IPR2016-01284
`U.S. Patent No. 6,900,221
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`____________________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________________________________
`
`APOTEX INC., APOTEX CORP., APOTEX PHARMACEUTICALS
`HOLDINGS INC., AND APOTEX HOLDINGS, INC.,
`Petitioners,
`
`v.
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`OSI PHARMACEUTICALS, INC.,
`Patent Owner.
`____________________________________________
`
`Case IPR2016-01284
`U.S. Patent No. 6,900,221
`____________________________________________
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`
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`PATENT OWNER’S PRELIMINARY RESPONSE
`UNDER 37 C.F.R. § 42.107
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`TABLE OF CONTENTS
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`IPR2016-01284
`U.S. Patent No. 6,900,221
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`Page
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`I. 
`II. 
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`B. 
`
`C. 
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`Introduction ...................................................................................................... 1 
`Background ...................................................................................................... 6 
`A. 
`State of the Art ...................................................................................... 6 
`Clinical Development and Approval of Tarceva® ................................ 7 
`B. 
`C. 
`The ’221 Patent ..................................................................................... 9 
`D.  District Court Litigation ...................................................................... 10 
`E. 
`Alleged Prior Art Relied on by Petitioner ........................................... 11 
`III.  Level of Ordinary Skill in the Art ................................................................. 17 
`IV.  Claim Construction ........................................................................................ 17 
`V. 
`The Petition Fails to Establish a Reasonable Likelihood that Any of
`Claims 44-46 or 53 Is Obvious Over Schnur in View of Gibbs or the
`OSI 10-K (Ground I) ..................................................................................... 18 
`A. 
`The Petition Fails to Identify a Motivation to Combine Schnur
`with Gibbs or the OSI 10-K ................................................................ 18 
`The Petition Fails to Establish that a POSA Would Have Had A
`Reasonable Expectation of Success By Combining Schnur with
`the OSI 10-K or Gibbs ........................................................................ 23 
`Ground I Includes Redundant Alternative Combinations and
`Should be Limited to a Single Combination ....................................... 32 
`VI.  The Petition Fails to Establish a Reasonable Likelihood That Claim 47
`Is Obvious Over Schnur Combined with Gibbs or Wakeling, in View
`of Moscatello (Ground II) .............................................................................. 33 
`A. 
`The Petition Fails to Identify a Motivation to Combine the
`References ........................................................................................... 34 
`The Petition Fails to Establish that a POSA Would Have Had A
`Reasonable Expectation of Success by Combining the
`References Relied on in Ground II ...................................................... 39 
`Ground II Includes Redundant Alternative Combinations and
`Should be Limited to a Single Combination ....................................... 41 
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`B. 
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`C. 
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`IPR2016-01284
`U.S. Patent No. 6,900,221
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`VII.  Objective Indicia Support the Non-Obviousness of the Challenged
`Claims ............................................................................................................ 42 
`VIII.  The Petition Fails to Establish a Reasonable Likelihood That All
`Challenged Claims are Anticipated by Schnur (Ground III) ......................... 45 
`A.  Ground III Should be Denied Because the Petition Does Not
`Apply the Correct Legal Standard ....................................................... 45 
`Ground III Should Be Denied Because It Presents the Same
`Prior Art and Argument That Previously Was Considered and
`Rejected by the Patent Office .............................................................. 47 
`Ground III Should Be Denied Because The Petition Concedes
`There is Not a Reasonable Likelihood That Petitioner Would
`Prevail .................................................................................................. 50 
`IX.  Conclusion ..................................................................................................... 51 
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`B. 
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`C. 
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`ii
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`IPR2016-01284
`U.S. Patent No. 6,900,221
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`TABLE OF AUTHORITIES
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`
`
`Page(s)
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`CASES
`Amgen Inc. v. Hoechst Marion Roussel, Inc.,
`
`314 F.3d 1313 (Fed. Cir. 2003) ..................................................................... 31
`
`Apotex Inc. v. Wyeth LLC,
`
`No. 2015-1871, (Fed. Cir. Aug. 16, 2016) .................................................... 38
`
`
`Atofina v. Great Lakes Chem. Corp.,
`
`441 F.3d 991 (Fed. Cir. 2006) ....................................................................... 46
`
`Boston Sci. Corp. v. Johnson & Johnson,
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`647 F.3d 1353 (Fed. Cir. 2011) ..................................................................... 37
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`Butamax Adv. Biofuels LLC v. Gevo, Inc., IPR2014-00581,
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`Paper 8 (Oct. 14, 2014) ............................................................................ 21, 49
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`Cisco Systems, Inc. v. C-Cation Techs., LLC, IPR2014-00454,
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`Paper 12 (Aug. 29, 2014) ............................................................................... 21
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`Denso Corp. v. Netlatch, LLC, IPR2015-00473,
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` Paper 9 (July 15, 2015) ................................................................................. 18
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`Funai Elec. Co. v. Gold Charm Ltd., IPR2015-01491,
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`Paper 15 (Dec. 28, 2015) ............................................................................... 48
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`Genzyme Corp. v. Genentech, Inc., IPR2016-00383,
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`Paper 16 (June 23, 2016) ............................................................................... 24
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`Geo. M. Martin Co. v. Alliance Machine Sys. Int’l,
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`618 F.3d 1294 (Fed. Cir. 2010) ..................................................................... 31
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`In re Magnum Oil Tools Int’l, No. 2015-1300,
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`2016 WL 3974202 (Fed. Cir. July 25, 2016) .......................................... 21, 38
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`iii
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`Integrated Global Concepts, Inc. v. Advanced Messaging Techs., Inc.,
`IPR2014-01027, Paper 16 (Dec. 22, 2014) ................................................... 49
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`IPR2016-01284
`U.S. Patent No. 6,900,221
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`InTouch Techs. v. VGO Commc’ns,
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`751 F.3d 1327 (Fed. Cir. 2014) ......................................................... 18, 23, 31
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`Kinetic Tech., Inc. v. Skyworks Solutions, Inc.,
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`IPR2014-00429, Paper 8 (Sept. 23, 2014) ....................................................... 6
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`Moses Lake Indus., Inc. v. Enthone, Inc., IPR2014-00243,
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`2014 WL 2810484 (June 18, 2014) ............................................................... 46
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`Ortho-McNeil-Janssen Pharm., Inc. v. Watson Labs., Inc.,
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`Case No. 08-cv-5103-SRC, 2011 WL 254313
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`(D.N.J. Jan. 25, 2011) .................................................................................... 46
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`OSI Pharms., Inc. v. Mylan Pharms. Inc., Case No. 09-cv-00185-SLR,
`Dkt. No. 239 (D. Del. May 1, 2012) ........................................ 3, 10, 11, 31, 47
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`Otsuka Pharm. v. Sandoz, Inc.,
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`678 F.3d 1280 (Fed. Cir. 2012) ..................................................................... 37
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`Pfizer Inc. v. Teva Pharm. U.S.A.,
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`882 F. Supp. 2d 643 (D. Del. 2012) .............................................................. 36
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`Ranbaxy Inc. v. Jazz Pharmaceuticals, Inc., IPR2016-00024,
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`Paper 10 (Apr. 12, 2016) ............................................................................... 25
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`S.S. Steiner, Inc. v. John I. Haas, Inc., IPR2014-01491,
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`Paper 7 (Mar. 16, 2015) ................................................................................. 22
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`Sanofi-Synthelabo v. Apotex, Inc.,
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`550 F.3d 1075 (Fed. Cir. 2008) ..................................................................... 46
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`Schrader-Bridgeport Int’l v. Continental Automotive Sys. US, Inc.,
`IPR2013-00014, Paper 12 (Mar. 13, 2013) ............................................. 33, 41
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`Tessera, Inc. v. Int’l Trade Comm’n,
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`646 F.3d 1357 (Fed. Cir. 2011) ..................................................................... 45
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`iv
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`Toyota Motor Corp. v. Am. Vehicular Sci. LLC, IPR2013-00421,
`Paper 15 (Jan. 13, 2014) .......................................................................... 33, 42
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`IPR2016-01284
`U.S. Patent No. 6,900,221
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`Unified Patents Inc. v. Olivistar, LLC, IPR2015-01216,
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`Paper 15 (Nov. 20, 2015) ............................................................................... 20
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`STATUTES AND REGULATIONS
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`37 C.F.R. § 1.104(e) ................................................................................................. 10
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`37 C.F.R. § 42.6(a)(3) .............................................................................................. 20
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`37 C.F.R. § 42.104(b)(5) .......................................................................................... 20
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`37 C.F.R. § 42.108 ..................................................................................................... 1
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`77 Fed. Reg. 48,612, (Aug. 14, 2012) ..................................................................... 21
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`35 U.S.C. § 314 .................................................................................................... 1, 51
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`35 U.S.C. § 325(d) ............................................................................................. 47, 48
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`v
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`I.
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`Introduction
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`IPR2016-01284
`U.S. Patent No. 6,900,221
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`Four related generic pharmaceutical entities (Apotex Inc., Apotex Corp.,
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`Apotex Pharmaceuticals Holdings Inc., and Apotex Holdings, Inc., collectively
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`“Apotex” or “Petitioner”) petition the Board to institute inter partes review of U.S.
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`Patent No. 6,900,221 (“the ’221 patent”) (Ex. 1001) based on legally deficient
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`grounds resting on demonstrably false premises. The Petition and accompanying
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`Declaration of Dr. Giuseppe Giaccone (“Giaccone Declaration”) (Ex. 1002) not
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`only reargue positions previously rejected by the Patent Office in issuing the
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`challenged claims and a federal district court in upholding the validity of one of the
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`challenged claims, but also distort the alleged prior art in an attempt to support the
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`petitioned grounds. The Petition, however, fails to establish that Petitioner is
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`reasonably likely to prevail in establishing the unpatentability of any challenged
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`claim. Accordingly, the Board should decline to institute inter partes review.
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`See 35 U.S.C. § 314; 37 C.F.R. § 42.108.
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`Petitioner has challenged claims 44-47 and 53 of the ’221 patent. The
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`challenged claims are directed to methods of treating certain hyperproliferative
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`disorders by administering erlotinib. More specifically, the challenged claims,
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`inter alia, recite a method for the treatment of non-small cell lung cancer
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`(“NSCLC”) comprising administering a therapeutically effective amount of a
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`1
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`pharmaceutical composition of erlotinib and a carrier.1 See, e.g., the ’221 patent,
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`IPR2016-01284
`U.S. Patent No. 6,900,221
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`claim 44-47, 53 (Ex. 1001). Erlotinib is the active pharmaceutical ingredient of
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`Tarceva®, Patent Owner’s successful NSCLC drug product.
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`The Petition asserts three invalidity grounds, none of which should be
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`instituted.
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`First, Petitioner asserts that claims 44-46 and 53 are obvious over Schnur
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`(Ex. 1009) in view of the OSI 10-K (Ex. 1011) or Gibbs (Ex. 1010).2 Schnur
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`discloses a genus of thousands of 4-anilinoquinazoline compounds that are
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`purported to be useful in the treatment of hyperproliferative disorders, and
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`identifies erlotinib among more than 100 specifically exemplified compounds in
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`the genus. See Schnur col. 1 ll. 8-10, col. 2 ll. 1-65 (Ex. 1009). But, as the Patent
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`Office and a prior federal district court both have concluded, Schnur does not
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`1 The Petition does not allege that any reference teaches or suggests any of the
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`disorders listed in claim 44 other than NSCLC and does not reference these
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`disorders at all, even in the supporting claim charts.
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`2 See U.S. Patent No. 5,747,498 (hereinafter “Schnur” or Ex. 1009); Jackson B.
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`Gibbs, Anticancer drug targets: growth factors and growth factor signaling, 105 J.
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`Clinical Investigation 9 (2000) (hereinafter “Gibbs” or Ex. 1010); Form 10-K for
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`OSI Pharmaceuticals Inc. (hereinafter “the OSI 10-K” or Ex. 1011).
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`2
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`disclose the use of any compound, much less erlotinib, for the treatment of
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`IPR2016-01284
`U.S. Patent No. 6,900,221
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`NSCLC. See, e.g., Statement of Reasons for Allowance for U.S. Patent Appl’n
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`No. 09/711,272, at 2 (June 18, 2003) (Ex. 1006); OSI Pharms., Inc. v. Mylan
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`Pharms. Inc., Case No. 09-cv-00185-SLR, Dkt. No. 239, at 37 (D. Del. May 1,
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`2012) (Ex.1028). Contrary to Petitioner’s characterization of both the OSI 10-K
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`and Gibbs as disclosing that erlotinib had entered Phase II clinical trials for the
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`treatment of NSCLC, thereby allegedly supplying the teaching missing from
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`Schnur, the OSI 10-K and Gibbs do not include such disclosure. As discussed in
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`detail below, at most, these references disclose that Phase I trials to assess safety
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`and pharmacokinetics of CP-358,774 (a clinical candidate that Petitioner fails to
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`demonstrate corresponds to erlotinib) have been completed, and a Phase II trial in
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`an undisclosed indication has commenced. Importantly, the first Phase II trial
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`evaluating erlotinib in NSCLC patients was not even initiated until after the filing
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`date of the OSI 10-K and the publication date of Gibbs. As explained below, the
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`Petition fails to demonstrate that a person of ordinary skill in the art (“POSA”)
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`would have been motivated to combine Schnur with the limited disclosures of the
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`OSI 10-K or Gibbs to arrive at the claimed inventions. The Petition also fails to
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`establish that a POSA would have had a reasonable expectation of success in
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`treating NSCLC with erlotinib—particularly given the limited disclosures of the
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`OSI 10-K and Gibbs and the lack of predictability in identifying which compounds
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`3
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`would be effective NSCLC treatments. Accordingly, Petitioner has failed to meet
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`U.S. Patent No. 6,900,221
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`its burden of establishing a reasonable likelihood that it will prevail on at least one
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`claim based on either of the alternative combinations presented in Ground I.
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`Second, Petitioner asserts that claim 47 (a dependent claim directed to the
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`use of erlotinib in treating tumors that express EGFRvIII) is obvious over Schnur
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`and Gibbs or Wakeling (Ex. 1013), in view of Moscatello (Ex. 1014).3 Wakeling
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`and Moscatello disclose in vitro data for compounds that are structurally distinct
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`from the genus described in Schnur. The Petition fails to demonstrate that a POSA
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`would have been motivated to combine Schnur’s teachings with references
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`regarding in vitro testing of different compounds, let alone have a reasonable
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`expectation of success in achieving the claimed invention by doing so—especially
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`given that a POSA would have understood that small structural differences
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`between compounds often correspond to significant differences in activity and
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`3 See A.E. Wakeling et al., Specific inhibition of epidermal growth factor receptor
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`tyrosine kinase by 4-anilinoqninazolines, 38 Breast Cancer Research Treatment 67
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`(1996) (hereinafter “Wakeling” or Ex. 1013); David K. Moscatello et al.,
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`Constitutive Activation of Phosphatidylinositol 3-Kinase by a Naturally Occurring
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`Mutant Epidermal Growth Factor Receptor, 273 J. Biological Chemistry 200
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`(1998) (hereinafter “Moscatello” or Ex. 1014).
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`4
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`other properties. Accordingly, Petitioner also has failed to meet its burden of
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`IPR2016-01284
`U.S. Patent No. 6,900,221
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`establishing a reasonable likelihood that it will prevail on at least one claim based
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`on either of the alternative combinations presented in Ground II.4
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`Third, Petitioner presents anticipation by Schnur as an “alternative”
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`invalidity ground. Petitioner, however, makes no attempt to apply the proper legal
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`standard to try to establish that Schnur anticipates the challenged claims. As
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`Petitioner acknowledges, anticipation by Schnur was expressly considered and
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`rejected by both a federal district court in prior litigation (see Pet. at 11 (citing Ex.
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`1028 at 36-37)), and the Patent Office during prosecution of the ’221 patent, (see
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`Pet. at 7-8 (citing Ex. 1004 at 10-11; Ex. 1005 at 24; Ex. 1006 at 1006-006).
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`Moreover, the Schnur anticipation ground contradicts other arguments Petitioner
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`makes in the Petition, and should be rejected on that basis alone. The Petition
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`itself acknowledges its inability to establish a reasonable likelihood of prevailing
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`with respect to anticipation by Schnur. See Pet. at 45 (“Schnur do[es] not
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`4 Each of Grounds I and II includes alternative combinations. The Petition does
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`not even argue that the alternatives within each ground are not redundant. At a
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`minimum, each of Grounds I and II should be limited to one of the redundant
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`alternative combinations.
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`5
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`expressly identify NSCLC as a treated hyperproliferative disorder.”). Accordingly,
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`IPR2016-01284
`U.S. Patent No. 6,900,221
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`Ground III also should be denied.
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`Each of the Grounds in the Petition thus falls short of providing the
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`“articulated reasoning with rational underpinning” necessary to support a legal
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`conclusion of anticipation or obviousness. Kinetic Tech., Inc. v. Skyworks
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`Solutions, Inc., IPR2014-00529, Paper 8 at 16 (Sept. 23, 2014). Petitioner has not
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`established a reasonable likelihood of prevailing on any of its anticipation or
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`obviousness grounds. Accordingly, inter partes review should not be instituted.
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`II. Background
`A.
`State of the Art
`During the 1980s and 1990s, the chemotherapy treatments available for
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`NSCLC were highly toxic and had many limitations. See, e.g., J. Cosaert & E.
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`Quoix, Platinum drugs in the treatment of non-small-cell lung cancer, 87 British J.
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`Cancer 825 (2002) (Ex. 2001). For example, prior to the invention of the ’221
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`patent, docetaxel (a chemotherapy treatment) was the only drug known to prolong
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`the survival of NSCLC patients whose disease progressed after the frontline
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`cisplatin-based chemotherapy, and there was almost no effective option for patients
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`whose NSCLC progressed after being treated with docetaxel or who were not
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`eligible for second-line chemotherapy. See Hirotsugu Kenmotsu & Yusuke
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`Tanigawara, Pharmacokinetics, dynamics and toxicity of docetaxel: Why the
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`6
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`Japanese dose differs from the Western dose, 106 Cancer Sci. 497 (2015) (Ex.
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`U.S. Patent No. 6,900,221
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`2002). In addition, docetaxel was associated with toxicities similar to other
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`traditional chemotherapy treatments.
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`A number of companies (including Pfizer and OSI) had initiated research
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`efforts to investigate the potential use of an inhibitor of epidermal growth factor
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`receptor (“EGFR”) for the treatment of certain cancers. See, e.g., Gibbs at 10
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`(Ex. 1010). No one knew, however, whether inhibition of EGFR would result in
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`the treatment of any given cancer. In vitro data and general results from mouse
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`xenograft models were not predictive of a particular compound’s therapeutic
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`activity against a particular cancer in patients, and did not provide information
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`regarding the compound’s safety or pharmacokinetic properties. Accordingly,
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`many compounds that inhibited EGFR in vitro failed to provide a safe and
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`effective therapeutic treatment for cancer patients. See, e.g., Elise A. Sudbeck
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`et al., Tyrosine Kinase Inhibitors Against EGF Receptor-Positive Malignancies,
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`166 Methods in Molecular Biology 193 (2001) (Ex. 2003).
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`B. Clinical Development and Approval of Tarceva®
`After the discovery of the EGFR inhibitor erlotinib, OSI and Pfizer began to
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`develop the compound as a possible cancer treatment. In order to evaluate the
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`safety and pharmacokinetics of erlotinib, OSI and Pfizer conducted Phase I studies
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`in patients with solid cancer tumors. These Phase I trials did not study the
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`treatment of any particular cancer (including NSCLC) with erlotinib. See the OSI
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`U.S. Patent No. 6,900,221
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`10-K at 1011-022 (Ex. 1011) (“During Phase I, when the drug is initially given to
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`human subjects, the product is tested for safety, dosage tolerance, absorption,
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`metabolism, distribution and excretion.”); id. at 1011-006 (Ex. 1011) (describing
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`completion of Phase I “safety trials”).
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`After completing Phase I trials, OSI and Pfizer initiated Phase II studies
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`directed to the treatment of specific cancers. The first patient in the Phase II
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`NSCLC trial was dosed on January 25, 2000. See Center for Drug Evaluation and
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`Research Approval Package for: Application Number 21-743 for Tarceva™
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`(erlotinib hydrochloride), Statistical Review(s), available at
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`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-
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`743_Tarceva_StatR.PDF (“Tarceva Approval Package”) at 2004-0006 (Ex. 2004).
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`Following numerous additional trials, the FDA first approved Tarceva® for
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`the treatment of patients with locally advanced or metastatic NSCLC after failure
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`of at least one prior chemotherapy regimen in 2004. Tarceva® is also approved for
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`the maintenance treatment of patients with locally advanced or metastatic NSCLC
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`whose disease has not progressed after four cycles of platinum-based first-line
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`chemotherapy, and for the treatment of metastatic NSCLC patients whose tumors
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`have EGFR exon 19 deletions or exon 21 substitution mutations as detected by an
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`FDA-approved test. See Package Insert for Tarceva® (erlotinib) (revised
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`September 2016) (Ex. 2005).
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`C. The ’221 Patent
`The ’221 patent claims priority to three U.S. provisional applications:
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`U.S. Provisional Application No. 60/164,907, filed on November 11, 1999; U.S.
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`Provisional Application No. 60/193,191, filed on March 30, 2000; and U.S.
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`Provisional Application No. 60/206,420, filed on May 23, 2000. The ’221 patent
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`issued from U.S. Application No. 09/711,272, filed on November 9, 2000 (“the
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`’272 application”).
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`The Schnur reference was before the Patent Office during prosecution of the
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`’272 application and explicitly considered by the Examiner. In the Examiner’s
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`Statement of Reasons for Allowance, the Examiner stated that what is now
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`independent claim 44 was allowed because the treatment of the specific cancers
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`recited in that claim “are not found in Schnur (’498).” Prosecution of U.S.
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`Application No. 09/711,272, Statement of Reasons for Allowance, at 2 (June 18,
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`2003) (Ex. 1006).5 The ’221 patent issued on May 31, 2005. See the ’221 patent
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`(Ex. 1001).
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`5 Petitioner suggests that the only reason the challenged claims were allowed to
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`issue “was because Schnur does not include a verbatim disclosure of NSCLC,” and
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`9
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`IPR2016-01284
`U.S. Patent No. 6,900,221
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`D. District Court Litigation
`Patent Owner successfully asserted the ’221 patent against multiple generic
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`entities in prior Hatch-Waxman litigation in federal district court. See OSI
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`Pharms., Inc. v. Mylan Pharms. Inc., Case No. 09-cv-00185-SLR, Dkt. No. 239
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`(Ex. 1028). At trial, Defendants asserted that claim 53 was invalid as anticipated
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`by Schnur and obvious in view of Schnur and supporting references, including the
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`OSI 10-K. Schnur is a component of each of the Petition’s three invalidity grounds
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`and Schnur is combined with OSI 10-K in Ground I. See Pet. at 4.
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`Following trial, the district court issued a comprehensive opinion holding
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`claim 53 valid based on its findings that Schnur does not disclose the use of
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`erlotinib (or any other compound) for the treatment of NSCLC because Schnur
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`only “lists ‘lung’ cancer among possible cancers for which 100 disclosed
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`compounds (including erlotinib) are useful” and that no “persuasive rationale for
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`why a person of ordinary skill in the art would have been motivated to select
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`asserts that, because Patent Owner did not respond to the Notice of Allowance, it
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`has acquiesced to this reason. Pet. at 26-27. Petitioner’s characterization of the
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`Patent Office’s Reasons for Allowance is not accurate. In any event, as
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`Petitioner’s own citation to 37 C.F.R. § 1.104(e) indicates, any alleged
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`acquiescence is to be determined by the Board or a court on a case-by-case basis.
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`10
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`erlotinib for the treatment of NSCLC, a specific subset of ‘lung’ cancer generally”
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`IPR2016-01284
`U.S. Patent No. 6,900,221
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`was offered. See OSI Pharms., Inc. v. Mylan Pharms. Inc., Case No. 09-cv-00185-
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`SLR, Dkt. No. 239, at 45-46 (Ex. 1028). The district court found that a person of
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`skill in the art would not have had a reasonable expectation of success using
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`erlotinib for the treatment of NSCLC, including because “there is poor correlation
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`between xenograft models and the treatment of actual human tumors.” See id. at
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`45 (Ex. 1028). The district court also found Patent Owner’s evidence on objective
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`indicia of non-obviousness “persuasive.” See id. at 46 (Ex. 1028). The district
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`court noted that “[d]espite a need in the art for an effective drug for treating
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`NSCLC, there exists an almost insurmountable failure rate for new drug
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`candidates.” Id. (Ex. 1028). Thus, the district court found that claim 53 was
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`neither anticipated by Schnur, nor rendered obvious by Schnur in combination with
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`any supporting references, including the OSI 10-K.
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`E. Alleged Prior Art Relied on by Petitioner
`The Petition presents three invalidity grounds based on five references
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`alleged to be prior art to the ’221 patent. But, in many instances, Petitioner’s
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`reliance on these references depends on a mischaracterization of their disclosures.
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`Schnur. U.S. Patent No. 5,747,498 (“Schnur”) discloses a class of
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`thousands of “4-(substituted phenylamino) quinazoline derivatives which are
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`useful in the treatment of hyperproliferative diseases, such as cancers, in
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`11
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`mammals.” Schnur col. 1, ll. 9-11 (Ex. 1009); id. col. 2, ll. 1-65 (Ex. 1009)
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`(setting forth the backbone structure of compounds of Formula I and possible
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`substituents in four different positions). Schnur identifies 12 types of cancers for
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`possible treatment with compounds of the claimed genus. See Schnur claim 14
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`(Ex. 1009) (“wherein said cancer is brain, lung, squamous cells, bladder, gastric,
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`pancreatic, breast, head, neck, oesophageal, gynecological or thyroid”). None of
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`the cancers enumerated in Schnur is the same as those identified in the challenged
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`claims of the ’221 patent, which list NSCLC, pediatric malignancies, cervical and
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`other tumors caused or promoted by human papilloma virus, Barrett’s esophagus
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`or neoplastic cutaneous diseases (claim 44), or only NSCLC (claim 53). See the
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`’221 patent claims 44-47 and 53 (Ex. 1001). Moreover, while erlotinib (N-(3-
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`ethynylphenyl)-6,7- bis(2-methoxyethoxy)-4-quinazolinamine) is exemplified in
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`Schnur, it is one of 105 compounds in working examples in the specification, and
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`one of 49 compounds recited in claim 8 of Schnur. Schnur includes no specific
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`teaching to use erlotinib, as opposed to other compounds of the genus, to treat any
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`of the cancers disclosed in Schnur, let alone any of the cancers in the challenged
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`claims of the ’221 patent.
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`The OSI 10-K. The Petition inaccurately characterizes the OSI 10-K, filed
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`in December 1998, as providing “disclosure that erlotinib completed Phase I
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`12
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`clinical studies and was in the process of Phase II clinical studies for an NSCLC
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`indication.” Pet. at 19 (emphases added). In fact, the OSI 10-K states:
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`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.
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`The OSI 10-K at 1011-005 to 06 (Ex. 1011) (emphases added).
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`Thus, the OSI 10-K refers generally to a Phase II study of a “clinical
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`candidate, CP-358,774”—not “erlotinib” or its chemical name—in “cancer
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`patients.” See id. (Ex. 1011). The OSI 10-K does not state that a Phase II trial
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`specific to NSCLC is ongoing—which, as noted above, it was not. Nor does the
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`OSI 10-K provide results of such a study that would indicate the clinical candidate
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`under investigation had been determined to be therapeutically effective in treating
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`any particular cancer, let alone NSCLC patients.
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`Gibbs. The Petition mischaracterizes Gibbs. The Petition states that “Gibbs
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`discloses . . . that erlotinib had entered Phase II clinical trials . . . [and] that
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`erlotinib was shown to have good anti-cancer activity ‘with an acceptable
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`13
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`therapeutic index, particularly in patients with NSCLC.’” Petition at 18. But the
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`Petition’s characterization of Gibbs ignores the context of the statements in Gibbs.
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`With respect to CP-358,774—not “erlotinib,” as Petitioner suggests—Gibbs
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`states:
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`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.
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`Gibbs at 10, col. 1 (Ex. 1010).
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`Gibbs is a review article broadly addressing growth factors and growth
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`factor signaling as anticancer drug targets. Gibbs at 9, Title, Abstract (Ex. 1010).
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`A POSA would observe that Gibbs includes no data regarding CP-358,774, and
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`that Gibbs’ statement that “these compounds appear to have good anti-cancer
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`activity in preclinical models” is a general statement that does not explicitly
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`reference CP-358,774 or ZD-1839 and is not supported by any citation. Gibbs at
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`14
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`10 (Ex. 1010). Moreover, a POSA would observe that the only support Gibbs
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`provides for the above-quoted statements is references 12 and 13. Reference 12
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`relates to ZD-1839, exclusively, and indicates that “ZD1839 has excellent oral
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`bioavailability and shows antitumor activity in a broad range of human solid tumor
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`xenografts implanted in nude mice in the dose range 12.5-200 mg/kg once per day
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`orally. Sensitive tumors include . . . A549 NSCLC . . . .” See J.R. Woodburn
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`et al., ZD1839, an epidermal growth factor tyrosine kinase inhibitor selected for
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`clinical development, 38 Proceedings Am. Assoc. for Cancer Research 633 (1997)
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`(Ex. 2006). Reference 13, which does relate to CP-358,774, has nothing to do with
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`studies in NSCLC patients, and instead reports on mouse xenograft studies in cell
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`lines that are not NSCLC. See James D. Moyer et al., Induction of Apoptosis and
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`Cell Cycle Arrest by CP-358,774, an Inhibitor of Epidermal Growth Factor
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`Receptor Tyrosine Kinase, 57 Cancer Research 4838, 4838 (1997) (Ex. 1016).
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`Accordingly, a POSA would have appreciated that—to the extent Gibbs’ statement
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`concerning “an acceptable therapeutic index, particularly in patients with NSCLC”
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`in “preclinical models” could be understood at all—contrary to Petitioner’s
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`assertion, it could only be about ZD-1839, not CP-358,774.
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`T