Filed October 17, 2016
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________________________________
`
`
`
`MYLAN PHARMACEUTICALS, INC.
`Petitioner
`
`v.
`
`ASTRAZENECA AB
`Patent Owner.
`______________________________________________
`
`Case IPR2016-01316
`U.S. Patent No. 6,774,122
`______________________________________________
`
`
`
`
`
`PATENT OWNER’S PRELIMINARY RESPONSE
` TO PETITION FOR INTER PARTES REVIEW
` OF U.S. PATENT NO. 6,774,122
`
`
`
`

`
`I.
`II.
`
`Page
`INTRODUCTION .......................................................................................... 1
`THE ’122 PATENT ........................................................................................ 5
`A.
`Specification ......................................................................................... 5
`B.
`Claims ................................................................................................... 6
`C.
`Prosecution history ............................................................................... 8
`III. PERSON OF ORDINARY SKILL IN THE ART ....................................... 11
`IV. CLAIM CONSTRUCTION ......................................................................... 12
`A. Malignant diseases of the breast ......................................................... 12
`B.
`Sufficient amount of castor oil vehicle .............................................. 12
`C. Whereby a therapeutically significant blood plasma fulvestrant
`concentration of at least 2.5 ngml-1 is attained for at least 2
`weeks after injection ........................................................................... 13
`Therapeutically significant ................................................................. 16
`D.
`Attained .............................................................................................. 16
`E.
`STATE OF THE ART .................................................................................. 17
`A. McLeskey [Ex. 1005] and Howell 1996 [Ex. 1006] .......................... 17
`B. Active: A skilled artisan had no reason to start with fulvestrant ....... 20
`1.
`Petitioner ignores the many other treatment options
`available to the skilled artisan .................................................. 21
`Fulvestrant had not been established to be an effective
`treatment ................................................................................... 23
`Critical questions remained about the amount of fulvestrant to
`deliver and how .................................................................................. 24
`1.
`Amount: Therapeutically effective blood plasma levels ......... 24
`2.
`Administration: Route, excipients, and result intertwined ...... 25
`3.
`Claimed combination of excipients was unconventional ........ 29
`VI. THE ’122 PATENT IS VALID AND NOT OBVIOUS .............................. 32
`A.
`Law of Obviousness ........................................................................... 32
`
`V.
`
`2.
`
`C.
`
`TABLE OF CONTENTS
`
`Case IPR2016-01316
`
`
`i
`
`

`
`Case IPR2016-01316
`
`
`TABLE OF CONTENTS
`(continued)
`
`Page
`B. Ground One: McLeskey ..................................................................... 34
`1. McLeskey describes the fulvestrant formulations as a
`“treatment failure”.................................................................... 39
`2. McLeskey utilizes a different route of administration
`(subcutaneous) with vastly different subjects (genetically
`engineered mice) ...................................................................... 42
`3. McLeskey provides no pharmacokinetic data nor any
`suggestion of the specific blood plasma levels and
`durations claimed ..................................................................... 46
`4. McLeskey does not disclose the “exact” formulation ............. 48
`C. Ground Two: McLeskey In Combination With Howell 1996 ........... 49
`1.
`No reason to combine McLeskey with Howell 1996 .............. 50
`2.
`No reasonable expectation of success ...................................... 53
`VII. OBJECTIVE INDICIA DEMONSTRATE THE NONOBVIOUS
`NATURE OF THE CLAIMED METHOD OF TREATMENT .................. 58
`VIII. CONCLUSION ............................................................................................. 60
`
`ii
`
`

`
`TABLE OF AUTHORITIES
`
`Case IPR2016-01316
`
`
`Page(s)
`
`Cases
`Apple, Inc. v. Contentguard Holdings, Inc.,
`IPR2015-00357, 2015 WL 9899009 (P.T.A.B. June 29, 2015) ......................... 46
`
`Apple, Inc. v. Contentguard Holdings, Inc.,
`IPR2015-00449, 2015 WL 4760572 (P.T.A.B. July 15, 2015) .......................... 38
`
`BioDelivery Scis. Int’l, Inc. v. RB Pharms. Ltd.,
`IPR2014-00325, 2015 WL 4045328 (P.T.A.B. June 30, 2015) ......................... 15
`
`Boehringer Ingelheim Int’l GmbH v. Biogen Inc.,
`IPR2015-00418, 2015 WL 4467391 (P.T.A.B. July 13, 2015) ................... 38, 54
`
`Bumble Bee Foods, LLC v. Kowalski,
`IPR2014-00224, 2014 WL 2584188 (P.T.A.B. June 5, 2014) ........................... 53
`
`Daiichi Sankyo Co. v. Matrix Labs., Ltd.,
`619 F.3d 1346 (Fed. Cir. 2010) .......................................................................... 55
`
`Eisai Co. Ltd. v. Dr. Reddy’s Labs., Ltd.,
`533 F.3d 1353 (Fed. Cir. 2008) .......................................................................... 55
`
`General Plastic Indus. Co. v. Canon Inc.,
`IPR2015-01954, 2016 WL 1084221 (P.T.A.B. Mar. 9, 2016) ........................... 46
`
`Griffin v. Bertina,
`285 F.3d 1029 (Fed. Cir. 2002) .......................................................................... 15
`
`Hoffer v. Microsoft Corp.,
`405 F.3d 1326 (Fed. Cir. 2005) .......................................................................... 13
`
`In re Cyclobenzaprine,
`676 F.3d 1063 (Fed. Cir. 2012) ............................................................. 33, 34, 54
`
`In re NTP, Inc.,
`654 F.3d 1279 (Fed. Cir. 2011) .......................................................................... 51
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ..................................................................................... 34, 50
`
`iii
`
`

`
`TABLE OF AUTHORITIES
`(continued)
`
`Case IPR2016-01316
`
`
`Page(s)
`
`Lupin Ltd. v. Pozen Inc.,
`IPR2015–01774, 2016 WL 1081583 (P.T.A.B. Mar. 1, 2016) ............. 41, 42, 54
`
`Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) .......................................................................... 34
`
`Panduit Corp. v. Dennison Mfg. Co.,
`810 F.2d 1561 (Fed. Cir. 1987) .......................................................................... 33
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .......................................................................... 57
`
`Unigene Labs., Inc. v. Apotex, Inc.,
`655 F.3d 1352 (Fed. Cir. 2011) ................................................................... 33, 38
`
`Universal Remote Control, Inc. v. Uei Cayman, Inc.,
`IPR2014-01111, 2014 WL 6737921 (P.T.A.B. Nov. 24, 2014) ......................... 45
`
`Statutes
`
`35 U.S.C. § 103(a) ................................................................................................... 32
`
`Regulations
`
`37 C.F.R. § 42.104(b)(2) ................................................................................... 37, 48
`
`
`
`iv
`
`

`
`Exhibit
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`
`2008
`
`2009
`
`2010
`
`2011
`
`2012
`
`Case IPR2016-01316
`
`
`LIST OF EXHIBITS
`
`
`Description
`Declaration of Lisbeth Illum, Ph.D. In Support Of Patent
`Owner’s Preliminary Response
`Declaration of John F. R. Robertson, M.D. In Support Of Patent
`Owner’s Preliminary Response
`Declaration of Ronald J. Sawchuk, Ph.D. In Support Of Patent
`Owner’s Preliminary Response
`Angelo Di Leo et al., Results of the CONFIRM Phase III Trial
`Comparing Fulvestrant 250 mg With Fulvestrant 500 mg in
`Postmenopausal Women With Estrogen Receptor-Positive
`Advanced Breast Cancer, 28 J. Clin. Oncol. 4594 (2010) (“Di
`Leo 2010”)
`Angelo Di Leo et al., Final Overall Survival: Fulvestrant 500 mg
`vs 250 mg in the Randomized CONFIRM Trial, 106 J. Nat’l
`Cancer Inst. 1 (2014) (“Di Leo 2014”)
`S. Ohno et al., Three dose regimens of fulvestrant in
`postmenopausal Japanese women with advanced breast cancer:
`results from a double-blind, phase II comparative study, 21
`Annals Oncol. 2342 (2010) (“FINDER 1”)
`Kathleen I. Pritchard et al., Results of a phase II study
`comparing three dosing regimens of fulvestrant in
`postmenopausal women with advanced breast cancer
`(FINDER2), 123 Breast Cancer Res. & Treat. 453 (2010)
`(“FINDER 2”)
`Robert T. Greenlee et al., Cancer Statistics, 2000, 50 CA Cancer
`J. Clin. 7 (2000) (“Greenlee”)
`J.F.R. Robertson, Oestrogen receptor: a stable phenotype in
`breast cancer, 73 Brit. J. Cancer 5 (1996) (“Robertson 1996”)
`Monica Fornier et al., Update on the Management of Advanced
`Breast Cancer, 13 Oncology 647 (1999) (“Fornier”)
`V. Craig Jordan, Alternate Antiestrogens and Approaches to the
`Prevention of Breast Cancer, 22 J. Cell. Biochem. 51 (Supp.
`1995) (“Jordan Supp. 1995”)
`Gabriel N. Hortobagyi et al., Anastrozole (Arimidex®), a New
`Aromatase Inhibitor for Advanced Breast Cancer: Mechanism of
`Action and Role in Management, 16 Cancer Investigation 385
`(1998) (“Hortobagyi Cancer Investigation 1998”)
`
`v
`
`

`
`Exhibit
`2013
`
`2014
`
`2015
`
`2016
`
`2017
`
`2018
`
`2019
`
`2020
`
`2021
`
`2022
`
`2023
`
`2024
`
`2025
`
`Case IPR2016-01316
`
`
`Description
`S.R.D. Johnston et al., The novel anti-oestrogen idoxifene inhibits
`the growth of human MCF-7 breast cancer xenografts and
`reduces the frequency of acquired anti-oestrogen resistance, 75
`Brit. J. Cancer 804 (1997) (“Johnston 1997”)
`Kathleen Pritchard, Effects on Breast Cancer: Clinical Aspects,
`in Estrogens and Antiestrogens: Basic and Clinical Aspects 175
`(R. Lindsay et al. eds., 1997) (“Pritchard 1997”)
`Aman U. Buzdar et al., Tamoxifen and Toremifene in Breast
`Cancer: Comparison of Safety and Efficacy, 16 J. Clin. Oncol.
`348 (1998) (“Buzdar Clin. Oncol. 1998”)
`Aman U. Buzdar et al., Update on Endocrine Therapy for Breast
`Cancer, 4 Clin. Cancer Res. 527 (1998) (“Buzdar Clin. Cancer
`Res. 1998”)
`V. Craig Jordan, TAMOXIFEN: Toxicities and Drug Resistance
`During the Treatment and Prevention of Breast Cancer, 35 Ann.
`Rev. Pharmacol. Toxicol. 195 (1995) (“Jordan 1995”)
`Monica Morrow et al., Molecular Mechanisms of Resistance to
`Tamoxifen Therapy in Breast Cancer, 128 Arch. Surg. 1187
`(1993) (“Morrow”)
`Valerie J. Wiebe et al., Tamoxifen resistance in breast cancer,
`14 Crit. Revs. Oncol. Hematol. 173 (1993) (“Wiebe”)
`V. Craig Jordan, The Strategic Use of Antiestrogens to Control
`the Development and Growth of Breast Cancer, 70 Cancer 977
`(Supp. 1992) (“Jordan Supp. 1992”)
`V. Craig Jordan, The Role of Tamoxifen in the Treatment and
`Prevention of Breast Cancer, Curr. Probl. Cancer 134 (1992)
`(“Jordan 1992”)
`Susan E. Minton, New Hormonal Therapies for Breast Cancer, 6
`Cancer Control J. 1 (1999) (“Minton”)
`T.A. Grese et al., Selective Estrogen Receptor Modulators
`(SERMs), 4 Current Pharm. Design 71 (1998) (“Grese 1998”)
`Gabriel N. Hortobagyi, Treatment of Breast Cancer, 339 New
`Eng. J. Med. 974 (1998) (“Hortobagyi New Eng. J. Med. 1998”)
`Shigeru Masamura et al., Aromatase inhibitor development for
`treatment of breast cancer, 33 Breast Cancer Res. & Treat. 19
`(1994) (“Masamura 1994”)
`
`vi
`
`

`
`Exhibit
`2026
`
`2027
`
`2028
`
`2029
`
`2030
`
`2031
`
`2032
`
`2033
`
`2034
`
`2035
`
`Case IPR2016-01316
`
`
`Description
`Gary J. Kelloff et al., Aromatase Inhibitors as Potential Cancer
`Chemopreventives, 7 Cancer Epidemiol., Biomarkers &
`Prevention 65 (1998) (“Kelloff 1998”)
`M. Dukes et al., Effects of a non-steroidal pure antioestrogen,
`ZM 189,154, on oestrogen target organs of the rat including
`bones, J. Endocrinol. 339 (1994) (“Dukes 1994”)
`A. Howell et al., Fulvestrant, Formerly ICI 182,780, Is as
`Effective as Anastrozole in Postmenopausal Women With
`Advanced Breast Cancer Progressing After Prior Endocrine
`Treatment, 20 J. Clin. Oncol. 3396 (2002) (“Howell 2002”)
`C.K. Osborne et al., Double-Blind Randomized Trial Comparing
`the Efficacy and Tolerability of Fulvestrant Versus Anastrozole
`in Postmenopausal Women with Advanced Breast Cancer
`Progressing on Prior Endocrine Therapy: Results of a North
`American Trial, 20 J. Clin. Oncol. 3386 (2002) (“Osborne 2002”)
`John F. Robertson et al., Comparison of the Short-Term
`Biological Effects of 7-α-[9- (4,4,5,5,5-
`pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, (10)-triene-3,17β-
`diol (Faslodex) versus Tamoxifen in Postmenopausal Women
`with Primary Breast Cancer, 61 Cancer Res. 6739 (2001)
`(“Robertson Cancer Res. 2001”)
`John F.R. Robertson et al., Pharmacokinetics of a Single Dose of
`Fulvestrant Prolonged-Release Intramuscular Injection in
`Postmenopausal Women Awaiting Surgery for Primary Breast
`Cancer, Clin. Ther. 1440 (2003) (“Robertson Clin. Ther. 2003”)
`Fernand Labrie, Activity and Safety of the Antiestrogen EM-800,
`the Orally Active Precursor of Acolbifene, in Tamoxifen-Resistant
`Breast Cancer, 22 J. Clin. Oncol. 864 (2004) (“Labrie 2004”)
`P. Van de Velde et al., RU 58668: Further In Vitro And In Vivo
`Pharmacological Data Related to its Antitumoral Activity, 59 J.
`Steroid Biochem. Molec. Biol. 449 (1996) (“Van de Velde”)
`Fernand Labrie, EM-652 (SCH 57068), a third generation SERM
`acting as pure antiestrogen in the mammary gland and
`endometrium, 69 J. Steroid Biochem. & Molec. Biol. 51 (1999)
`(“Labrie 1999”)
`Gabriel N. Hortobagyi, Progress in Endocrine Therapy for Breast
`Carcinoma, 83 Cancer 1 (1998) (“Hortobagyi 1998”)
`
`vii
`
`

`
`Exhibit
`2036
`
`2037
`
`2038
`
`2039
`
`2040
`
`2041
`
`2042
`2043
`
`2044
`
`2045
`
`2046
`
`2047
`
`2048
`2049
`
`2050
`
`Case IPR2016-01316
`
`
`Description
`J.F.R. Robertson et al., Onapristone, a Progesterone Receptor
`Antagonist, as First-line Therapy in Primary Breast Cancer, 35
`Eur. J. Cancer 214 (1999) (“Robertson 1999”)
`Gabriel Hortobagyi, What New Drugs, Biologics, and
`Treatment Approaches Show Promise in Breast Cancer?, 4
`Cancer Control J. 1 (Supp. 1997) (“Hortobagyi 1997”)
`M. Dowsett, Response to specific anti- oestrogen (ICI182780) in
`tamoxifen-resistant breast cancer, 345 Lancet 525 (1995)
`(“Dowsett 1995”)
`E.J. Thomas, The effects of ICI 182,780, a pure anti-oestrogen,
`on the hypothalamic-pituitary-gonadal axis and on endometrial
`proliferation in pre-menopausal women, 9 Hum. Reprod. 1991
`(1994) (“Thomas”)
`Anthony Howell et al., Recent advances in endocrine therapy of
`breast cancer, 315 Br. Med. J. 863 (1997) (“Howell 1997”)
`John F.R. Robertson et al., Duration of remission to ICI 182,780
`compared to megestrol acetate in tamoxifen resistant breast
`cancer, 6 Breast 186 (1997) (“Robertson 1997”)
`AACR Journals Online
`Declaration of Sandra McLeskey, Ph.D. (Oct. 1, 2014)
`(“McLeskey Declaration”)
`Innovative Research of America, Time Release Pellets for
`Biomedical Research, 2014 Product Catalog (“Innovative
`Research”)
`Physician’s Desk Reference, 53rd ed., 3425-28 (1999) (“PDR
`1999 Nolvadex®”)
`Physician’s Desk Reference, 53rd ed., 2025-28 (1999) (“PDR
`1999 Femara®”)
`R.J. Santen, Use of aromatase inhibitors in breast carcinoma, 6
`Endocrine-Related Cancer 75 (1999) (“Santen”)
`Zoladex® (goserelin acetate implant) (“Zoladex label”)
`AstraZeneca Pharmaceuticals LP v. Sagent Pharmaceuticals,
`Inc., No. 14-cv-03547-RMB-KMW, Trial Transcript (July 14,
`2016) (“July 14 Trial Tr.”)
`D.G. Bratherton, A comparison of two doses of tamoxifen
`(Nolvadex*) in postmenopausal women with advanced breast
`cancer: 10 mg bd versus 20 mg bd, 50 Br. J. Cancer 199 (1984)
`(“Bratherton”)
`
`viii
`
`

`
`Exhibit
`2051
`
`2052
`
`2053
`
`2054
`
`2055
`
`2056
`
`2057
`
`2058
`
`2059
`
`2060
`
`Case IPR2016-01316
`
`
`Description
`Adam Cohen, What does the investigator need to know about the
`drug?, Ch. 3, A Guide To Clinical Drug Research (1995)
`(“Cohen”)
`Stephanie Sweetana, Solubility Principles and Practices for
`Parenteral Drug Dosage Form Development, 50 PDA J. Pharm.
`Sci. & Tech. 330 (1996) (“Sweetana”)
`L. Fallowfield et al., Patients’ preference for administration of
`endocrine treatments by injection or tablets: results from a study
`of women with breast cancer, 17 Ann. Oncol. 205 (2006)
`(“Fallowfield 2006”)
`Suzanne C. Beyea et al., Administering IM Injections The Right
`Way, 96 A. J. Nursing 34 (1996) (“Beyea”)
`John F.R. Robertson et al., Activity of Fulvestrant 500 mg Versus
`Anastrozole 1 mg as First-Line Treatment for Advanced Breast
`Cancer: Results from the FIRST Study, 27 J. Clin. Oncol. 4530
`(2009) (“Robertson 2009”)
`John F.R. Robertson et al., Fulvestrant 500 mg versus
`anastrozole 1 mg for the first-line treatment of advanced breast
`cancer: follow-up analysis from the randomized ‘FIRST’ study,
`136 Breast Cancer Res. & Treat. 503 (2012) (“Robertson 2012”)
`John F.R. Robertson et al., Fulvestrant 500 mg versus
`Anastrozole as a First-line Treatment for Advanced Breast
`Cancer: Overall Survival from the Phase II ‘FIRST’ Study, 37th
`Annual San Antonio Breast Cancer Symposium, Publication No.
`S6-04 (2014) (“Robertson SABCS 2014”)
`Matthew J. Ellis et al., Fulvestrant 500 mg Versus Anastrozole 1
`mg for the First-Line Treatment of Advanced Breast Cancer:
`Overall Survival Analysis from the Phase II FIRST Study, J. Clin.
`Oncol. 1 (2015) (“Ellis 2015”)
`I. Vergote et al., Postmenopausal women who progress on
`fulvestrant (‘Faslodex’) remain sensitive to further endocrine
`therapy, 79 Breast Cancer Res. & Treat. 207 (2003) (“Vergote
`2003”)
`John F.R. Robertson et al., Pharmacokinetic Profile of
`Intramuscular Fulvestrant in Advanced Breast Cancer, 43 Clin.
`Pharmacokinet. 529 (2004) (“Robertson 2004”)
`
`ix
`
`

`
`Exhibit
`2061
`
`2062
`
`2063
`
`2064
`
`2065
`
`2066
`
`2067
`
`2068
`
`2069
`
`2070
`
`Case IPR2016-01316
`
`
`Description
`John F.R. Robertson et al., Fulvestrant versus Anastrozole for the
`Treatment of Advanced Breast Carcinoma in Postmenopausal
`Women: A Prospective Combined Analysis of Two Multicenter
`Trials, 98 Cancer 229 (2003) (“Robertson Cancer 2003”)
`Stephen Chia et al., Double-Blind Randomized Placebo
`Controlled Trial of Fulvestrant Compared with Exemestane
`After Prior Nonsteroidal Aromatase Inhibitor Therapy in
`Postmenopausal Women with Hormone Receptor-Positive,
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`Oncol. 1664 (2008) (“Chia 2008”)
`Stephen R.D. Johnston et al., Fulvestrant plus anastrozole or
`placebo versus exemestane alone after progression on non-
`steroisal aromatase inhibitors in postmenopausal patients with
`hormone-receptor-positive locally advanced or metastatic breast
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`trial, 14 Lancet Oncol. 989 (2013) (“Johnston 2013”)
`J.F.R. Robertson et al., Sensitivity to further endocrine therapy is
`retained following progression on first-line fulvestrant, 92 Breast
`Cancer Res. & Treat. 169 (2005) (“Robertson 2005”)
`S. Johnston, Fulvestrant and the sequential endocrine cascade
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`R. Jeffrey Baumann et al., Clomiphene Analogs with Activity In
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`Biochem. Pharmacol. 841 (1998) (“Baumann 1998”)
`Seppo Pyrhönen et al., High dose toremifene in advanced breast
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`Breast Cancer Res. & Treat. 223 (1994) (“Pyrhönen 1994”)
`Lars E. Stenbygaard, Toremifene and tamoxifen in advanced
`breast cancer - a double-blind cross-over trial, 25 Breast
`Cancer Res. & Treat. 57 (1993) (“Stenbygaard 1993”)
`
`x
`
`

`
`Exhibit
`2071
`
`2072
`
`2073
`
`2074
`
`2075
`
`2076
`
`2077
`
`2078
`
`2079
`
`2080
`
`2081
`
`2082
`
`Case IPR2016-01316
`
`
`Description
`John F.R. Robertson et al., A Good Drug Made Better: The
`Fulvestrant Dose-Response Story, 14 Clin. Breast Cancer 381
`(2014) (“Robertson 2014”)
`C. Barrios et al., The sequential use of endocrine treatment for
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`(2012) (“Barrios 2012”)
`J.F.R. Robertson et al., Endocrine treatment options for advanced
`breast cancer ‒ the role of fulvestrant, 41 Eur. J. Cancer 346
`(2005) (“Robertson Eur. J. Cancer 2005”)
`“Clinical Practice Guidelines in Oncology: Breast Cancer,”
`National Comprehensive Cancer Network, version 1, MS-16
`(2003) (“Clinical Practice Guidelines 2003”)
`I. Vergote et al., Fulvestrant, a new treatment option for
`advanced breast cancer: tolerability versus existing agents, 17
`Ann. Oncol. 200 (2006) (“Vergote 2006”)
`A. Agrawal, Bone turnover markers in postmenopausal breast
`cancer treated with fulvestrant ‒ A pilot study, 18 Breast 204
`(2009) (“Agrawal 2009”)
`Irene Kuter et al., Dose-dependent change in biomarkers during
`neoadjuvant endocrine therapy with fulvestrant: results from
`NEWEST, a randomized Phase II study, 133 Breast Cancer Res.
`& Treat. 237 (2012) (“Kuter 2012”)
`Aman U. Buzdar et al., Fulvestrant: Pharmacologic Profile
`Versus Existing Endocrine Agents for the Treatment of Breast
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`AstraZeneca’s Faslodex met primary endpoint in first-line
`treatment of advanced breast cancer (May 27, 2016) (“FALCON
`Press Release”)
`Mark A. Longer et al., Sustained-Release Drug Delivery Systems,
`in REMINGTON’S PHARMACEUTICAL SCIENCES, Ch. 91 (Alphonso
`R. Gennaro ed., 18th ed. 1990) (“Remington’s Ch. 91”)
`Louis G. Ravin et al., Preformulation, in REMINGTON’S
`PHARMACEUTICAL SCIENCES, Ch. 75 (Alfonso Gennaro ed., 18th
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`SCIENCE OF DOSAGE FORM DESIGN, Ch. 1 (M.E. Aulton ed.,
`1988) (“Aulton Ch. 1”)
`
`xi
`
`

`
`Exhibit
`2083
`
`2084
`
`2085
`
`2086
`
`2087
`
`2088
`
`2089
`2090
`2091
`
`2092
`
`2093
`
`2094
`
`2095
`
`Case IPR2016-01316
`
`
`Description
`Howard C. Ansel et al., Dosage Form Design: Biopharmaceutic
`& Pharmacokinetic Considerations, in PHARMACEUTICAL
`DOSAGE FORMS & DRUG DELIVERY SYSTEMS, Ch. 4 (7th ed.
`1999) (“Ansel Ch. 4”)
`Kenneth E. Avis, Parental Preparations, in Remington’s
`Pharmaceutical Sciences, Ch. 84 (Alphonso R. Gennaro ed., 18th
`ed. 1990) (“Remington’s Ch. 84”)
`J.L. Ford, Parenteral Products, in PHARMACEUTICS: THE
`SCIENCE OF DOSAGE FORM DESIGN, Ch. 21 (M.E. Aulton ed.,
`1988) (“Aulton Ch. 21”)
`Michael J. Groves, Perspectives on the Use and Essential
`Requirements of Parenteral Products, in PARENTERAL
`TECHNOLOGY MANUAL, Ch. 2 (2d ed. 1989) (“Groves Ch. 2”)
`Michael J. Akers, Challenges in the Development of Injectable
`Products, in INJECTABLE DRUG DEVELOPMENT: TECHNIQUES TO
`REDUCE PAIN & IRRITATION, Ch. 1 (Pramod K. Gupta & Gayle
`A. Brazeau eds., 1999) (“Gupta Ch. 1”)
`Sandeep Nema et al., Excipients and Their Use in Injectable
`Products, 51 PDA J. Pharm Sci. Tech. 166 (1997) (“Nema”)
`Vidal® 1999 Le Dictionnaire (75th ed. 1999) (“Vidal 1999”)
`Vidal® 1997 Le Dictionnaire (73d ed. 1997) (“Vidal 1997”)
`ABPI Compendium of Data Sheets and Summaries of Product
`Characteristics (1999-2000) (“ABPI 1999-2000”)
`Steven Abbott & Charles M. Hansen, HANSEN SOLUBILITY
`PARAMETERS IN PRACTICE, Introduction (2013), available at
`http://www.pirika.com/ENG/HSP/E-Book/Introduction.html
`(“Abbott & Hansen”)
`Edward Rudnic et al., Oral Solid Dosage Forms, in
`REMINGTON’S PHARMACEUTICAL SCIENCES, Ch. 89 (Alphonso R.
`Gennaro ed., 18th ed. 1990) (“Remington’s Ch. 89”)
`J.I. Wells et al., Preformulation, in PHARMACEUTICS: THE
`SCIENCE OF DOSAGE FORM DESIGN, Ch. 13 (M.E. Aulton ed.,
`1988) (“Aulton Ch. 13”)
`Howard C. Ansel et al., Capsules and Tablets, in
`PHARMACEUTICAL DOSAGE FORMS & DRUG DELIVERY SYSTEMS,
`Ch. 7 (7th ed. 1999) (“Ansel Ch. 7”)
`
`xii
`
`

`
`Exhibit
`2096
`
`2097
`
`2098
`
`2099
`
`2100
`
`2101
`2102
`
`2103
`
`2104
`
`2105
`
`2106
`
`2107
`
`Case IPR2016-01316
`
`
`Description
`Howard C. Ansel et al., Solutions, in PHARMACEUTICAL DOSAGE
`FORMS & DRUG DELIVERY SYSTEMS, Ch. 12 (7th ed. 1999)
`(“Ansel Ch. 12”)
`Howard C. Ansel et al., Disperse Systems, in PHARMACEUTICAL
`DOSAGE FORMS & DRUG DELIVERY SYSTEMS, Ch. 13 (7th ed.
`1999) (“Ansel Ch. 13”)
`M.H. Rubinstein, Tablets, in PHARMACEUTICS: THE SCIENCE OF
`DOSAGE FORM DESIGN, Ch. 18 (M.E. Aulton ed., 1988) (“Aulton
`Ch. 18”)
`B.E. Jones et al., Capsules, in PHARMACEUTICS: THE SCIENCE OF
`DOSAGE FORM DESIGN, Ch. 19 (M.E. Aulton ed., 1988) (“Aulton
`Ch. 19”)
`Shen Gao et al., In vitro percutaneous absorption enhancement
`of a lipophilic drug tamoxifen by terpenes, 51 J. Controlled
`Release 193-199 (1998) (“Gao 1998”)
`THE MERCK INDEX (12th ed. 1996) (“Merck Index”)
`Howard C. Ansel et al., Transdermal Drug Delivery Systems, in
`PHARMACEUTICAL DOSAGE FORMS & DRUG DELIVERY SYSTEMS,
`Ch. 10 (7th ed. 1999) (“Ansel Ch. 10”)
`Sol Motola et al., Preformulation Research of Parenteral
`Medications, in 1 PHARMACEUTICAL DOSAGE FORMS:
`PARENTERAL MEDICATION, Ch. 4 (Kenneth E. Avis et al. eds., 2d
`ed. 1992) (“Avis Ch. 4”)
`J.B. Kayes, Disperse Systems, in PHARMACEUTICS: THE SCIENCE
`OF DOSAGE FORM DESIGN, Ch. 6 (M.E. Aulton ed., 1988)
`(“Aulton Ch. 6”)
`Arturo G. Porras et al., Pharmacokinetics of Alendronate, 36
`Clin. Pharmacokinet. 315 (1999) (“Porras”)
`Howard C. Ansel et al., Parenterals, in PHARMACEUTICAL
`DOSAGE FORMS & DRUG DELIVERY SYSTEMS, Ch. 14 (7th ed.
`1999) (“Ansel Ch. 14”)
`Richard J. Duma et al., Parenteral Drug Administration: Routes,
`Precautions, Problems, Complications, and Drug Delivery
`Systems, in 1 PHARMACEUTICAL DOSAGE FORMS: PARENTERAL
`MEDICATION , Ch. 2 (Kenneth E. Avis et al. eds., 2d ed. 1992)
`(“Avis Ch. 2”)
`
`xiii
`
`

`
`Exhibit
`2108
`
`2109
`
`2110
`
`2111
`
`2112
`
`2113
`
`2114
`
`2115
`
`2116
`
`2117
`
`2118
`
`Case IPR2016-01316
`
`
`Description
`Francis L.S. Tse et al., Bioavailability of Parenteral Drugs I.
`Intravenous and Intramuscular Doses, 34 J. Parenteral Drug
`Ass’n 409 (1980) (“Tse I”)
`George N. Wade et al., ICI 182,780 antagonizes the effects of
`estradiol on estrous behavior and energy balance in Syrian
`hamsters, 265 Am. J. Physiol. R1399 (1993) (“Wade 1993”)
`Scott G. Lundeen et al., Characterization of the Ovariectomized
`Rat Model for the Evaluation of Estrogen Effects on Plasma
`Cholesterol Levels, 138 Endocrinology 1552 (1997) (“Lundeen
`1997”)
`Patrick P. DeLuca et al., Formulation of Small Volume
`Parenterals, in 1 PHARMACEUTICAL DOSAGE FORMS:
`PARENTERAL MEDICATIONS, Ch. 5 (Kenneth E. Avis et al. eds.,
`2d ed. 1992) (“Avis Ch. 5”)
`Robert G. Strickley, Parenteral Formulations of Small Molecules
`Therapeutics Marketed in the United States (1999)—Part I, 53
`PDA J. Pharm. Sci. Tech. 324 (1999) (“Strickley I”)
`Sol Motola, Biopharmaceutics of Injectable Medication, in 1
`PHARMACEUTICAL DOSAGE FORMS: PARENTERAL MEDICATION,
`Ch. 3 (Kenneth E. Avis et al. eds., 2d ed. 1992) (“Avis Ch. 3”)
`J. Zuidema et al., Release and absorption rates of
`intramuscularly and subcutaneously injected pharmaceuticals
`(II), 105 Int’l J. of Pharmaceutics 189, 189 (1994) (“Zuidema
`1994”)
`Berton E. Ballard, Biopharmaceutical Considerations in
`Subcutaneous and Intramuscular Drug Administration, 57 J.
`Pharm. Sci. 357 (1968) (“Ballard 1968”)
`Koichiro Hirano, Studies on the Absorption of practically Water-
`insoluble Drugs following Injection. I. Intramuscular Absorption
`from Water-immiscible Oil Solutions in Rats, 29 Chem. Pharm.
`Bull. 519 (1981) (“Hirano 1980”)
`D.J. Greenblatt et al., Absorption of Oral and Intramuscular
`Chlordiazepoxide, 13 Eur. J. Clin. Pharmacol. 267 (1978)
`(“Greenblatt 1978”)
`John T. Litchfield, Forecasting Drug Effects in Man from Studies
`in Laboratory Animals, 177 J. Am. Med. Ass’n 34 (1961)
`(“Litchfield 1961”)
`
`xiv
`
`

`
`Exhibit
`2119
`
`2120
`
`2121
`
`2122
`
`2123
`
`2124
`
`2125
`
`2126
`
`2127
`
`2128
`
`2129
`
`Case IPR2016-01316
`
`
`Description
`Francis L.S. Tse et al., Bioavailability of Parenteral Drugs II:
`Parenteral Doses Other Than Intravenous and Intramuscular
`Routes, 34 J. Parenteral Drug Ass’n 484 (1980) (“Tse II”)
`A. Lifschitz et al., Ivermectin disposition kinetics after
`subcutaneous and intramuscular administration of an oil-based
`formulation to cattle, 86 Veterinary Parasitology 203 (1999)
`(“Lifschitz 1999”)
`E. Lavy et al., Pharmacokinetics of clindamycin HCl
`administered intravenously, intramuscularly, and subcutaneously
`to dogs, 22 J. Vet. Pharmacol. Ther. 261 (1999) (“Lavy 1999”)
`C. H. U. Chu, A Study of the Subcutaneous Connective Tissue of
`the Mouse, with Special Reference to Nuclear Type, Nuclear
`Division and Mitotic Rhythm, 11 Anatomical Record 11 (1960)
`(“Chu 1960”)
`Larry A. Gatlin et al., Formulation and Administration
`Techniques to Minimize Injection Pain and Tissue Damage
`Associated with Parenteral Products, in INJECTABLE DRUG
`DEVELOPMENT: TECHNIQUES TO REDUCE PAIN & IRRITATION, Ch.
`17 (Pramod K. Gupta & Gayle A. Brazeau eds., 1999) (“Gupta
`Ch. 17”)
`U.S. Patent No. 3,164,520, Raymond Huber, Injectable steroid
`compositions containing at least 75% benzyl benzoate (“’520
`Patent”)
`Affidavit of Internet Archive (Oct. 2016) (“Affidavit of Internet
`Archive”)
`Physician’s Desk Reference, 53rd ed., 3404-6 (1999) (“PDR 1999
`Arimidex®”)
`Physician’s Desk Reference, 53rd ed., 3404-6 (1999) (“PDR 1999
`Estrace®”)
`Skougaard MR et al., Comparative effectiveness of
`intraperitoneal and intramuscular 3H-TDR injection routes in
`mice, 45 Exp. Cell Res. 158 (1967) (“Skougaard”)
`Eagle H et al., The serum concentration of penicillin G in mice,
`rabbits, and men after its intramuscular injection in aqueous
`solution, 57 J. Bacteriol. 119 (1949) (“Eagle”)
`
`xv
`
`

`
`Case IPR2016-01316
`
`
`Description
`Levine HB et al., Immunologic impairment in mice treated
`intravenously with killed Coccidioides immitis spherules:
`suppressed response to intramuscular doses, 97 J. Immunol. 297
`(1966) (“Levine”)
`Yarinsky A et al., The uptake of tritiated hycanthone by male and
`female Schistosoma mansoni worms and distribution of the drug
`in plasma and whole blood of mice following a single
`intramuscular injection, 42 Bull. World Health Organ. 445
`(1970) (“Yarinsky”)
`Dec. 3, 2002 Office Action, File History for U.S. Patent No.
`6,774,122 (“Dec. 3, 2002 Office Action”)
`Aug. 21, 2008 Amendment and Response, File History for U.S.
`Patent No. 7,456,160 (“Aug. 21, 2008 Amendment”)
`Nicholas G. Lordi, Sustained Release Dosage Forms, in THE
`THEORY & PRACTICE OF INDUSTRIAL PHARMACY, Ch. 14 (Leon
`Lachman et al. eds., 1986) (“Lachman’s”)
`Aug. 21, 2008 Declaration, File History for U.S. Patent No.
`7,456,160 (“Aug. 21, 2008 Declaration”)
`June 20, 2011 Information Disclosure Statement, File History for
`U.S. Patent No. 8,329,680 (“June 20, 2011 IDS”)
`Sept. 16, 2011 Office Action, File History for U.S. Patent No.
`8,329,680 (“McLeskey Office Action”)
`Jan. 13, 2012 Declaration, File History for U.S. Patent No.
`8,329,680 (“Jan. 13, 2012 Declaration”)
`Mar. 20, 2012 Office Action, File History for U.S. Patent No.
`8,329,680 (“Mar. 20, 2012 Office Action”)
`June 4, 2012 Notice of Allowance, File History for U.S. Patent
`No. 8,329,680 (“June 4, 2012 Notice of Allowance”)
`Jan. 17, 2012 Amendment, File History for U.S. Patent No.
`8,329,680 (“Jan. 17, 2012 Amendment”)
`June 20, 2011 Amendment, File History for U.S. Patent No.
`8,329,680 (“June 20, 2011 Amendment”)
`
`Exhibit
`2130
`
`2131
`
`2132
`
`2133
`
`2134
`
`2135
`
`2136
`
`2137
`
`2138
`
`2139
`
`2140
`
`2141
`
`2142
`
`
`
`xvi
`
`

`
`Case IPR2016-01316
`
`
`I.
`
`INTRODUCTION
`
`The ’122 Patent claims are method of treatment claims—methods to treat
`
`hormonal dependent breast cancer with the active ingredient (fulvestrant)
`
`administered intramuscularly with a combination of ingredients that interact with
`
`the muscle, to provide and maintain specific blood levels over extended periods of
`
`time. At the time the patent application was filed, the skilled artisan reviewing the
`
`prior art would never have expected it to be a successful treatment—it combined
`
`an active ingredient with then-unproven efficacy administered through the
`
`unpredictable intramuscular route using ingredients that interact with the muscle in
`
`a still-unknown manner to achieve blood plasma levels that differed from then-
`
`conventional wisdom and were maintained for 2-5 weeks.
`
`The Petition uses the patent claims to filter out unknowns, failures, and
`
`critical