By James Love
This is a story about U.S. patent number 6,958,335, and how it took more than 18 years for Novartis to acknowledge National Institutes of Health (NIH) funding in a key patent for Gleevec, allowing Novartis to shape the narrative regarding its role in the development of Gleevec, and also to avoid demands that Novartis make the invention “available to the public on reasonable terms,” which is an obligation under the Bayh-Dole Act.
On May 10, 2001, the United States FDA approved a new drug, imatinib, initially for the treatment of a rare indication: chronic myeloid leukemia (CML). The drug was registered by Novartis, which sold the drug under the brand name Gleevec in the United States and several other markets, and as Glivec in others.
Eventually the FDA would expand the approved uses, including for nine approved orphan drug indications, greatly increasing the number of patients using the drug. Among the new indications were approvals for the treatment of gastrointestinal stromal tumors (GIST).
Gleevec was a remarkable new medicine. Dr. Klausner, then head of the NIH National Cancer Institute (NCI), told the New York Times that Gleevec was the ”first molecularly targeted drug,” which was described as “the first in a new class of drugs that disrupts specific signaling proteins that are liable to go awry in cancer and cause the cell to divide incessantly.”
According to the NCI, in addition to treating CML, Gleevec “helped establish a group of cancer drugs, called targeted therapies, that are designed to attack cancer cells with specific genetic abnormalities.”
On May 26, 2001, Gleevec made the cover of Time Magazine.
The early evidence of efficacy was so robust that imatinib was approved in just 72 days, making it the fastest ever FDA approval for a new drug, and one that gave patients a new lease on life.
With Gleevec, Novartis has sought to cultivate a narrative about its leadership and the risks it took in making massive investments in a drug for a new unproven approach to controlling cancer, but the reality was different.
Dr. Brian Druker, an oncologist working at the Dana Farber Cancer Institute and later at the Oregon Health & Science University, in Portland, Oregon, is widely credited with persuading Novartis to proceed with trials on Gleevec, and for playing the most important role in the drug’s development.
In 2002, Michael Palmedo asked Dr. Druker to describe the funding of research for Gleevec. Druker told Palmedo that “[d]uring the years that Gleevec was developed, my lab was funded 50% by the National Cancer Institute (government), 30% by the Leukemia and Lymphoma Society (private sector), 10% by Novartis (pharmaceutical) and 10% by OHSU, my home institution.” Druker did give credit to Novartis for its investments in the clinical trials, and in manufacturing the drug. But the trials were not large, and the initial Phase 1 trial, the riskiest stage of development, was partly funded by the NIH.
In a recent “Talks at Google,” Dr. Druker indicated that Novartis was reluctant to proceed because they had predicted that if the drug worked, it would only be used to treat 5,000 patients per year, generating $100 million in revenue ($20,000 per patient). But based upon Dr. Druker’s persistence and the dramatic results from the Phase I testing, the development proceeded.
Today, imatinib is used to treat more than ten types of cancer and about 200,000 patients per year. The initial price of Gleevec for CML was even considered aggressive in 2001, but by 2016 Novartis more than tripled the price in the U.S., despite the greatly expanded patient populations it was now used to treat. By 2010, Gleevec was generating more than $4 billion per year for Novartis, more than 40 times the initial projection. By the end of 2018, Novartis cumulative sales for Gleevec exceeded $53 billion.
Druker and other oncologists have criticized Novartis and other companies for the high prices of drugs for chronic myeloid leukemia (CML), notably in an article in the journal Blood. Druker has frequently said that he has not earned any royalties from the drug, which was subject to a broad patent on the compound held by Novartis.
Whether or not Druker received any royalties for Gleevec, he is one of ten inventors listed in U.S. Patent Number 6,958,335, which is listed in the FDA Orange Book for Gleevec. The patent was assigned to Novartis, the Dana-Farber Cancer Institute, and the Oregon Health & Science University, and has an expiration date in the FDA Orange Book of June 19, 2022. The patent is related to a provisional patent application dated October 27, 2000, before the Gleevec NDA application was filed.
Even more surprising is that this patent (6,958,335), was corrected on July 29, 2019, to disclose that the invention benefited from federal funding. The disclosure, coming more than 18 years after the original patent application, was for the use of Gleevec for treatment of gastrointestinal stromal tumors (GIST). The grant on the disclosure was CA 605823. According to the NIH RePORT database, the grant number is associated with 23 NIH projects at Oregon Health and Science University (OHSU), including grants every year from 1995 to 2019. From 1995 to 2015, the title of the grants was the same: Chronic Myelogenous Leukemia and BCR-ABL Substrates.
Overall, including CA 605823 and other grants, the NIH lists $48 million in grants to Dr. Druker, through five institutions, including OHSU and the Dana Farber Cancer Institute.
The patent, which lists inventors from and assignments to three entities, Novartis, Dana Farber and OHSU, was probably filed by Novartis.
Patent 6,958,335 was granted in 2005. The disclosure of federal funding should have appeared in the original application, as well as on the granted patent.
A certificate of correction on patents is not in itself unusual (11 percent of all U.S. patents assigned to Novartis contain certificates of correction), although normally the corrections are related to other issues, such as the technical specification of the invention. Failures to disclose government rights are of particular interest because they relate to the U.S. government’s rights to insist that inventions are available to the public on reasonable terms and are manufactured in the United States, as well as other government rights in patents.
The penalty for non-disclosure of U.S. government rights in patents includes as one possible sanction, the federal government taking possession of the patent itself. The NIH has rarely if ever gone down that path, but it is possible. The U.S. Army declared that a contractor, Campbell Plastics, forfeited title to a patent developed with Army support by failing to comply with disclosure requirements. Campbell Plastics appealed, and the United States Court of Appeals for the Federal Circuit affirmed the Army’s decision. Campbell Plastics Engineering & Mfg., Inc. v. Brownlee, 389 F.3d 1243 (Fed. Cir. 2004). Contractors widely regarded the Campbell Plastics decision as a warning about the possible consequences of failing to disclose government rights.
In this case, Novartis, Dana Farber, and OHSU appear to be in the clear because they have corrected the patent. We don’t know why, after more than 18 years, a correction was finally made, and who intervened to make the correction happen. But it is a stark reminder of how lax the NIH is in monitoring this obligation that Novartis was able to conceal federal funding on a key Orange Book patent on a famous drug that has generated more than $53 billion in sales, and which has been the subject of intense criticism over Novartis’s aggressive pricing policies.
KEI has written the NIH on several occasions to identify cases where inventors have failed to acknowledge federal funding in patent applications. Such cases have not been difficult to find. In the 1990s, Congress and HHS investigated such failures to disclose, and found widespread non-compliance with disclosure mandates, and lax oversight. This is an area where new Congressional oversight would be welcome, particularly as the question of the federal role in drug development is being spun by various parties.