Ashley Jean Yeager Freelance Writer GEN

Patent Disputes Bring Immunotherapy Technology and Patent Review Process into Focus

A patent fight continues over engineered chimeric antigen receptors for T-cell therapies (CAR-T). In December 2016, the Patent Trial and Appeal Board upheld a patent for a specific design of a chimeric antigen receptor (CAR) designed by researchers at Memorial Sloan Kettering Cancer Center, despite Kite Pharma’s argument that the technology designed for cancer immunotherapy was not patentable.

Kite Pharma—bought by Gilead for $11.9 billion on August 28, 2017—has appealed a decision of the Patent Trial and Appeal Board (PTAB), filed on June 29, 2017. In the document submitted to the U.S. Court of Appeals for the Federal Circuit Court, the pharmaceutical company’s legal council argues that upholding patent US 7,446,190 violates the Administrative Procedure Act (APA) and Section 103 of the U.S. Patent Act. The legal team also notes that the U.S. Supreme Court is slated to assess the constitutionality of the Patent Trial and Appeal Board’s inter partes review (IPR) process for upholding or revoking patents, which could affect the validity of the patent as well.

Both CAR-T patents and the patent review process itself appear to be in the hands of the court.

The Promise and Patentability of CAR-T

Collecting and using patients’ immune cells to treat their specific cancer has emerged as a promising technique to combat the disease. Tumor cells send signals to suppress the immune response, making them difficult to attack and kill. CAR technology reprograms a patient’s T cells, allowing them to home in on tumor cells, bind to them, and provide the necessary signals to kill them.

In 2008, researchers at Sloan Kettering received a patent on a CAR-T that combines an activation signaling region called CD3 zeta, a costimulatory signaling region called CD28, and a binding element for specific interaction with a selected target.

Kite Pharma claims that CAR-T is not patentable because of the “obviousness” in combining the pieces. The appeal references a patent in 1993 for a CAR-T designed by Weizmann Institute of Science researcher Zelig Eshhar, which was comprised of a fragment of an antibody that allows the CAR to bind to a specific target, CD3 zeta, and CD28 to allow T-cell signaling after binding. The appeal also reports on a paper trail, citing the references that describe the development of costimulatory signaling regions of CD28, its combination with the CD3 zeta chain, the successful cloning of human CD28 cDNA, and development of the specific sequence of CD28 cDNA for the T cell, along with work on a chimeric CD28 specific to Gd2, a molecule overexpressed on the surface of tumor cells. This work establishes motivation for researchers in the field to combine the existing elements to create the exact CAR T-cell described in the patent, Kite claims, therefore, the work of the Sloan Kettering researchers was obvious and not patentable.

Lawyers Jing Zhou and Anthony Sabatelli of Dilworth IP, an intellectual property firm in Trumbull, CT, note in a post on the law firm’s site that Sloan Kettering representatives don’t dispute that the cited references provide information about each of the elements used in the patented CAR-T. However, the Sloan Kettering representatives argue that Kite has not shown sufficient reason for researchers to combine the prior pieces of the CAR-T described in earlier references. Had someone with ordinary skill tried to create the combination, he or she would have been unsuccessful, the cancer center’s legal council claims.

While reluctant to speak about the case, Zhou and Sabatelli explain in the post that the PTAB sided with Sloan Kettering because Kite did not express evidence that reveals the advantages of one particular CD28 sequence versus another in the prior art. It would not, in fact, be obvious to a person of ordinary skill in the art to combine the pieces of the CAR-T as they were in the patented CAR-T, the trial and appeal board argues. Prior art actually discourages the replacement of one CD28 region with the other because of the risk that the receptor may have caused off-target binding, which would have led to the death of other T cells or limited the immune response or presented a safety risk, the PTAB concluded. The patent was, therefore, upheld.

PTAB Called into Question

Kite, however, isn’t satisfied with the decision. The pharmaceutical company’s legal representatives argue that the trial and appeal board “shirked that most basic of agency obligations here, failing to provide a reasoned explanation for its decision to reject Kite’s challenge to the ’190 Patent.”

It’s left to the federal circuit court to decide if the PTAB in fact failed to provide sufficient support to satisfy the APA when it decided to uphold the patent, says lawyer Stacie Ropka of Axinn, Veltrop & Harkrider LLP in Hartford, Connecticut. She tells GEN that any ruling regarding PTAB and the APA will provide guidance on how much of an explanation the board must provide to support its decisions in future patent reviews, and, if the federal circuit court focuses on section 103 of the U.S. Patent Act, the ruling will provide guidance on “obviousness” arguments, which will affect future patent challenges, whether in an IPR or a civil litigation.

But, perhaps the bigger question is what the U.S. Supreme Court will say about the PTAB’s process for reviewing and revoking patents. The PTAB was established and began reviewing patents through the IPR process in 2012 as part of the America Invents Act. The review process may be unconstitutional, however. In 1898, the Supreme Court ruled in McCormick Harvesting Mach. Co. v. Aultman & Co. that once a patent is granted it “is not subject to be revoked or canceled by the president, or any other officer of the Government” because “[i]t has become the property of the patentee, and as such is entitled to the same legal protection as other property.”

The U.S. Supreme court will soon decide on the question of the constitutionally of the PTAB’s review process in a case unrelated to CAR-T: Oil States Energy Services, LLC v. Greene’s Energy Group, LLC.

If the court rules that the patent review process is constitutional, the ‘190 patent remains valid, not because the PTAB said it was valid in its final written decision, but because the ‘190 patent was issued in the first place. Issued patents are presumed valid, Ropka says. That would throw a wrench in Kite’s ability to challenge the ‘190 patent and also use the same arguments if the company is sued for violation of the ‘190 patent. Here’s why: if the petitioner—Kite in this case—fails to obtain a finding of invalidity (in a final written decision) after going through the PTAB’s review process, 35 U.S.C. § 315(e)(2) prevents a challenge to that patent in a subsequent civil action “on any ground that the petitioner raised or reasonably could have raised during that inter partes review.”

However, if the Supreme Court holds that the PTAB’s reviews are unconstitutional, then the board’s finding that the ‘190 patent is valid does not matter, and Kite will be able to present the same arguments presented in the inter partes review in a subsequent civil action.

Kite is already facing a suit regarding the ‘190 patent. Not long after the PTAB upheld the Sloan-Kettering patent, Juno Therapeutics Inc. filed a patent infringement lawsuit in Delaware against Kite. Juno has an exclusive licensing agreement with Sloan-Kettering for patent ‘190 to develop off-the-shelf T-cell immunotherapies. Juno argues that one of Kite’s investigational therapies called KTE-C19, which is in clinical trials for the treatment of aggressive non-Hodgkin lymphoma, will infringe on patent ‘190 if the product becomes commercially available.

This isn’t Juno’s first patent fight. In 2014, Juno licensed a CAR-T patent (US 8,399,645) from St. Jude’s Children’s Hospital. At the same time, Novartis licensed a University of Pennsylvania patent (US 7,638,325), which stemmed from a research partnership between Dr. Dario Campana at St. Jude’s Children’s Hospital and Dr. Carl June at the University of Pennsylvania. The team split, however, leading to two separate patents and the rise of the patent challenge. In the end, Novartis and Juno settled. “Novartis agreed to pay $12.25 million to Juno and hand over certain royalties on all future sales of CAR-T based on the U.S. market,” Zhou and Sabatelli write.

Now, the market for CAR-T is officially open. On August 30, 2017, the FDA announced its first approval of a CAR-T-cell therapy: Kymriah. It is meant to treat children and young adults with B-cell acute lymphoblastic leukemia was developed based on the St. Jude/UPenn research. A single infusion is said to cost $475,000.

Cancer immunotherapy will be profitable, Zhou and Sabatelli write. More companies will join the market, which could lead to more patent applications and, possibly, more challenges in the future—depending on what the courts decide about the constitutionality of calling the validity of existing patents into question.

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