Trials@uspto.gov Paper No. 49
`571.272.7822 Filed: January 8, 2018
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________
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`APOTEX INC., APOTEX CORP., APOTEX PHARMACEUTICALS
`HOLDINGS INC., AND APOTEX HOLDINGS, INC.,
`Petitioner,
`v.
`OSI PHARMACEUTICALS LLC,
`Patent Owner.
`____________________
`
`Case IPR2016-01284
`Patent 6,900,221 B1
`____________
`
`Before LORA M. GREEN, RAMA G. ELLURU, and ZHENYU YANG,
`Administrative Patent Judges.
`
`
`GREEN, Administrative Patent Judge.
`
`
`FINAL WRITTEN DECISION
`Determining That Claims 44‒46 and 53 Are Shown to Be Unpatentable
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
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`571.272.7822 Filed: January 8, 2018
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________
`
`APOTEX INC., APOTEX CORP., APOTEX PHARMACEUTICALS
`HOLDINGS INC., AND APOTEX HOLDINGS, INC.,
`Petitioner,
`v.
`OSI PHARMACEUTICALS LLC,
`Patent Owner.
`____________________
`
`Case IPR2016-01284
`Patent 6,900,221 B1
`____________
`
`Before LORA M. GREEN, RAMA G. ELLURU, and ZHENYU YANG,
`Administrative Patent Judges.
`
`
`GREEN, Administrative Patent Judge.
`
`
`FINAL WRITTEN DECISION
`Determining That Claims 44‒46 and 53 Are Shown to Be Unpatentable
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
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`IPR2016-01284
`Patent 6,900,221 B1
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`I.
`INTRODUCTION
`Apotex Inc., Apotex Corp., Apotex Pharmaceuticals Holdings Inc.,
`and Apotex Holdings, Inc., (“Apotex” or “Petitioner”) filed a Petition
`requesting an inter partes review of claims 44–47 and 53 of U.S. Patent
`No. 6,900,221 B1 (Ex. 1001, “the ’221 patent”). Paper 3 (“Pet.”). OSI
`Pharmaceuticals LLC1 (“OSI” or “Patent Owner”) filed a Preliminary
`Response to the Petition.2 Paper 7 (“Prelim. Resp.”). We determined that
`the information presented in the Petition and the Preliminary Response
`demonstrated that there was a reasonable likelihood that Petitioner would
`prevail in challenging claims 44–47 and 53 as unpatentable under 35 U.S.C.
`§ 103(a). Pursuant to 35 U.S.C. § 314, we instituted trial on January 9,
`2017, as to all of the challenged claims of the ’221 patent. Paper 8
`(“Institution Decision” or “Dec. Inst.”).
`On February 8, 2017, the parties filed a Joint Motion to Limit Petition
`Under 37 C.F.R. § 42.71, seeking to remove claim 47 from trial. Paper 12.
`We granted that Motion. Paper 19. Thus, trial is limited to claims 44‒46
`and 53.
`Patent Owner filed a Response (Paper 20, “PO Resp.”) and Petitioner
`filed a Reply (Paper 33, “Reply”). Patent Owner also filed a Motion to
`Exclude Evidence (Paper 37, “Mot. Exclude”), to which Petitioner filed an
`Opposition (Paper 40, “Opp. Mot. Exclude”), and Patent Owner filed a
`
`
`1 Patent Owner underwent a name change from OSI Pharmaceuticals Inc. to
`OSI Pharmaceuticals LLC, which change was recorded at the United States
`Patent and Trademark Office. Reply 1 n.2.
`2 OSI further identifies Astellas US LLC, Astellas US Holding, Inc., Astellas
`Pharma Inc., and Genentech, Inc., as real parties-in-interest. Paper 5, 1.
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`Reply (Paper 43). Oral hearing was held on October 3, 2017, and a
`transcript of that hearing has been entered into the record. Paper 48 (“Tr.”).
`We have jurisdiction under 35 U.S.C. § 6. Petitioner bears the burden
`of proving unpatentability of the challenged claims, and the burden of
`persuasion never shifts to Patent Owner. Dynamic Drinkware, LLC v. Nat’l
`Graphics, Inc., 800 F.3d 1375, 1378 (Fed. Cir. 2015). To prevail, Petitioner
`must establish facts supporting its challenge by a preponderance of the
`evidence. See 35 U.S.C. § 316(e); 37 C.F.R. § 42.1(d). This Final Written
`Decision is issued pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73.
`Based on the record before us, we conclude that Petitioner has
`demonstrated by a preponderance of the evidence that claims 44–46 and 53
`of the ’221 patent are unpatentable. We also deny Patent Owner’s Motion to
`Exclude in part, and dismiss it in part.
`A.
`Related Proceedings
`According to Patent Owner, the ’221 Patent is presently at issue “in
`OSI Pharms. LLC. et al. v. Apotex Inc. et al., Case No. 1:15-cv-00772-SLR
`(D. Del. Sept. 2, 2015) and OSI Pharms. LLC. et al. v. Breckenridge
`Pharms. Inc. et al., Case No. 1:15-cv-01063-SLR (D. Del. Nov. 17, 2015),
`which are consolidated in lead Case No. 1:15-00772-SLR.” Paper 5, 3–4.
`Patent Owner further identifies a number of closed matters involving the
`’221 patent, including OSI Pharms, Inc. v. Mylan Pharms Inc., Case No.
`1:09-cv-00185-SLR (D. Del. Mar. 19, 2009). Id.
`B.
`The ’221 Patent (Ex. 1001)
`The ’221 patent is generally directed to the B polymorph of N-(3-
`ethynylphenyl)-6, 7-bis(2-methoxyethoxy)-4-quinazolinamine
`hydrochloride. Ex. 1001, Abstract. The ’221 patent further discloses that
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`“N-(3-ethynylphenyl)-6, 7-bis(2-methoxyethoxy)-4-quinazolinamine, in
`either its hydrochloride or mesylate forms, or in an anhydrous and hydrous
`form, is useful in the treatment of hyperproliferative disorders, such as
`cancers, in mammals.” Id. at 1:21‒25. The ’221 patent references U.S.
`Patent No. 5,747,498 (Ex. 1009, “Schnur”), and incorporates it by reference
`in its entirety. Id. at 1:27‒29. In addition, the ’221 patent notes that
`Example 20 of Schnur refers
`to
`[6,7-bis(2-methoxyethoxy)-quinazolin-4-yl]-(3-
`ethynylphenyl)amine hydrochloride [i.e., the hydrochloride salt
`of erlotinib], which, the patent discloses, is an inhibitor of the
`erbB family of oncogenic and protooncogenic protein tyrosine
`kinases, such as epidermal growth factor receptor (EGFR), and
`is therefore useful for the treatment of proliferative disorders,
`such as cancers, in humans.
`Id. at 1:28‒35.
`According to the ’221 patent, the method of treating cancer using the
`disclosed compound
`may be for the treatment of a cancer selected from brain,
`squamous cell, bladder, gastric, pancreatic, breast, head, neck,
`oesophageal, prostate, colorectal, lung, renal, kidney, ovarian,
`gynecological and thyroid cancer.
`The method may also be for the treatment of a cancer
`selected from non-small cell lung cancer (NSCLC), refractory
`ovarian cancer, head and neck cancer, colorectal cancer and renal
`cancer.
`Id. at 4:23‒30.
`
`Illustrative Claim
`C.
`As discussed above, the claims challenged in this proceeding are 44–
`46 and 53 of the ’221 patent. Claim 44, representative of the challenged
`subject matter, is the only independent challenged claim and is reproduced
`below:
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`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 (HFV),
`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 carrier.
`Ex. 1001, 35:26‒36. Challenged claim 53 limits the cancer to be treated to
`non-small cell lung cancer. Id. at 35:64‒65.
`
`Instituted Challenge
`D.
`We instituted trial on the challenged claims based on the following
`ground of unpatentability (Dec. Inst. 29):
`References
`Basis
`Schnur3 and OSI’s 10K4 or
`§ 103
`Gibbs5
`Petitioner relies also on the Declaration of Giuseppe Giaccone, M.D.,
`
`Ph.D. (Ex. 1002), the Declaration of Laurence S. Lese, Esq. (Ex. 1012), as
`well as the Reply Declaration of Dr. Giaccone (Ex. 1053) and
`Kristopher A. Boushie (Ex. 1054).
`
`Claims Challenged
`44‒46 and 53
`
`
`3 Schnur et al., U.S. Patent No. 5,747,498, issued May 5, 1998 (Ex. 1009)
`(“Schnur”).
`4 Annual Report pursuant to Section 13 or 15(d) of the Securities Exchange
`Act of 1934 for the Fiscal Year Ended September 30, 1998, Commission
`File Number 0-15190, OSI Pharmaceuticals, Inc. (Ex. 1011) (“OSI’s 10K”).
`5 J.B. Gibbs, “Anticancer Drug Targets: Growth Factors and Growth
`Factor Signaling,” 105 J. CLIN. INV. 9‒13 (2000) (Ex. 1010) (“Gibbs”).
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`Patent Owner relies on the Declarations of Paul Bunn, M.D. (Ex.
`2021), and Mark L. Reisenauer (Ex. 2023).
`II. ANALYSIS
`Claim Construction
`A.
`In an inter partes review, claim terms in an unexpired patent are
`interpreted according to their broadest reasonable construction in light of the
`specification of the patent in which they appear. See 37 C.F.R. § 42.100(b);
`Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–45 (2016)
`(upholding the use of the broadest reasonable interpretation standard).
`Under that standard, we presume that a claim term carries its “ordinary and
`customary meaning,” which “is the meaning that the term would have to a
`person of ordinary skill in the art in question” at the time of the invention.
`In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007); see also
`TriVascular, Inc. v. Samuels, 812 F.3d 1056, 1062 (Fed. Cir. 2016) (“Under
`a broadest reasonable interpretation, words of the claim must be given their
`plain meaning, unless such meaning is inconsistent with the specification
`and prosecution history.”). Any special definition for a claim term must be
`set forth in the specification with reasonable clarity, deliberateness, and
`precision. In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994).
`In the Institution Decision, we determined that none of the terms in
`the challenged claims required express construction at that time. Dec. Inst. 6
`(citing Wellman, Inc. v. Eastman Chem. Co., 642 F.3d 1355, 1361 (Fed. Cir.
`2011) (“[C]laim terms need only be construed ‘to the extent necessary to
`resolve the controversy.’”)). In its Response, Patent Owner agrees that the
`claims terms should be construed according to their ordinary and customary
`meaning (PO Resp. 28 (citing Pet. 13)), and Petitioner does not dispute that
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`in its Reply. We note, however, that for purposes of our final written
`decision there is now a need to clarify the construction of “treatment” and
`“therapeutically effective amount” based on the specific definition of
`“treatment” in the ’221 patent.
`i.
`“treatment” and “therapeutically effective amount”
`Independent claim 44 is drawn to treatment of non-small cell lung
`cancer, pediatric malignancies, cervical and other tumors caused or
`promoted by human papilloma virus, Barrett’s esophagus (pre-malignant
`syndrome), or neoplastic cutaneous diseases in a mammal comprising
`administering to said mammal a therapeutically effective amount of erlotinib
`or a pharmaceutically acceptable salt thereof to a mammal. As discussed
`above, the parties agree that the terms of the claim should be given their
`ordinary and customary meaning.
`According to the ’221 patent:
`
`The term “treating” as used herein, unless otherwise
`indicated, means reversing, alleviating, inhibiting the progress
`of, or preventing the disorder or condition to which such term
`applies, or one or more symptoms of such disorder or condition.
`The term “treatment”, as used herein, refers to the act of treating,
`as “treating” is defined immediately above.
`Ex. 1001, 14:9‒15. Both parties agree this construction of “treating”
`provided in the specification is the proper construction of that term. See,
`e.g., Tr. 30 (Counsel for Patent Owner stating “[t]he term ‘treatment’ both
`sides agree is defined in the patent.”). We further conclude that this
`construction is consistent with its ordinary and customary meaning and how
`the ordinary artisan would understand the term “treat,” “treating,” or
`“treatment.” In view of this construction of “treatment,” we conclude that
`the ordinary artisan would understand the ordinary and customary meaning
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`of “a therapeutically effective amount” of erlotinib for the treatment of the
`conditions listed by the preamble to claim 44 to be an amount sufficient to
`treat the mammal as defined above. The challenged claims, therefore, do not
`require administration of a clinically effective amount of erlotinib to a
`human. Cf. Tr. 50:16‒17 (counsel for Patent Owner noting that a “major
`clinical response” is “a higher standard than treatment as defined in the
`claims”).
`
`Level of Ordinary Skill in the Art
`B.
`Petitioner contends, relying on its expert, Dr. Giaccone:
`A person of ordinary skill in the art relevant to the
`challenged claims of the ’221 patent would have a medical
`degree and at least some specialized training in oncology, and
`more particularly, specialized training in thoracic oncology. (See
`Ex. 1002 at ¶ 52.) A person of ordinary skill in the art would
`also have several years of clinical experience, and a substantive
`understanding and experience using the medications and
`therapies effective for treating various lung cancers at the
`relevant time. (See 1002 at ¶ 52.) A person of ordinary skill in
`the art may have collaborated with others having expertise in
`pharmaceutical formulation development and pharmaceutical
`drug development. (Ex. 1002 at ¶ 51.)
`Pet. 13.
`Patent Owner responds, relying on its expert, Dr. Bunn, that the
`ordinary artisan “would be a medical oncologist who would hold an M.D.
`degree and would have completed several years of practice in the field of
`oncology.” PO Resp. 26 (citing Ex. 2021 ¶¶ 22‒23).
`Patent Owner disagrees with Petitioner’s expert, Dr. Giaccone, that
`the ordinary artisan would have specialized training in thoracic oncology
`and a substantive understanding using medications and therapies for treating
`various lung cancers. Id. at 26‒27 (citing Ex. 1002 ¶ 52). Petitioner
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`responds that under its definition, the ordinary artisan “would have the
`ability to infer facts from disclosures in the prior art directed to the
`development of drugs to treat lung cancer, and specifically NSCLC, and
`would not require every fact to be explicitly laid out in the prior art.” Reply
`2.
`Given that claim 44 encompasses cancers in addition to non-small cell
`
`lung cancer, we adopt Patent Owner’s statement of the level of ordinary skill
`in the art. Because the claim’s requirement to treat cancers in addition to
`non-small cell lung cancer, we find that the ordinary artisan would be a
`medical oncologist who would hold an M.D. degree and would have
`completed several years of practice in the field of oncology. Moreover, we
`note that the level of ordinary skill in the art in this proceeding is reflected
`by the prior art of record. See Okajima v. Bourdeau, 261 F.3d 1350, 1355
`(Fed. Cir. 2001); In re GPAC Inc., 57 F.3d 1573, 1579 (Fed. Cir. 1995). In
`addition, during oral hearing, counsel for both parties opined that the
`outcome of the obviousness analysis would be the same under either parties’
`definition of the ordinary artisan. Tr. 22:3‒8, 37:9‒11. Thus, our analysis
`would be the same under either Petitioner’s or Patent Owner’s definition of
`the ordinary artisan.
`C. Obviousness over Schnur and OSI’s 10-K or Gibbs
`Petitioner asserts that claims 44‒46 and 53 are rendered obvious by
`the combination of Schnur and OSI’s 10-K or Gibbs. Pet. 23‒35. Petitioner
`presents a claim chart demonstrating where the limitations of the challenged
`claims may be found in the relied upon references. Pet., Appendix A.
`Patent Owner disagrees with Petitioner’s contentions, asserting that the
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`Petition fails to demonstrate the obviousness of the challenged claims by a
`preponderance of the evidence. PO Resp. 29‒66.
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`i.
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`Overview of the Prior Art Relied Upon
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`
`
`We find the following as to the teachings of the relevant prior art.
`a.
`Schnur (Ex. 1009)
`Schnur “relates to 4-(substituted phenylamino) quinazoline derivatives
`which are useful in the treatment of hyperproliferative diseases, such as
`cancers, in mammals.” Ex. 1009, 1:9‒11. Schnur recognizes that there is a
`continuing need for anti-cancer pharmaceuticals. Id. at 1:64‒67. Schnur
`notes that it is known that a cell may become cancerous through
`transformation of a portion of its DNA into an oncogene, many of which
`“encode proteins which are aberrant tyrosine kinases capable of causing cell
`transformation.” Id. at 1:20‒25. According to Schnur:
`Receptor tyrosine kinases are large enzymes which span
`the cell membrane and possess an extracellular binding domain
`for growth factors such as epidermal growth factor, a
`transmembrane domain, and an intracellular portion which
`functions as a kinase to phosphorylate specific tyrosine residues
`in proteins and hence to influence cell proliferation. It is known
`that such kinases are frequently aberrantly expressed in common
`human cancers such as breast cancer, gastrointestinal cancer such
`as colon, rectal or stomach cancer, leukemia, and ovarian,
`bronchial or pancreatic cancer. It has also been shown that
`epidermal growth factor receptor (EGFR) which possesses
`tyrosine kinase activity is mutated and/or overexpressed in many
`human cancers such as brain, lung, squamous cell, bladder,
`gastric, breast, head and neck, oesophageal, gynecological and
`thyroid tumors.
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`Id. at 1:30‒44. Thus, Schnur teaches that is known that inhibitors of
`receptor tyrosine kinases “are useful as [ ] selective inhibitors of the growth
`of mammalian cancer cells.” Id. at 1:45‒47.
`
`Of the 4-(substituted phenylamino) quinazoline derivatives taught by
`Schnur, Schnur teaches that [6,7-bis(2-methoxyethoxy)quinazolin-4-yl]-(3-
`ethynylphenyl)-amine (i.e., erlotinib) is preferred (id. at 3:47‒48; 4:8‒9),
`and specifically discloses its synthesis (id. at 22:30‒49 (Example 20)).
`
`Schnur teaches:
`The active compounds of this invention 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. In particular. the compounds of
`this invention are therapeutants or prophylactics 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
`(e.g., BPH). It is, in addition, expected that a quinazoline of the
`present invention may possess activity against a range of
`leukemias and lymphoid malignancies.
`Id. at 14:1‒16 (emphasis added).
`
`Schnur teaches that the “amount of active compound administered
`will, of course, be dependent on the subject being treated, on the severity of
`the affliction, on the manner of administration and on the judgment of the
`prescribing physician.” Id. at 15:55‒58. Schnur teaches, however, that “an
`effective dosage is in the range of approximately 0.001‒100 mg/kg,
`preferably 1 to 35 mg/kg in single or divided doses,” which, “[f]or an
`average 70 kg human, this would amount to 0.05 to 7 g/day, preferably 0.2
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`to 2.5 g/day.” Id. at 15:58‒62. Schnur also discusses pharmaceutical
`composition comprising the active compound. Id. at 15:63‒16:45.
`
`In addition, Schnur discloses both in vitro and in vivo methods for
`testing the activity of the compounds. Id. at 14:31‒15:47. Schnur explicitly
`claims erlotinib (i.e., [6,7-bis(2-methoxyethoxy)quinazolin-4-yl]-(3-
`ethynylphenyl)-amine. Id. at 39:33, 40:1‒2, claim 8. Schnur also claims
`pharmaceutical compositions comprising a pharmaceutically effective
`amount of the disclosed compounds (see, e.g., id. at 39:15‒18, claim 3;
`41:51‒54, claim 11), as well as methods of treatment of hyperproliferative
`disorders, such as lung cancer (see, e.g., id. at 41:55, claim 12; id. at 41:61‒
`62, claim 14).
`
`OSI’s 10K (Ex. 1011)
`b.
`OSI’s 10K is a filing with the Securities and Exchange Commission
`(“SEC”) by OSI Pharmaceuticals, Inc. Ex. 1011, 1.
`
`OSI’s 10 K discloses
`With its collaborative partner Pfizer, OSI has focused
`since 1986 on the discovery and development of novel classes of
`orally active, molecularly targeted, small molecule anticancer
`drugs based on oncogenes and tumor suppressor genes and the
`fundamental mechanisms underlying tumor growth. The first of
`these programs to yield a clinical candidate, CP-358,774, which
`targets a variety of cancers including ovarian, pancreatic, non-
`small cell lung and head and neck, achieved a significant
`milestone with the completion of Phase I safety trials and the
`initiation of Phase II clinical trials in the United States in cancer
`patients. CP-358,774 is a potent, selective and orally active
`inhibitor of the epidermal growth factor receptor, a key
`oncogene in these cancers. In addition, two other compounds,
`CP-564,959 and CP-609,754, have been identified and are in
`advanced stages of pre-clinical development. Nine other targets
`are in active R&D at OSI. CP-564,959 is being developed as an
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`orally available, potent and selective inhibitor of a key protein
`tyrosine kinase receptor involved in blood vessel growth or
`angiogenesis. Angiogenesis is induced by solid tumors which
`require nutrients that will enable growth. The Company believes
`that the ability to safely and effectively inhibit this process
`represents one of the most exciting areas of cancer drug
`development. CP-609,754 is an orally active inhibitor of the ras
`oncogene, which is another important target involved in many
`major tumors including colon and bladder. The types of novel
`anticancer drugs being developed in the OSI/Pfizer collaboration
`are expected to be safer and more effective than standard
`chemotherapeutic agents.
`Ex. 1011, 5‒6 (emphasis added).
`c.
`Gibbs (Ex. 1010)
`Gibbs provides “a broad overview of a growth factor signal
`transduction system, with a focus on those points that have been translated to
`drugs or clinical candidates.” Ex. 1010, 9. Gibbs notes, however, that
`“[d]ue to editorial restrictions limiting the number of reference citations,
`much of the clinical data gleaned from abstracts is not listed in the
`references,” and points the reader to additional references. Id.
`Gibbs teaches:
`The EGF receptor is also the target for the development of
`inhibitors of the intracellular tyrosine kinase domain. ZD-1839
`and CP-358,774, competitive inhibitors of ATP binding to the
`receptor’s active site, are currently in clinical trials (12, 13).
`Their mechanism of action has led to some concern about safety,
`given the variety and physiological significance of protein
`kinases and other enzymes that bind ATP. 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.
`Id. at 10 (emphasis added).
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`Gibbs provides Table 1, which sets forth examples of inhibitors of
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`growth factor signaling, and their development status, which is reproduced
`below:
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`
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`Id.
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`Principles of Law
`ii.
`A claim is unpatentable under 35 U.S.C. § 103(a) if “the differences
`between the subject matter sought to be patented and the prior art are such
`that the subject matter as a whole would have been obvious at the time the
`invention was made to a person having ordinary skill in the art to which said
`subject matter pertains.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
`(2007). The question of obviousness is resolved on the basis of underlying
`factual determinations, including: (1) the scope and content of the prior art;
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`(2) any differences between the claimed subject matter and the prior art;
`(3) the level of skill in the art; and (4) objective evidence of nonobviousness,
`i.e., secondary considerations. Id. (citing Graham v. John Deere Co.,
`383 U.S. 1, 17–18 (1966)).
`Secondary considerations may include commercial success, long-felt
`but unsolved needs, failure of others, and unexpected results. KSR, 550 U.S.
`at 406; Leo Pharm. Prods., Ltd. v. Rea, 726 F.3d 1346, 1358–59 (Fed. Cir.
`2013). Secondary considerations are “not just a cumulative or confirmatory
`part of the obviousness calculus but constitute[ ] independent evidence of
`nonobviousness” and “enable[ ] the court to avert the trap of hindsight.” Leo
`Pharm. Prods., Ltd., 726 F.3d at 1358 (first alteration in original) (internal
`quotation marks and citations omitted). “This objective evidence must be
`‘considered as part of all the evidence, not just when the decisionmaker
`remains in doubt after reviewing the art.’” Transocean Offshore Deepwater
`Drilling, Inc. v. Maersk Drilling USA, Inc., 699 F.3d 1340, 1349 (Fed. Cir.
`2012) (citations omitted).
`The obviousness analysis requires that “the factfinder should further
`consider whether a person of ordinary skill in the art would [have been]
`motivated to combine those references, and whether in making that
`combination, a person of ordinary skill would have [had] a reasonable
`expectation of success,” even “[i]f all elements of the claims are found in a
`combination of prior art references.” Merck & Cie v. Gnosis S.p.A., 808
`F.3d 829, 833 (Fed. Cir. 2015). We analyze the asserted grounds of
`unpatentability in accordance with the above-stated principles.
`
`15
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`Patent 6,900,221 B1
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`
`iii. Analysis
`Petitioner relies on Schnur for teaching a genus of compounds that
`includes erlotinib, asserting that Schnur discloses that erlotinib is a preferred
`compound. Pet. 24 (citing Ex. 1009, 3:47‒48, 4:8‒9, 38:13‒39:12, 39:33‒
`40:65; Ex. 1002 ¶ 93). In particular, Petitioner asserts that Schnur’s claim 8
`includes erlotinib as one of 49 preferred compounds. Id. (citing Ex. 1009,
`3:47‒48; 4:8‒9; 39:33‒40:65; Ex. 1002 ¶ 93). According to Petitioner,
`Schnur “discloses that the compounds can be administered to a mammal for
`the treatment of a hyperproliferative disorder.” Id. (citing Ex. 1009, 5:49‒
`52).
`
`Petitioner further relies on Schnur for teaching a “therapeutically
`effective amount” of erlotinib. Id. at 25. Specifically, Petitioner asserts that
`Schnur teaches that the “therapeutically effective amount can depend on the
`subject being treated, on the severity of the affliction, on the manner of
`administration, and on the judgment of a prescribing physician.” Id. (citing
`Ex. 1009, 15:55‒58). According to Petitioner, Schnur teaches that a
`generally therapeutically effective dose is in the range of 0.001‒100 mg/kg,
`preferably from 1 to 35 mg/kg, making the dose for an average 70 kg person
`from 0.05 to 7 g/day, preferably 0.2 to 2.5 g/day. Id. (citing Ex. 1009,
`15:58‒62). Petitioner contends that “Schnur’s disclosure of the
`therapeutically effective dose is identical to that disclosed by the ’221
`patent.” Id. (emphasis removed) (citing Ex. 1009, 15:55‒62; Ex. 1001,
`24:19‒27, 24:33‒43, 30:29‒35).
`The only difference between Schnur and the method of challenged
`claims 44 and 53, Petitioner asserts, is that Schnur “does not expressly
`identify ‘NSCLC’ as a hyperproliferative disorder.” Id. at 26 (citing
`
`16
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`IPR2016-01284
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`Ex. 1005, 23; Ex. 1006, 2). Petitioner notes, however, that Schnur
`“discloses that erlotinib is useful to treat, inter alia, ‘lung cancer.’” Id.
`(citing Ex. 1009, 14:1‒6). Petitioner notes further that the Examiner
`“reached the same conclusion during prosecution of the ’221 patent, and
`allowed claim 44 to issue because it was ‘drawn to treatment of specific
`cancers by any polymorph of the claimed compounds. These specific
`cancers are not found in Schnur (‘498).’” Id. (quoting Ex. 1006, 2).
`
`Petitioner relies on Gibbs for teaching that CP-358,774, which
`Petitioner contends is anhydrous erlotinib hydrochloride, is “a kinase
`inhibitor ‘with an acceptable therapeutic index, particularly in patients with
`non-small cell lung cancer,’ and had entered Phase-II clinical trials.” Id. at
`27 (citing Ex. 1010, 9‒10, Table 1).
`
`Petitioner relies on OSI’s 10K for similarly teaching that CP-358,774
`is “a clinical candidate that had ‘achieved a significant milestone with the
`completion of Phase I safety trials and the initiation of Phase II clinical trials
`in the United States in cancer patients.’” Id. at 28 (quoting Ex. 1011, 6).
`Petitioner relies on OSI’s 10K also for its disclosure “that CP-358,774 is a
`potent, selective and orally active inhibitor of the EGFR and being used to
`target ovarian, pancreatic, non-small cell lung, and head and neck cancers.”
`Id. (citing Ex. 1011, 6).
`
`Petitioner asserts, therefore, that Gibbs or OSI’s 10K would have
`pointed an ordinary artisan towards erlotinib from the compounds of Schnur
`(id. at 28 (citing Ex. 1002 ¶¶ 102‒105)), and would have also taught its use
`to treat non-small cell lung cancer (id. (citing Ex. 1010, 10, Ex. 1011, 6,
`Ex. 1002 ¶ 106)). That is, Petitioner asserts, “the preferred use of erlotinib
`to treat NSCLC is made explicit when Schnur is viewed through the lens of
`
`17
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`IPR2016-01284
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`Gibbs or OSI’s 10-K.” Id. at 29 (citing Ex. 1002 ¶ 107); see also id. at 33‒
`35 (discussing the reason to combine Schnur with Gibbs or OSI 10-K).
`Moreover, Petitioner asserts, the teachings of Schnur as combined with
`Gibbs or OSI’s 10K would have provided a reasonable expectation of
`success of achieving the method of challenged claim 44. Id. at 29 (citing
`Ex. 1002 ¶¶ 105, 109).
`
`Patent Owner responds initially that the Petition does not “establish a
`link between the compounds discussed in OSI 10-K and Gibbs [i.e., CP-
`358,774] and any compound disclosed in Schnur—let alone erlotinib,
`specifically.” PO Resp. 30; see id. at 30‒32. We note that Patent Owner is
`not arguing that CP-358,774 is not erlotinib. Rather, as counsel for Patent
`Owner, Ms. Wigmore, stated during oral argument, Patent Owner is arguing
`that there is “a procedural deficiency in the[ ] petition.” Tr. 35:6.
`
`As noted in our Decision on Institution (Dec. Inst. 15‒16), Petitioner
`pointed us to paragraph 28 of the Declaration of Dr. Giaccone in discussing
`the structure of erlotinib (see Pet. 24 n. 3). We noted (Dec. Inst. 15‒16) that
`the next paragraph of the Declaration specifically stated:
`During joint clinical development of erlotinib between
`OSI and Pfizer, and
`then subsequently, only OSI,
`the
`hydrochloride salt of erlotinib was commonly referred by the
`identifier CP-358,774, which was prepared as set forth in PCT
`Pub. No. WO 96/30347. (See Ex. 10166 at 4839, col. 1; See also
`V.A. Pollack et al., “Inhibition of Epidermal Growth Factor
`Receptor-Associated Tyrosine Phosphorylation
`in Human
`Carcinomas with CP-358,774: Dynamics of Receptor Inhibition
`In Situ and Antitumor Effects in Athymic Mice,” J. Pharmacol.
`
`
`6 Moyer et al., Induction of Apoptosis and Cell Cycle Arrest by CP-358,774,
`an Inhibitor of Epidermal Growth Factor Receptor Tyrosine Kinase. 57
`CANCER RESEARCH 4838‒4848 (1997) (“Moyer”).
`
`18
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`
`Exp. Ther. 291(2):739‒748 (Nov. 1999) (“Pollack,” Ex. 1015)
`at 740 (“CP-358,774 . . . a colorless, crystalline, anhydrous
`compound, was synthesized in our laboratories (Arnold and
`Schnur, 1998)).)
`Ex. 1002 ¶ 29. We noted further that statement is supported by Moyer,
`which defines “CP-358,774” as “[6,7-Bis(2-methoxy-ethoxy)-quinazolin-4-
`yl]-(3-ethynylphenyl) amine.” Dec. Inst. 16 (quoting Ex. 1016, 4839); see
`Ariosa Diagnostics v. Verinata Health, Inc., 805 F. 3d 1359, 1365 (Fed. Cir.
`2015) (“Art can legitimately serve to document the knowledge that skilled
`artisans would bring to bear in reading the prior art identified as producing
`obviousness.”).
`
`Thus, the Decision on Institution clearly put Patent Owner on notice
`as to the evidence we were relying on in establishing that the ordinary
`artisan would have understood at the time of invention that CP-358,774 is
`the hydrochloride salt of erlotinib. In that regard, we agree with Petitioner
`that Moyer is indicative of the state of the art, and as Patent Owner’s expert,
`Dr. Bunn admitted, “at least by 1997, Moyer (Ex. 1016) defined CP-358,774
`with the chemical name for erlotinib, and also admitted that Moyer defines
`CP-358,774 with a chemical structure, which has remained the same.”
`Reply 13 (citing Ex. 1048, 90:7‒92:20; Ex. 1016 at 4839). Thus,
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