Osi Pharm., LLC v. Apotex Inc.
| Decision Date | 04 October 2019 |
| Docket Number | 2018-1925 |
| Citation | 939 F.3d 1375 |
| Parties | OSI PHARMACEUTICALS, LLC, Appellant v. APOTEX INC., Apotex Corp., Apotex Pharmaceuticals Holdings Inc., Apotex Holdings Inc., Appellees United States, Intervenor |
| Court | U.S. Court of Appeals — Federal Circuit |
Thomas Saunders, Wilmer Cutler Pickering Hale and Dorr LLP, Washington, DC, argued for appellant. Also represented by Amy K. Wigmore, Amanda L. Major ; Emily R. Whelan, Kevin M. Yurkerwich, Boston, MA.
William Blake Coblentz, Cozen O'Connor, Washington, DC, argued for appellees. Also represented by Barry P. Golob, Aaron S. Lukas, Kerry Brendan McTigue.
Dennis Fan, Appellate Staff, Civil Division, United States Department of Justice, Washington, DC, argued for intervenor. Also represented by Katherine Twomey Allen, Joseph H. Hunt, Scott R. McIntosh; Thomas W. Krause, Joseph Matal, Farheena Yasmeen Rasheed, Office of the Solicitor, United States Patent and Trademark Office, Alexandria, VA.
Before Newman, Taranto, and Stoll, Circuit Judges.
OSI Pharmaceuticals, LLC appeals the decision of the Patent Trial and Appeal Board holding claims 44–46 and 53 of U.S. Patent No. 6,900,221 unpatentable as obvious. We conclude that the Board’s finding of reasonable expectation of success is not supported by substantial evidence and reverse the Board’s obviousness determination.
and the ’221 Patent
Non-small cell lung cancer
(NSCLC) was the leading cause of cancer deaths in 2000, claiming more than 1 million lives. The standard for treating NSCLC at the time was chemotherapy, which ameliorated some lung cancer-related symptoms, but was limited in use due to toxicity. Chemotherapy nonspecifically kills normal proliferating cells in addition to cancerous cells, and can result in the patient experiencing side effects such as nausea, vomiting, hair loss, and neuropathy.
By the late 1990s, there was a recognized need for a new therapy that would be both effective and well tolerated. In response, investigators pursued targeted therapies as alternatives to chemotherapy. One avenue of research involved investigating agents that inhibit the epidermal growth factor receptor (EGFR). Activation of the EGFR triggers a cascade of events leading to cell reproduction, and it was hypothesized that inhibiting the EGFR would be beneficial in treating tumor cells. EGFR inhibitors were investigated as potential agents for treating NSCLC, but many of these compounds failed in clinical trials.
treatment is highly unpredictable. Even though the EGFR was identified in some cancers as a drug target, the in vitro (i.e., in a test tube) effectiveness of a drug in inhibiting the EGFR turned out to be a poor proxy for how effective that drug actually was in treating cancer
in vivo (i.e., in the body). Numerous EGFR inhibitors that showed promising in vitro activity failed for a variety of reasons.
These included poor pharmacokinetics due to poor absorption or rapid metabolism (or both), undesirable drug-drug interactions, drug toxicity
due to drug binding onto healthy cells, drug toxicity due to binding onto other receptors, and metabolite toxicity. Some drug candidates were limited by one or more of these shortcomings, further underscoring the unpredictable nature of cancer treatment.
A drug compound must pass three phases of human clinical trials in order to obtain FDA approval. A threshold step is to gain the FDA’s permission to test the compound in humans in the first place. After a drug developer has conducted preclinical studies, i.e., tested the compound in vitro (in a test tube; outside of a living organism) and in animals, it submits an Investigational New Drug (IND) application to the FDA. An IND submission includes an investigator’s brochure, which discloses information such as animal safety and preclinical efficacy data, clinical trial proposals, and toxicology data. If the FDA approves the IND, then Phase I studies can commence. Phase I studies involve administering the compound to a small group of healthy volunteers or advanced cancer
patients with a variety of tumor types. Phase I studies are conducted primarily to evaluate safety, to determine a safe dosing range, and to identify any side effects.
Clinical trials do not focus on efficacy until Phase II, which typically involves administering the compound to a specific patient population. The goals of a Phase II study include evaluating efficacy in specific patient populations, determining dose tolerance and optimal dosage, and identifying possible adverse effects and safety risks. Phase III studies are larger scale and are undertaken to evaluate clinical efficacy and safety in an expanded patient population. After completing Phase III studies, a developer submits a New Drug Application to the FDA for approval.
A great majority of therapies for NSCLC failed in clinical trials. "In non-small-cell lung cancer
alone, between 1990 and 2005, a total of 1,631 new drugs were studied in phase II. Only seven of these new agents gained FDA approval." Govindan at 1;1 J.A. 4131. One of the compounds that ultimately gained FDA approval was N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, also known as erlotinib. OSI markets erlotinib under the name Tarceva®.
After years of study, the inventors of erlotinib discovered that it was an effective targeted therapy for NSCLC. They claimed their invention in the ’221 patent. OSI’s ’221 patent issued on May 31, 2005 and claims priority to three provisional applications filed on November 11, 1999, March 30, 2000, and May 23, 2000. The ’221 patent is listed in the Orange Book for Tarceva
®. Claims 44–46 and 53 are at issue in this appeal and are reproduced below:
’221 patent col. 35 ll. 26–42, 64–65. It is not disputed that the date of invention for the asserted claims is March 30, 2000.
The Board determined that ’221 patent claims 44–46 and 53 would have been obvious over Schnur2 in view of Gibbs3 or OSI’s 10-K.4 We discuss each reference in turn.
Schnur relates to a class of "4-(substituted phenylamino)quinazoline derivatives which are useful in the treatment of hyperproliferative diseases, such as cancers
, in mammals." Schnur col. 1 ll. 9–11. Schnur specifically discloses 105 different compounds recited as examples. Id. at col. 17 l. 5–col. 36 l. 61. Erlotinib is listed as a preferred compound, and a method for synthesizing erlotinib is described. Id. at col. 4 ll. 8–9, col. 22 ll. 30–49. Schnur states that these compounds are "potent inhibitors of the erbB family of oncogenic and protooncogenic protein tyrosine kinases such as epidermal growth factor receptor (EGFR), erbB2, HER3, or HER4 and thus are all adapted to therapeutic use as antiproliferative agents (e.g., anticancer) in mammals, particularly humans." Id. at col. 14 ll. 1–6. It also discloses that the compounds in this class are therapeutics "for the treatment of a variety of human tumors (renal, liver, kidney, bladder, breast, gastric, ovarian, colorectal, prostate, pancreatic, lung , vulval, thyroid, hepatic carcinomas, sarcomas, glioblastomas, various head and neck tumors ), and other hyperplastic conditions such as benign hyperplasia of the skin (e.g., psoriasis ) or prostate." Id. at col. 14 ll. 7–14 (emphasis added). While Schnur states that lung cancer is one of the many conditions that could be treated by this class of compounds, it does not discuss NSCLC.
Gibbs is a review article authored by Dr. Jackson B. Gibbs. Gibbs discusses various signaling mechanisms in the cell and how they are associated with tumor malignancy. The article reviews and discusses the data of over thirty published research studies, including one discussing erlotinib
, which Gibbs refers to as CP-358,774. Gibbs states that the EGFR is a drug development target and notes:
ZD-1839 and [erlotinib
], competitive inhibitors of ATP binding to the [EGFR]’s active site, are currently in clinical trials (12, 13).... However, these compounds appear to have good anti-cancer activity in preclinical models, with an acceptable therapeutic index, particularly in patients with non-small cell lung cancer.
J.A. 1406. Gibbs’s reference 12 refers to Woodburn,5 a study investigating the antitumor effects of the ZD-1839 compound—a different compound than erlotinib—on several solid human cancers
including NSCLC. Woodburn does not discuss erlotinib at all. Reference 13 refers to Moyer,6 which discloses how erlotinib inhibits EGFR in mouse liver tumors and in human HN5 tumors. J.A. 1524. Moyer does not discuss NSCLC at all, let alone suggest that erlotinib could treat NSCLC. There is no data regarding the use of erlotinib to treat NSCLC in Gibbs or in any of the references cited in Gibbs. Dr. Gibbs, the author, confirmed this in a declaration submitted to the Board:
Based on references 12 and 13, the abstracts from the 1999 ASCO and AACR Conferences, and my own personal recollection, my research at the time of my article did not identify any information suggesting that [erlotinib] exhibited anti-tumor activity in NSCLC. I was...
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Case Comments
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