Marcela; Thomas, Anna


US 6,319,494 Chimeric chains for receptor-associated signal transduction pathways Cell Genesys, Inc. Capon, Daniel J.; Weiss, Arthur; Irving, Brian A.; Roberts, Margo R.; Zsebo, Krisztina


US 7,741,465 Chimeric receptor genes and cells transformed therewith


Eshhar, Zelig;

Waks, Tova;

Gross, Gideon

Eshhar, Zelig; Schindler, Daniel; Waks, Tova; Gross, Gideon

– Jing Zhou, PhD and Anthony D. Sabatelli, PhD, JD

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