from the United States Patent and Trademark Office, Patent
Trial and Appeal Board in No. IPR2016-01284.
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.
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.
Newman, Taranto, and Stoll, Circuit Judges.
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.
Non-Small Cell Lung Cancer and the '221 Patent
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.
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
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.
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
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.
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; 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
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:
44. A method for the treatment of NSCLC (non small cell lung
cancer), pediatric malignancies, cervical and other tumors
caused or promoted by human papilloma virus (H[P]V),
Barrett's esophagus (pre-malignant syndrome), or
neoplastic cutaneous diseases in a mammal comprising
administering to said mammal a therapeutically effective
amount of a pharmaceutical composition comprised of at least
one of N-(3-ethynylphenyl)-6,
7-bis(2-methoxyethoxy)-4-quinazolinamine, or pharmaceutically
acceptable salts thereof in anhydrous or hydrate forms, and a
45.The method of claim 44, wherein the treatment further
comprises a palliative or neo-adjuvant/adjuvant monotherapy.
46.The method of claim 44, wherein the treatment further
comprises blocking epidermal growth factor receptors (EGFR).
53. The method of claim 44 for the treatment of non-small
cell lung cancer (NSCLC).
'221 patent col. 35 ll. 26-42, 64-65. It is not disputed
that the date of invention for the asserted claims is March
Asserted Prior Art
Board determined that '221 patent claims 44-46 and 53
would have been obvious over Schnur in view of
Gibbs or OSI's 10-K. We discuss each reference in
relates to a class of "4-(substituted
phenyla-mino)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 ki-nases 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,
colo-rectal, prostate, pancreatic, lung, vulval,
thyroid, hepatic carcinomas, sarcomas, glioblastomas, various
head and neck tumors), and other hyperplastic ...