Paper No. ________
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`
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`MYLAN TECHNOLOGIES, INC.
`Petitioner,
`
`v.
`
`NOVEN PHARMACEUTICALS, INC.
`Patent Owner.
`
`
`Patent No. 9,833,419
`
`Title: TRANSDERMAL ESTROGEN DEVICE AND DELIVERY
`_______________
`
`Inter Partes Review No. IPR2018-01119
`____________________________________________________________
`
`
`PATENT OWNER PRELIMINARY RESPONSE
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`
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`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`MYLAN TECHNOLOGIES, INC.
`Petitioner,
`
`v.
`
`NOVEN PHARMACEUTICALS, INC.
`Patent Owner.
`
`
`Patent No. 9,833,419
`
`Title: TRANSDERMAL ESTROGEN DEVICE AND DELIVERY
`_______________
`
`Inter Partes Review No. IPR2018-01119
`____________________________________________________________
`
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`PATENT OWNER PRELIMINARY RESPONSE
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`IPR2018-01119
`Patent Owner Preliminary Response
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`TABLE OF CONTENTS
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`Introduction ........................................................................................................... 1
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`Institution Should Be Denied Under 35 U.S.C. §§ 314(a) or 325(d) ................... 2
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`
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`I.
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`II.
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`III. Overview Of The Patent And Prosecution History .............................................. 7
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`IV. Level Of Skill In The Art ................................................................................... 10
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`V.
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`Technological Background ................................................................................. 11
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`A.
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`B.
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`C.
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`Transdermal Drug Delivery and Drug Flux ............................................. 11
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`Developing Transdermal Drug Delivery Systems ................................... 12
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`Coat Weight Was Not Known To Impact Flux ........................................ 17
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`1.
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`2.
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`Kim (EX1010) Does Not Evidence A General Understanding ..... 19
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`Ghosh (EX1014) Does Not Evidence A General Understanding .. 21
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`3. Wong (EX1028) Does Not Evidence a General Understanding ... 22
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`4.
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`5.
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`6.
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`Bronaugh (EX1026) Is Not Related to TDSs ................................ 23
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`Benson (EX1039) Does Not Link Coat Weight To Occlusion ..... 23
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`Chien (EX1009) Does Not Support Petitioner’s Case ................... 24
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`7. Mueller (EX1005) Did Not Recognize Coat Weight To Impact
`Flux ................................................................................................ 25
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`D.
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`Estradiol Transdermal Drug Delivery Systems ....................................... 26
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`VI. Claim Construction ............................................................................................. 28
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`A.
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`B.
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`Legal Standard .......................................................................................... 28
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`“About”..................................................................................................... 28
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`C.
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`D.
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`E.
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`“Coat Weight” .......................................................................................... 29
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`“Flux” ....................................................................................................... 30
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`“Therapeutically Effective Amount” ....................................................... 33
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`VII. Standard For Institution ...................................................................................... 33
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`VIII. The Cited References .......................................................................................... 34
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`A. Mueller (EX1005) .................................................................................... 34
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`B.
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`C.
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`D.
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`Vivelle-Dot® Label (EX1006) ................................................................. 36
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`Kanios (EX1007) ...................................................................................... 37
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`Chien (EX1009) ....................................................................................... 39
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`IX. Petitioner Failed To Satisfy 37 C.F.R. §§ 42.61(c) and 42.65(b) ...................... 40
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`X. Grounds 1-4 Improperly Rely On Petitioner’s Own Interpretations
`Of Figures ........................................................................................................... 41
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`XI. The Petition Does Not Demonstrate A Reasonable Likelihood Of
`Unpatentability On Ground 1 ............................................................................. 43
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`A.
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`Petitioner has not carried its burden on anticipation of claims 1, 2, 8,
`and 10-15 by Mueller Example 3. ............................................................ 44
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`1. Mueller does not disclose or show that Example 3 achieved the
`claimed estradiol flux ..................................................................... 45
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`2. Mueller Example 3 did not use a control ....................................... 47
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`3. Mueller presents Fig. 3 qualitatively and imprecisely ................... 49
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`XII. Petitioner Has Not Carried Its Burden On Obviousness Of Claims 1-2
`And 8-15 In View Of Mueller And The Vivelle-Dot® Label For
`Ground 2 ............................................................................................................. 53
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`XIII. Petitioner Has Not Carried Its Burden On Obviousness Of Claims 3-7 In
`View Of Mueller, The Vivelle-Dot® Label And Kanios For Ground 3 ............ 55
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`A.
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`B.
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`Petitioner has not shown the requisite motivation or
`reasonable expectation of success ............................................................ 56
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`A POSA would have been discouraged from attempting Petitioner’s
`asserted modifications of Mueller ............................................................ 58
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`C.
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`Petitioner relies on an invalid comparison of Mueller and Kanios .......... 59
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`XIV. Petitioner Has Not Carried Its Burden On Obviousness Of Claims 1-15
`In View Of Mueller, Vivelle-Dot® Label, Kanios, And Chien For
`Ground 4 ............................................................................................................. 62
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`XV. Conclusion .......................................................................................................... 64
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`XVI. CERTIFICATE OF COMPLIANCE WITH 37 C.F.R. § 42.24(b)(1) ............... 65
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`iii
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`TABLE OF AUTHORITIES
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`Cases
`3M Innovative Props. Co. v. Tredegar Corp.,
`725 F.3d 1315 (Fed. Cir. 2013) .................................................................. 29, 33
`
`Callaway Golf Co. v. Acushnet Co.,
`576 F.3d 1331 (Fed. Cir. 2009) .................................................................. 55, 62
`
`Continental Can Co. U.S.A. v. Monsanto Co.,
`948 F.2d 1264 (Fed. Cir. 1991) ............................................................ 43, 44, 48
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) .............................................................................................. 53
`
`Harmonic Inc. v. Avid Tech, Inc.,
`815 F.3d 1356 (Fed. Cir. 2016) ........................................................................... 3
`
`Hockerson-Halberstadt, Inc. v. Avia Group Int’l,
`222 F.3d 951 (Fed. Cir. 2007) .................................................................... 42, 63
`
`In re Gartside,
`203 F.3d 1305 (Fed. Cir. 2000) ......................................................................... 53
`
`In re Magnum Oil Tools International,
`829 F.3d 1364 (Fed. Cir. 2016) ......................................................................... 53
`
`In re Mraz,
`455 F.2d 1069 (CCPA1972) .............................................................................. 43
`
`In re Oelrich,
`666 F.2d 578 (CCPA 1981) ............................................................................... 44
`
`In re Translogic Tech., Inc.,
`504 F.3d 1249 (Fed. Cir. 2007) ......................................................................... 28
`
`In re Wright,
`569 F.2d 1124 (CCPA 1976) ...................................................................... 42, 45
`
`Nystrom v. Trex Co.,
`424 F.3d 1136 (Fed. Cir. 2005) ...................................................... 41, 42, 44, 63
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`iv
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`RCA Corp. v. Applied Digital Data Sys., Inc.,
`730 F.2d 1440 (1984) ........................................................................................ 53
`
`United States v. Adams,
`383 U.S. 39 (1966) ............................................................................................ 53
`
`Verdegaal Bros. v. Union Oil Co. of California,
`814 F.2d 628 (Fed. Cir. 1987) ........................................................................... 43
`
`
`Statutes
`35 U.S.C. § 314(a) .................................................................................... 2, 3, 7, 33
`
`35 U.S.C. § 325(d) ......................................................................................... passim
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`35 U.S.C. § 102 ..................................................................................................... 43
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`35 U.S.C. § 103 ..................................................................................................... 53
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`35 U.S.C. § 313 ....................................................................................................... 1
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`Rules and Regulations
`37 C.F.R. § 42.100(b) ............................................................................................ 28
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`37 C.F.R. § 42.20(c) .............................................................................................. 33
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`37 C.F.R. § 42.61(c) ................................................................................. 34, 40, 47
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`37 C.F.R. § 42.63(b) .............................................................................................. 47
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`37 C.F.R. § 42.65(a) ....................................................................................... 31, 46
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`37 C.F.R. § 42.65(b) ................................................................................. 34, 40, 41
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`Administrative Materials
`Office Patent Trial Practice Guide Update (August 2018) .................................2, 3
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`Office Patent Trial Practice Guide (August 2012) ................................................ 28
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`
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`Inter Partes Reviews
`Abiomed, Inc. v. Maquet Cardiovascular, LLC,
`IPR2017-02151 (PTAB Mar. 12, 2018) .............................................................. 5
`
`Becton, Dickinson and Co. v. B. Braun Melsungen AG,
`IPR2017-01586 (PTAB Dec. 15, 2017) ..........................................................4, 5
`
`Fresenius Kabi USA, LLC v. Cephalon, Inc.,
`IPR2016-00098 (PTAB May 4, 2016) .............................................................. 42
`
`Fresenius-Kabi USA LLC v. AstraZeneca A.B.,
`IPR2017-01913 (PTAB Dec. 11, 2017) .............................................................. 5
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`General Plastic Indus. Co. v. Canon Kabushiki Kaisha,
`IPR2016-01357 (PTAB Sept. 6, 2017) ............................................................... 3
`
`Huawei Techs. Co. v. Samsung Elecs. Co.,
`IPR2017-01983 (PTAB Mar. 16, 2018) ............................................................ 46
`
`Mylan Techs. Inc. v. Noven Pharm., Inc.,
`IPR2018-00174 (PTAB June 12, 2018) .............................................................. 2
`
`Mylan Techs. Inc. v. Noven Pharm., Inc.,
`IPR2018-00173 (PTAB June 12, 2018) .................................................... passim
`
`Neil Ziegmann, N.P.Z., Inc. v. Stephens,
`IPR2015-01860 (PTAB Feb. 24, 2016) ............................................................... 6
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`NetApp Inc. v. Crossroads Sys., Inc.,
`IPR2015-00776 (PTAB Sept. 8, 2015) ............................................................... 5
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`Nu Mark LLC v. Fontem Holdings 1, B.V.,
`IPR2016-01309 (PTAB Dec. 15, 2016) .............................................................. 7
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`vi
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`Samsung Display Co. v. Gold Charm Ltd.,
`IPR2015-01469 (PTAB Jan. 4, 2016) ........................................................ 42, 43
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`Samsung Elecs. Co. v. Elm 3DS Innovations, LLC,
`IPR2017-01305 (PTAB Oct. 17, 2017) ...........................................................3, 4
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`vii
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`Ex #
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`2001
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`IPR2018-01119
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`EXHIBITS
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`Description
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`Declaration of Dr. Adrian C. Williams
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`2002
`
`Curriculum Vitae of Dr. Adrian C. Williams
`
`2003 Minivelle® Product Label
`
`2004
`
`J. Hadgraft and R. Guy, Feasibility Assessment in Topical and
`Transdermal Delivery, in TRANSDERMAL DRUG DELIVERY 3-4 (R.
`Guy & J. Hadgraft eds., 2d ed. 2003)
`
`2005
`
`J. Hadgraft, Passive enhancement strategies in topical and
`transdermal drug delivery, 184 INT’L J. PHARMACEUTICS 1-6 (1999)
`
`2006
`
`2007
`
`B. Barry, Transdermal Drug Delivery, in AULTON’S PHARMACEUTICS
`– THE DESIGN AND MANUFACTURE OF MEDICINES 565, 571-72, 577
`(M. Aulton ed., 3d ed. 2007)
`
`A. Williams & B. Barry, Urea analogues in propylene glycol as
`penetration enhancers in human skin, 36 INT’L J. PHARMACEUTICS
`43-50 (1989)
`
`viii
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`Ex #
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`2008
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`IPR2018-01119
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`Description
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`K. Brain & R. Chilcott, Physicochemical Factors Affecting Skin
`Absorption, in PRINCIPLES AND PRACTICE OF SKIN TOXICOLOGY 83-92
`(R. Chilcott and S. Price eds., 2008)
`
`2009
`
`Esclim® Product Label
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`2010
`
`Intentionally Left Blank
`
`2011
`
`2012
`
`2013
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`A. Williams & B. Barry, Chemical Permeation Enhancement, in
`ENHANCEMENT IN DRUG DELIVERY 233, 248-50 (E. Touitou & B.
`Barry eds., 2007)
`
`A. Williams & B. Barry, The enhancement index concept applied to
`terpene penetration enhancers for human skin and model lipophilic
`(oestradiol) and hydrophilic (5-fluorouracil) drugs, 74 INT’L J.
`PHARMACEUTICS 157-168 (1991)
`
`K. Walters & K. Brain, Dematological Formulation and Transdermal
`Systems, in DEMATOLOGICAL AND TRANSDERMAL FORMULATIONS
`338-43 (K. Walters, ed., 2002)
`
`ix
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`Ex #
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`2014
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`Description
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`Google Scholar search results obtained March 7, 2018 – citations of
`Kim et al., Penetration Enhancement of β2-Selective Agonist,
`Tulobuterol, Across Hairless Mouse Skin, J. Pharm. Invest. 33: 79-84
`(2003), available online at https://scholar.google.com/scholar?cites=
`7903453726087495818&as_sdt=2005&sciodt=0,5&hl=en
`
`2015
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`A. Ghosh et al., Current Pharmaceutical Design on Adhesive Based
`Transdermal Drug Delivery Systems, 21 CURR. PHARM. DESIGN
`2771-2783 (2015)
`
`2016
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`U.S. Patent No. 8,029,820
`
`2017
`
`2018
`
`2019
`
`B. Godin & E. Touitou, Transdermal skin delivery: Predictions for
`humans from in vivo, ex vivo and animal models, 59(11) ADV. DRUG
`DELIV. REVIEWS 1152-1161 (2007)
`
`R. Hinz et al., In vitro percutaneous penetration: evaluation of the
`utility of hairless mouse skin, 93(1) J. INVEST. DERMATOL. 87-91
`(1989)
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`J. Bond & B. Barry, Hairless mouse skin is limited as a model for
`assessing the effects of penetration enhancers in human skin, 90(6) J.
`INVEST. DERMATOL. 810-813 (1988)
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`x
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`Ex #
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`2020
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`Description
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`R. Subedi et al., Influence of formulation variable in transdermal
`drug delivery system containing zolmitriptan, 419 INT’L J.
`PHARMACEUTICS 209-214 (2011)
`
`2021
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`R. Subedi et al., Formulation and in vitro evaluation of transdermal
`drug delivery system for donezil, 42 J. PHARMA. INVEST. 1-7 (2012)
`
`2022
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`Intentionally Left Blank
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`2023
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`J. van de Sandt et al., In vitro predictions of skin absorption of
`caffeine, testosterone, and benzoic acid: a multi-centre comparison
`study, 39 REG. TOXICOL. PHARMACOL 271–281 (2004)
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`2024
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`Comparison of Claims 1-15 of U.S. 9,833,419 and U.S. 9,724,310
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`xi
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`I.
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`Introduction
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`IPR2018-01119
`Patent Owner Preliminary Response
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`Patent Owner timely submits this preliminary response under 35 U.S.C.
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`§ 313 to Mylan Technologies, Inc.’s (“Petitioner’s”) request for inter partes review
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`(“IPR”) of claims 1-15 of U.S. Patent No. 9,833,419 (“the ’419 Patent,” EX1001)
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`within three months of the Board’s May 23, 2018 notice according a filing date.
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`For the reasons herein and as supported by the cited exhibits, Petitioner’s request
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`for IPR should be denied.
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`The challenged claims generally relate to monolithic estradiol transdermal
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`drug delivery systems (“TDSs” or “patches”) that deliver estradiol through the skin
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`at a particular rate (“flux”). These claims cover Patent Owner’s FDA approved
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`MINIVELLE® product, which is a transdermal patch applied twice weekly for the
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`treatment of moderate to severe vasomotor symptoms due to menopause (e.g., “hot
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`flashes”) and the prevention of postmenopausal osteoporosis. EX2003, 1.
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`MINIVELLE® is the smallest FDA-approved estradiol patch, and offers patients
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`advantages such as reduced skin irritation and better aesthetics. See EX1001, 1:67-
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`2:1. Petitioner sought FDA approval to market a generic version of Patent Owner’s
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`MINIVELLE® product. See, e.g., Noven Pharmaceuticals, Inc. v. Mylan
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`Technologies Inc. et al., C.A. No. 1-17-01777 (D. Del.).
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`Petitioner alleges the claims are anticipated or rendered obvious by one or
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`more cited references, but each asserted ground of unpatentability is fatally flawed.
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`1
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`IPR2018-01119
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`To justify institution, Petitioner must demonstrate a “reasonable likelihood” that it
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`will prevail as to at least one of the claims challenged. 35 U.S.C. § 314(a). With
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`regard to both anticipation and obviousness, Petitioner cannot make out its case
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`based on express teachings of the cited references, but improperly relies on
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`unsupported interpretations of figures and other inferences that go far beyond what
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`a person of ordinary skill in the art (“POSA”) would have understood. However,
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`even “[e]xpert testimony … cannot take the place of a disclosure in a prior art
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`reference.” Office Patent Trial Practice Guide Update (Aug. 2018), at 4. On
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`motivation and expectation of success, Petitioner’s positions are contrary to what
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`was understood in the art, and contrary to previous writings by its expert. Petitioner
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`has not met the standard for institution; therefore institution should be denied.
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`II.
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`Institution Should Be Denied Under 35 U.S.C. §§ 314(a) or 325(d)
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`Institution should be denied under 35 U.S.C. §§ 314(a) or 325(d) because the
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`asserted grounds are effectively the same as those raised, considered, and denied in
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`parallel proceedings for related U.S. Patent Nos. 9,724,310 (“the ’310 Patent”) and
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`9,730,900 (“the ’900 Patent”). Compare Petition, 22, with Mylan Techs. Inc. v.
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`Noven Pharm., Inc., IPR2018-00173, Paper 9 at 6, 24 (PTAB June 12, 2018) and
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`IPR2018-00174, Paper 8 at 6, 24 (PTAB June 12, 2018). Indeed, Petitioner relies
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`on the same grounds, same references, and same arguments the Board found
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`inadequate in IPR2018-00173 and IPR2018-00174 (the “previous IPRs”).
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`2
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`Denial of institution would be consistent with the Board’s decisions, case
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`law, and 35 U.S.C. §§ 314(a) and 325(d), and would conserve the Board’s limited
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`resources. See, e.g., General Plastic Indus. Co. v. Canon Kabushiki Kaisha,
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`IPR2016-01357, Paper 19 (PTAB Sept. 6, 2017); Samsung Elecs. Co. v. Elm 3DS
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`Innovations, LLC, IPR2017-01305, Paper 11 (PTAB Oct. 17, 2017); Harmonic
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`Inc. v. Avid Tech, Inc., 815 F.3d 1356, 1367 (Fed. Cir. 2016) (“[T]he PTO is
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`permitted, but never compelled, to institute an IPR proceeding.”). The Board has
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`applied a non-limiting, seven-factor test for denying institution under § 314(a) that
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`has been used where a related patent was the subject of a follow-on petition.1
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`Office Patent Trial Practice Guide Update (Aug. 2018), at 9-11; General Plastic,
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`Paper 19 at 9-10. These factors weigh in favor of denial here:
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`Petitioner previously filed petitions against parallel claims of related patents
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`(factor 1); the very same grounds and references are asserted (factors 2, 4); the
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`Petition was filed three months after Petitioner received the previous Patent Owner
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`Preliminary Responses (factor 3); no explanation for the delay in challenging the
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`’419 Patent has been given (factor 5); and Board resources are better spent
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`elsewhere (factors 6, 7).
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`1 See, e.g., Samsung Elecs., Paper 11, 12-13.
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`3
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`As noted above, Samsung Elecs., Paper 11 at 12-13, indicates that factor 1
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`can weigh towards denial when the follow-on petition challenges a different but
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`related patent. Like the patents discussed there, the ’419 Patent is related as a
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`continuation to the ’900 and ’310 Patents, and so shares the same disclosure and
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`priority date. Independent claim 1 of the ’419 Patent differs from independent
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`claim 1 of the ’310 Patent only by one word (one instance of “about” is not recited
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`in claim 1 of the ’419 Patent), and the ’419 Patent is subject to a Terminal
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`Disclaimer over the ’310 Patent.2
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`In the informative decision Becton, Dickinson and Co. v. B. Braun
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`Melsungen AG, IPR2017-01586, Paper 8 at 22-23, 28 (PTAB Dec. 15, 2017),
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`institution was denied where the Examiner had cited the same references in
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`“obviousness rejections in the parent application over claims with scope similar to
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`that of the [challenged] patent.” The Petition here raises the very same grounds
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`based on the same references asserted previously, and both the Petition and Brain
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`Declaration (EX1001) are largely identical to those filed in the previous IPRs. Like
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`the Petition denied institution in Becton, the Petition here does not present “new
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`2 EX2024 provides a claim-by-claim comparison of the claims of the ’419 and ’310
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`Patents, which differ only in one instance of “about” in each of claims 1, 10, and
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`11.
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`4
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`evidence of unpatentability that was not evaluated previously by the Office.” Id. at
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`23.
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`Because institution may be denied under § 325(d) where prior art or
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`arguments were previously presented to the Board, denial is appropriate for this
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`reason as well. See Abiomed, Inc. v. Maquet Cardiovascular, LLC, IPR2017-
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`02151, Paper 10 at 5-6 (PTAB Mar. 12, 2018) (exercising discretionary denial
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`based on denial of previous petition); NetApp Inc. v. Crossroads Sys., Inc.,
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`IPR2015-00776, Paper 12 at 7-8 (PTAB Sept. 8, 2015) (same).
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`When exercising discretion to deny a follow-on petition, it is appropriate for
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`the Board to focus only on new aspects of the Petition. See, e.g., Fresenius-Kabi
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`USA LLC v. AstraZeneca A.B., IPR2017-01913, Paper 9 at 23-24 (PTAB Dec. 11,
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`2017) (“[O]ur prior Mylan Decision addressed essentially the same factual inquiry
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`centered on substantially the same asserted prior art references….[T]he rub of this
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`dispute is whether ‘[f]our differences’ set forth in the Petition overcome the
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`shortcomings we previously identified in the Mylan Decision.”). Here, the Petition
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`refers to four new references, but none are cited in any asserted grounds: Benson
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`(EX1039), cited at Petition, 4, 18, 20; Mantelle 1999 (EX1040), cited at Petition,
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`52; Mantelle 2008 (EX1041), cited at Petition, 18, 52; and DE10012908 (EX1042),
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`cited at Petition, 10. Of these, only Benson and DE10012908 were not of record in
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`5
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`IPR2018-01119
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`the previous IPRs.3 The Petition includes a few new sentences (see Petition, 7, 19,
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`20, 22, 23, 27, 28, 30, 38, 42, 44, 45, 46, 47, 48, 49, 52, 62, 63), but otherwise is
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`effectively the same as those filed in the previous IPRs. None of the newly cited
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`references or new sentences overcome the deficiencies the Board found when
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`denying institution in the previous IPRs.
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`Under § 325(d), a petition that does not raise new art or arguments should be
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`rejected if it: (1) relies on a reference the Office considered during prosecution;
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`and (2) advances arguments that involve the same factual considerations that the
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`Office considered during prosecution. Neil Ziegmann, N.P.Z., Inc. v. Stephens,
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`IPR2015-01860, Paper No. 11 at 9 (PTAB Feb. 24, 2016). That is precisely the
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`case here for Grounds 1-3.
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`Grounds 1-3 rely on Mueller, the Vivelle-Dot® Label, and Kanios ’602
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`which each were submitted (EX1004, 51, 53) and considered (id., 145, 147) during
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`prosecution. Thus, all of the references cited in Grounds 1-3 were before the
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`Examiner, previously assessed with respect to their relevance to the claims, and not
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`deemed more relevant than the references cited in rejections that were overcome.
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`Like the petition in Ziegmann, the Petition here “asks the Board to, essentially,
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`3 Mantelle 1999 (EX1040) was EX2010 in the previous IPRs; Mantelle 2008
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`(EX1041) was EX2022.
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`Patent Owner Preliminary Response
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`second-guess the Office’s previous decision.” IPR2015-01860, Paper 11 at 12-14.
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`Therefore, institution would be an inefficient use of Board resources. Nu Mark
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`LLC v. Fontem Holdings 1, B.V., IPR2016-01309, Paper 11 at 9-11 (PTAB Dec.
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`15, 2016) (rejecting petition that relied on a new reference that was cumulative of
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`references considered during prosecution).
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`The Board should deny institution under § 314(a) or § 325(d) because the
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`Examiner and the Board have considered the asserted references, and the Board
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`rejected Petitioner’s arguments in two previous IPRs. The third time is not the
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`charm.
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`III. Overview Of The Patent And Prosecution History
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`The ’419 Patent was filed September 30, 2015, and issued December 5,
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`2017, from U.S. patent application no. 14/870,574 (“the ’574 application”), which
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`was a continuation of U.S. patent application no. 14/738,255 (pending), which was
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`a continuation of U.S. patent application no. 14/024,985 (now the ’310 Patent),
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`which was a continuation of U.S. patent application no. 13/553,972 (now the ’900
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`Patent), which was a continuation of U.S. patent application no. 12/216,811 (now
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`U.S. Patent No. 8,231,906). EX1001, 1. The claims of the ’419 Patent are directed
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`to monolithic TDSs for delivering estradiol.
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`Independent claim 1 (the sole independent claim) recites:
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`Patent Owner Preliminary Response
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`1. A monolithic transdermal drug delivery system for estradiol,
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`consisting of (i) a backing layer, (ii) a single adhesive polymer
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`matrix layer defining an active surface area and, optionally, (iii)
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`a release liner, wherein the single adhesive polymer matrix
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`layer comprises an adhesive polymer matrix comprising
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`estradiol as the only drug, wherein the adhesive polymer matrix
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`layer has a coat weight of greater than 10 mg/cm2 and includes
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`greater than 0.156 mg/cm2 estradiol, and the system achieves an
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`estradiol flux of from 0.0125 to about 0.05 mg/cm2/day, based
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`on the active surface area.
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`A “monolithic” system has a single polymer matrix layer comprising the drug and
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`adhesive. EX1001, 6:42-46. These drug-in-adhesive systems consist of (i) a
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`backing layer, (ii) a drug-in-adhesive polymer matrix layer, and, optionally, (iii) a
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`protective release liner that is removed before application. EX1004, 204.
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`During prosecution, the claims were rejected as allegedly obvious over U.S.
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`Patent No. 6,638,528 (EX1030) in view of U.S. Patent No. 4,624,665 (EX1031).
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`EX1004, 129-133. Patent Owner overcame these rejections with arguments and
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`clarifying claim amendments. EX1004, 183-193.
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`Patent Owner conducted an interview with the Examiner and submitted the
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`Declaration Under 37 C.F.R. § 1.132 of Dr. Richard H. Guy (the “Guy
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`Declaration”)4. EX1004, 138, 159-181, 200-306. The Guy Declaration explained
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`the state of the art and presented experimental data of unexpected results. Dr. Guy
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`attested that “a person of ordinary skill in the art would not have thought of coat
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`weight as a parameter to be adjusted to affect the flux of a drug from a transdermal
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`patch” and that none of the art of record “suggests that increasing coat weight
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`would increase flux.” EX1004, 207, 227. Dr. Guy also attested that the only
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`predictable way to increase drug flux from a TDS is to increase the size of the
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`TDS. Id., 227. Dr. Guy also presented experimental data showing the unexpected
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`result that increasing the coat weight of the drug-containing polymer matrix of the
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`monolithic estradiol TDS increased flux. Id., 214-224.
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`Thereafter, the Examiner issued a Notice of Allowance (EX1004, 319-325)
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`explaining that “[t]he prior art does not teach nor reasonably suggest the claimed
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`4 Dr. Guy is a professor of Pharmaceutical Sciences at the University of Bath (UK)
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`in the Department of Pharmacy & Pharmacology and has more than 30 years’
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`research experience in the field of topical and transdermal drug delivery, including
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`the study of drug absorption into and through the skin. He has co-authored more
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`than 350 peer-reviewed articles and over 70 book chapters, and served as the
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`Associate Editor of the Journal of Pharmaceutical Sciences from 2002-2007.
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`monolithic transdermal drug delivery system,” and that “Applicant’s arguments of
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`unexpected results…are persuasive” (id., 324).
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`IV. Level Of Skill In The Art
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`Petitioner alleges that a POSA would have “an advanced degree…in
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`pharmaceutical chemistry, physical chemistry, bioengineering, or a drug delivery
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`related discipline” or “a bachelor’s degree plus two to five years’ experience in the
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`transdermal delivery industry.” Petition, 15. Without acquiescing to Petitioner’s
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`definition, Patent Owner is willing to adopt it for purposes of this Preliminary
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`Response, with the clarification that a POSA who does not have an advanced
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`degree in the fields mentioned would have a bachelor’s degree in a field related to
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`drug delivery. EX2001, ¶¶26-28. The Board adopted Petitioner’s (same)
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`description with Patent Owner’s (same) clarification in the previous IPRs. See,
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`e.g., Mylan Techs. Inc. v. Noven Pharm., Inc., IPR2018-00173, Paper 9 at 7-8
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`(PTAB June 12, 2018).5
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`5 For convenience, citations are made to Paper 9 of IPR2018-00173; similar
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`findings are made in Paper 8 of IPR2018-00174.
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`V. Technological Background
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`A. Transdermal Drug Delivery and Drug Flux
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`The flux of a drug is the rate at which it diffuses through the skin. EX2001,
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`¶¶40-44. A TDS intended to be applied for an extended period, such as for 3 days,
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`ideally would exhibit a “zero-order” flux profile over the intended application
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`period, reflecting delivery of a uniform dose over time. EX2001, ¶49; EX1007,
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`¶11. On the other hand, a flux profile that exhibits an increase in flux followed by a
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`more rapid decrease is referred to as a “first-order” flux profile, and is not desirable
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`for a TDS intended to be applied for an extended period. EX2001, ¶49; EX1007,
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`¶7.
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`While the flux of a TDS is an in vivo property, it is typically measured by in
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`vitro methodology, such as in vitro skin permeation studies using human cadaver
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`skin, as illustrated in Example 1 of the ’419 Patent. EX2001, ¶¶46-47; EX1001,
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`15:1-40; EX1004, 165. In such studies, the amount of drug delivered through skin
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`over time is measured and used to calculate flux. EX2001, ¶¶48-50.
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`When assessing flux of a TDS, it is essential to account for variations in skin
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`permeability, because there can be large variations in permeability between
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`different skin samples. EX1004, 224; EX2001, ¶50. The impact of skin
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`permeability on flux and the use of well-known techniques to account for it is
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`illustrated in the Guy Declaration. EX1004, 224. The data presented in ¶¶40-42 of
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`the Guy Declaration show significant variations in flux (e.g., 1.5 to 2.5-fold higher)
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`when the well-characterized Vivelle-Dot® formulation was tested on different
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`human cadaver skin samples. EX1004, 224-226. The flux observed for Vivelle-
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`Dot® in those studies was not characteristic of Vivelle-Dot® per se, but reflected
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`the higher than usual permeability of the skin samples used. EX2001, ¶50. Dr.
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`Brain acknowledges this “high amount of variability that routinely occurs in flux
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`measurements.” EX1002, ¶¶40, 42, 57.
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`As of July 10, 2008, a POSA understood that the passive flux of a drug from
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`a TDS can be quantitatively described and m
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