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. 9,730,900
`
`Title: TRANSDERMAL ESTROGEN DEVICE AND DELIVERY
`_______________
`
`Inter Partes Review No. IPR2018-00174
`____________________________________________________________
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`
`PATENT OWNER PRELIMINARY RESPONSE
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`

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`IPR2018-00174
`Patent Owner Preliminary Response
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`TABLE OF CONTENTS
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`Introduction ...................................................................................................... 1
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`Overview of the ’900 Patent and Prosecution History .................................... 2
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`
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`I.
`
`II.
`
`III. Level of Skill in the Art ................................................................................... 7
`
`IV. Technological Background .............................................................................. 8
`A.
`Transdermal Drug Delivery and Drug Flux .......................................... 8
`B.
`Developing Transdermal Drug Delivery Systems .............................. 10
`C.
`Coat Weight Was Not Known To Impact Flux ................................... 14
`1.
`Kim (EX1010) Does Not Evidence A General Understanding 16
`2.
`Ghosh (EX1014) Does Not Evidence A General Understanding19
`3.
`Bronaugh (EX1026) Is Not Related to TDSs ........................... 20
`4.
`Chien (EX1009) Does Not Support Petitioner’s Case .............. 21
`5. Mueller (EX1005) Did Not Recognize
`Coat Weight To Impact Flux .................................................... 22
`Estradiol Transdermal Drug Delivery Systems .................................. 23
`
`D.
`
`V.
`
`Claim Construction ........................................................................................ 25
`A.
`Legal Standard ..................................................................................... 25
`B.
`“About”................................................................................................ 26
`C.
`“Coat Weight” ..................................................................................... 26
`D.
`“Flux” .................................................................................................. 27
`E.
`“Therapeutically Effective Amount” .................................................. 30
`
`VI. Standard for Institution .................................................................................. 30
`
`VII. The Cited References ..................................................................................... 31
`A. Mueller (EX1005) ............................................................................... 32
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`B.
`C.
`D.
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`Vivelle-Dot® Label (EX1006) ............................................................ 34
`Kanios (EX1007) ................................................................................. 35
`Chien (EX1009) .................................................................................. 37
`
`VIII. Petitioner Failed To Satisfy 37 C.F.R. §§ 42.61(c) and 42.65(b)
`For The Figures Relied Upon ........................................................................ 38
`
`IX. Grounds 1-4 Improperly Rely On Petitioner’s Own Interpretations
`Of Figures ...................................................................................................... 39
`
`X.
`
`The Petition Does Not Demonstrate A Reasonable Likelihood Of
`Unpatentability Based On Ground 1 ............................................................. 40
`A.
`Petitioner has not carried its burden of establishing a reasonable
`likelihood of anticipation of claims 1, 2, 8, 10-16 and 18-23 by
`Mueller Example 3. ............................................................................. 41
`1. Mueller Does Not Disclose Or Show That Example 3 Achieved
`The Claimed Estradiol Flux ...................................................... 42
`2. Mueller Example 3 Did Not Use A Control ............................. 43
`3. Mueller Presents Fig. 3 Qualitatively and Imprecisely ............ 44
`Claims 1, 2, 8, and 10-15 are separately patentable over Mueller. ..... 48
`
`B.
`
`XI. Petitioner has not carried its burden of establishing a reasonable
`likelihood that claims 1-2 and 8-23 are obvious in view of Mueller and
`the Vivelle-Dot® Label for Ground 2 ........................................................... 49
`
`XII. Petitioner has not carried its burden of establishing a reasonable
`likelihood that claims 3-7 are obvious in view of Mueller, the Vivelle-
`Dot® Label and Kanios for Ground 3 ........................................................... 52
`A.
`Petitioner has not shown the requisite motivation or
`reasonable expectation of success ....................................................... 52
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`B.
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`C.
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`A POSA would have been discouraged from attempting Petitioner’s
`asserted modifications of Mueller ....................................................... 54
`Petitioner relies on an invalid comparison of Mueller and Kanios ..... 55
`
`XIII. Petitioner has not carried its burden of establishing a reasonable
`likelihood of obviousness of claims 1-23 in view of Mueller, the
`Vivelle-Dot® Label, Kanios, and Chien for Ground 4 ................................. 58
`
`XIV. The Petition Should Be Denied Under 35 U.S.C. § 325(d) Because the
`Primary References Were Considered During Prosecution .......................... 60
`
`XV. Conclusion ..................................................................................................... 63
`
`XVI. CERTIFICATE OF COMPLIANCE WITH 37 C.F.R. § 42.24(b)(1) .......... 64
`
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`TABLE OF AUTHORITIES
`
`Cases
`In re Magnum Oil Tools International,
`829 F.3d 1364 (Fed. Cir. 2016) ...................................................................... 50
`
`3M Innovative Props. Co. v. Tredegar Corp.,
`725 F.3d 1315 (Fed. Cir. 2013) ............................................................... 26, 30
`
`Callaway Golf Co. v. Acushnet Co.,
`576 F.3d 1331 (Fed. Cir. 2009) ............................................................... 52, 58
`
`Continental Can Co. U.S.A. v. Monsanto Co.,
`948 F.2d 1264 (Fed. Cir. 1991) ............................................................... 41, 44
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) ............................................................................................ 50
`
`Hockerson-Halberstadt, Inc. v. Avia Group Int’l,
`222 F.3d 951 (Fed. Cir. 2007) ................................................................. 40, 60
`
`In re Cuozzo Speed Techs.,
`778 F.3d 1271 (Fed. Cir. 2015) ...................................................................... 25
`
`In re Gartside,
`203 F.3d 1305 (Fed. Cir. 2000) ...................................................................... 50
`
`In re Oelrich,
`666 F.2d 578 (CCPA 1981) ............................................................................ 41
`
`In re Wright,
`569 F.2d 1124 (CCPA 1976) ................................................................... 40, 42
`
`Net MoneyIN, Inc. v. Verisign, Inc.,
`545 F.3d 1359 (Fed. Cir. 2008) ...................................................................... 48
`
`Nystrom v. Trex Co.,
`424 F.3d 1136 (Fed. Cir. 2005) ......................................................... 40, 41, 60
`
`RCA Corp. v. Applied Digital Data Sys., Inc.
`730 F.2d 1440 (1984) ...................................................................................... 48
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`United States v. Adams,
`383 U.S. 39 (1966) .......................................................................................... 50
`
`Verdegaal Bros. v. Union Oil Co. of California,
`814 F.2d 628 (Fed. Cir. 1987) ........................................................................ 40
`
`
`Statutes
`
`35 U.S.C § 312(a)(3) ............................................................................................ 31
`
`35 U.S.C. § 102 ............................................................................................. 40, 48
`
`35 U.S.C. § 103 ............................................................................................. 49, 50
`
`35 U.S.C. § 314(a) ........................................................................................... 2, 31
`
`35 U.S.C. § 316(e) ................................................................................................ 50
`
`35 U.S.C. § 325(d) .................................................................................. 60, 61, 62
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`
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`Rules and Regulations
`
`37 C.F.R. § 42.100(b)........................................................................................... 25
`
`37 C.F.R. § 42.61(c) ...................................................................................... 38, 39
`
`37 C.F.R. § 42.65 ................................................................................................. 28
`
`37 C.F.R. § 42.65(b) ...................................................................................... 38, 39
`
`77 Fed. Reg. 48,756, 48,766 ................................................................................ 25
`
`
`
`Inter Partes Reviews
`
`Alarm.com Inc. v. Vivint, Inc.,
`IPR2015-01967 (PTAB Mar. 30, 2016) ......................................................... 61
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`Microsoft Corp. v. Parallel Networks Licensing, LLC,
`IPR2015-00483 (PTAB July 15, 2015) .......................................................... 61
`
`Neil Ziegmann, N.P.Z., Inc. v. Stephens,
`IPR2015-01860 (PTAB Feb. 24, 2016) ................................................... 60, 62
`
`Nu Mark LLC v. Fontem Holdings 1, B.V.,
`IPR2016-01309 (PTAB Dec. 15, 2016) .......................................................... 62
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`Ex #
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`2001
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`Patent Owner Preliminary Response
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`EXHIBITS
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`Description
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`Declaration of Dr. Adrian C. Williams
`
`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)
`
`vii
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`Ex #
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`2008
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`IPR2018-00174
`Patent Owner Preliminary Response
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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
`
`2010
`
`2011
`
`2012
`
`2013
`
`J. Mantelle, et al., Effect of Silicone/Acrylic PSA Blends on Skin
`Permeation, 26 PROCEEDINGS OF THE INTERNATIONAL SYMPOSIUM ON
`CONTROLLED RELEASE OF BIOACTIVE MATERIALS 415-16 (Rev. July
`1999) (“the Mantelle Article”)
`
`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)
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`viii
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`Ex #
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`2014
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`IPR2018-00174
`Patent Owner Preliminary Response
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`Description
`
`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
`
`A. Ghosh et al., Current Pharmaceutical Design on Adhesive Based
`Transdermal Drug Delivery Systems, 21 CURR. PHARM. DESIGN
`2771-2783 (2015)
`
`2016
`
`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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`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
`
`R. Subedi et al., Formulation and in vitro evaluation of transdermal
`drug delivery system for donezil, 42 J. PHARMA. INVEST. 1-7 (2012)
`
`2022
`
`2023
`
`J. Mantelle, DOT Matrix® Technology, in MODIFIED RELEASE DRUG
`DELIVERY TECHNOLOGY 405-14 (Rathbone et al. eds., 2d ed. 2008)
`(“the Mantelle Chapter”)
`
`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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`
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`x
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`I.
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`Introduction
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`IPR2018-00174
`Patent Owner Preliminary Response
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`Patent Owner submits this preliminary response under 35 U.S.C. § 313 to
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`Mylan Technologies, Inc.’s (“Petitioner’s”) request for inter partes review (“IPR”)
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`of claims 1-23 of U.S. Patent No. 9,730,900 (“the ’900 Patent,” EX1001). This
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`preliminary response is timely filed within three months of the Board’s notice
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`according a filing date (IPR2018-00174, Paper No. 3), mailed December 14, 2017.
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`For the reasons set forth herein and supported by the cited exhibits, Petitioner’s
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`request for IPR should be denied.
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`The challenged claims of the ’900 Patent generally relate to methods of
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`administering estradiol using a monolithic transdermal drug delivery system
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`(“patch” or “TDS”) that delivers estradiol through the skin at a particular rate
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`(“flux”). These claims cover Patent Owner’s FDA approved MINIVELLE®
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`product, which is a transdermal patch applied twice weekly for the treatment of
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`moderate to severe vasomotor symptoms due to menopause and the prevention of
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`postmenopausal osteoporosis. EX2003, 1. Minivelle® is the smallest FDA-
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`approved estradiol patch, and offers patients advantages such as reduced skin
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`irritation and better aesthetics. EX1001, 2:3-5. Petitioner is seeking FDA approval
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`to market a generic version of Patent Owner’s MINIVELLE® product. See, e.g.,
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`Noven Pharmaceuticals, Inc. v. Mylan Technologies Inc. et al., C.A. No. 1-17-
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`01777 (D. Del.).
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`Petitioner alleges the claims of the ’900 Patent are either anticipated or
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`rendered obvious by one or more cited references, but each asserted ground of
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`unpatentability is fatally flawed. With regard to both anticipation and obviousness,
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`Petitioner cannot make out its case based on express teachings of the cited
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`references, but improperly relies on unsupported interpretations of figures and
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`other inferences that go far beyond what a person of ordinary skill in the art would
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`have understood. With regard to motivation and expectation of success,
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`Petitioner’s positions are contrary to what was understood in the art, including
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`positions contrary to previous writings by its own expert.
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`To justify institution, Petitioner must demonstrate that there is a “reasonable
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`likelihood” that it will prevail as to at least one of the claims challenged. 35 U.S.C.
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`§ 314(a). Petitioner has not meet this standard, because Petitioner relies on
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`“teachings” that are not disclosed in the cited references and mischaracterizations
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`of the cited references and what was known in the art. Petitioner’s arguments are
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`contradicted by its own references and its own expert’s previous writings.
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`Accordingly institution should be denied.
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`II. Overview of the ’900 Patent and Prosecution History
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`The ’900 Patent issued from U.S. patent application no. 13/553,972 (“the
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`’972 application”), which was a continuation of U.S. patent application no.
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`12/216,811 (now U.S. 8,231,906). The ’972 Application was filed July 20, 2012,
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`and issued August 15, 2017. Id. The claims of the’900 Patent are directed to
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`methods of administering estradiol using monolithic TDSs or methods of making
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`the same.
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`Independent claim 1 of the ’900 Patent recites:
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`1. A method for administering estradiol, comprising applying to
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`the skin or mucosa of a subject in need thereof a monolithic
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`transdermal drug delivery system consisting of (i) a backing
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`layer and (ii) a single adhesive polymer matrix layer defining an
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`active surface area and comprising an adhesive polymer matrix
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`comprising estradiol as the only drug, wherein the polymer
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`matrix has a coat weight of greater than about 10 mg/cm2 and
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`includes greater than 0.156 mg/cm2 estradiol, and the system
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`achieves an estradiol flux of from about 0.0125 to about 0.05
`
`mg/cm2/day, based on the active surface area.
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`Independent claim 16 recites:
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`16. A method of making a monolithic transdermal drug delivery
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`system for administering estradiol consisting of (i) a backing
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`layer, (ii) a single adhesive polymer matrix layer and,
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`optionally, (iii) a release liner, comprising forming an adhesive
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`polymer matrix comprising estradiol as the only drug and a
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`polymer blend comprising an acrylic adhesive, a silicone
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`adhesive, and soluble PVP, and applying the adhesive polymer
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`matrix to a support layer to form a single adhesive polymer
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`matrix layer such that the adhesive polymer matrix layer has a
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`coat weight of greater than about 10 mg/cm2 and includes
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`greater than 0.156 mg/cm2 estradiol, wherein the system
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`achieves an estradiol flux of from about 0.0125 to about 0.05
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`mg/cm2/day, based on the active surface area.
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`A “monolithic” system is one in which the drug and adhesive are part of the
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`same layer. EX1001, 6:49-52. 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, 557.
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`During prosecution of the ’972 application, the claims were rejected as
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`allegedly anticipated by U.S. Patent Application Publication No. 2006/0078601
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`(EX1029; “Kanios ’601”); allegedly obvious over Kanios ’601 in view of U.S.
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`Patent No. 6,638,528 (EX1030; “Kanios ’528”); allegedly obvious over Kanios
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`’601 in view of U.S. Patent No. 4,624,665 (EX1031; “Nuwayser”); allegedly
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`obvious over Kanios ’528 in view of Nuwayser; and allegedly obvious over Kanios
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`’528 and Nuwayser further in view of U.S. Patent Application Publication No.
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`2009/0041831 (EX1032; “Miller”). EX1004, 99-103, 147-151, 251-254.
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`Patent Owner overcame these rejections with arguments and clarifying claim
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`amendments. As acknowledged by the Examiner in the Notice of Allowance
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`mailed October 2, 2015 (EX1004, 296-303), “[t[he prior art does not teach nor
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`reasonably suggest a method for administering estradiol with the claimed
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`monolithic transdermal drug delivery system. Further, the prior art does not teach
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`nor reasonably suggest a method for making the claimed monolithic transdermal
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`drug delivery system.” Id., 302.
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`Following receipt of the October 2015 Notice of Allowance, Patent Owner
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`filed an Amendment Under 37 CFR § 1.312 seeking to amend the allowed claims
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`to recite specific embodiments with regard to the amount of estradiol per unit area
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`and flux. EX1004, 314-319. When the Examiner would not enter the amendments
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`“after final,” Patent Owner filed a request for continued examination (“RCE”) to
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`pursue similar claim amendments. Id., 330-331. Once agreement was reached on
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`revised claim language, another Notice of Allowance was issued in August 2016.
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`Id., 412-418.
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`Thereafter, Patent Owner filed additional RCEs in order to obtain
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`consideration of information disclosure statements (“IDSs”). EX1004, 433-441,
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`475-480. After consideration of each IDS, the Examiner issued a Notice of
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`Allowance with similar reasons for allowance. Id., 446-452, 481-487. With the
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`final RCE, Patent Owner presented new dependent claims that were granted as
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`claims 15 and 23. Id., 524-532.
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`After the final RCE, Patent Owner conducted an interview with the
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`Examiner and submitted the Declaration Under 37 CFR § 1.132 of Dr. Richard H.
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`Guy (the “Guy Declaration”)1. EX1004, 538-540, 564-601. In his declaration, Dr.
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`Guy explained the state of the art and presented experimental data of unexpected
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`results. Dr. Guy attested that “a person of ordinary skill in the art would not have
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`thought of coat weight as a parameter to be adjusted to affect the flux of a drug
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`from a transdermal patch” and that none of the art of record “suggests that
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`increasing coat weight would increase flux.” EX1004, 599-600. Dr. Guy also
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`attested that the only predictable way to increase drug flux from a TDS is to
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`increase the size of the TDS. Id., 600. Dr. Guy also presented experimental data
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`showing the unexpected result embodied in the claimed subject matter, that
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`1 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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`increasing the coat weight of the drug-containing polymer matrix of the monolithic
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`estradiol TDS increased flux. Id., 587-596.
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`Thereafter, the Examiner issued the final Notice of Allowance. EX1004,
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`684-691. The Examiner reiterated her finding that “[t]he prior art does not teach
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`nor reasonably suggest the claimed monolithic transdermal drug delivery system,”
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`and separately noted that “Applicant’s arguments of unexpected results…are
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`persuasive.” Id., 689.
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`III. Level of Skill in the Art
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`Petitioner alleges that the person of ordinary skill in the art (“POSA”) would
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`have “an advanced degree…in pharmaceutical chemistry, physical chemistry,
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`bioengineering, or a drug delivery related disciple” or, alternatively, “a bachelor’s
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`degree plus two to five years’ experience in the transdermal delivery industry.”
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`Petition, 15.
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`Without acquiescing to Petitioner’s definition, Patent Owner is willing to
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`adopt Petitioner’s description for purposes of this Preliminary Response with the
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`clarification that a POSA who does not have an advanced degree in the fields
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`mentioned would have a bachelor’s degree in a field related to drug delivery.
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`EX2001, ¶¶26-28.
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`IV. Technological Background
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`IPR2018-00174
`Patent Owner Preliminary Response
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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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`¶¶42-44. 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, ¶51; 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, ¶51; EX1007,
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`¶7.
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`While the flux of transdermal drug delivery system is an in vivo property, it
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`is measured by in vitro methodology, such as in vitro skin permeation studies using
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`human cadaver skin, as illustrated in Example 1 of the ’900 Patent. EX2001, ¶¶48-
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`49; EX1001, 15:10-47; EX1004, 580-581. In such studies, the amount of drug
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`delivered through the skin sample over time is measured and used to calculate flux.
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`EX2001, ¶¶50-52. Because data collected at initial time points usually reflect a lag
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`time, values from a time period once steady state is reached are used to calculate
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`flux. Id.
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`When assessing the flux of TDS, it is essential to account for variations in
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`skin permeability, because there can be a large variation in permeability between
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`different skin samples. EX1004, 597; EX2001, ¶52. The impact of skin
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`permeability on flux and the use of well-known techniques to account for this
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`factor is illustrated in the Guy Declaration submitted during prosecution of the
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`’900 Patent. EX1004, 597. The data presented in ¶¶41-42 of the Guy Declaration
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`show a significant variation in flux (e.g., 1.5 to 2.5-fold higher) when the well-
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`characterized Vivelle-Dot® formulation was tested on different human cadaver
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`skin samples. EX1004, 597-99. The flux observed for Vivelle-Dot® in those
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`studies was not characteristic of Vivelle-Dot® per se, but reflected the higher than
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`usual permeability of the skin samples used in the study. EX2001, ¶¶52. Dr. Brain
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`acknowledges this “high amount of variability that routinely occurs in flux
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`measurements.” EX1002, ¶¶65, 67, 172.
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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 modelled by Fick’s 1st law of diffusion:
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`J = A x kp x ∆C
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`where A is the active surface area of the patch, kp is the drug’s permeability
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`coefficient across the skin (defined as kp = {D x K}/L, where D is the drug’s
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`diffusivity through the skin, K is its partition coefficient, and L is the path length
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`for diffusion across the skin), and ∆C is the difference in concentration of the drug
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`between the patch (Cpatch) and the “downstream” side of the skin barrier
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`(Cdownstream). EX1004, 577; EX2001, ¶¶44-45; EX2004, 3-4.
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`B. Developing Transdermal Drug Delivery Systems
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`The field of transdermal drug delivery is a highly unpredictable art. EX1002,
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`¶172 (“[N]umbers associated with flux are highly variable.”); EX2001, ¶53. Dr.
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`Brain himself has emphasized that the fact that “[s]kin absorption of chemicals is a
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`passive process…does not mean that the process of dermal absorption is simple
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`and highly predictable, as there are a diverse range of factors that can affect the
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`rate and extent to which a chemical is absorbed.” EX2008, 83. In fact, according to
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`Dr. Brain:
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`[O]ne could even imagine that the services of an astrologer may
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`be a useful adjunct to predicting skin absorption!
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`Id., 84.
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`Fick’s 1st law indicates that there are four general ways to increase flux:
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`(1) Increase the active surface area of the patch to cause a proportional
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`change in flux.
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`(2) Increase the drug concentration in the patch until it reaches its limiting
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`solubility.
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`(3) Adjust the formulation for a given drug loading such that the drug
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`reaches its limiting solubility.
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`(4) Introduce a penetration enhancer into the formulation to increase the
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`drug’s diffusivity (D) and/or alter the value of its partition coefficient (K).
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`EX1004, 577-579; EX2001, ¶¶46-47; EX2005, 2-5.
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`Out of the four general ways to increase flux embodied in Fick’s 1st law, the
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`only predictable way is to increase the active surface, i.e., increase the size of the
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`patch. EX2001, ¶¶46, 54. This is because out of all the factors embodied in Fick’s
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`1st law, only active surface area has a directly proportional impact on flux. Id. The
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`predictability of increasing flux by increasing patch size is reflected in commercial
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`TDS products, where different doses of the same product are provided by different
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`patch sizes. Id.; EX1006, 12; EX1016, 18; EX 1015, 5.
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`Other ways of trying to increase flux are unpredictable, and must be tested
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`empirically. EX2001, ¶¶55-56. This is illustrated in several references cited by
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`Petitioner, including Kanios (EX1007), and U.S. Patent Nos. 5,656,286 (EX1011)
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`and 6,024,976 (EX1033) (collectively, the “Miranda Patents”). EX2001, ¶¶56-60.
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`For example, while it is generally expected that increasing drug concentration will
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`have some positive impact on flux up to a point, this approach is useful only until
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`the saturation concentration of the drug is reached. EX2001, ¶55. Increasing drug
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`concentration beyond the saturation point can undermine other important patch
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`properties. Id.; EX1007, ¶13; EX1019, 2:55-3:4; EX2005, 2.
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`Other approaches are even more unpredictable. For example, increasing the
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`silicone to acrylic polymer ratio in the drug-containing polymer matrix of an
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`estradiol TDS has been reported to increase initial flux but shift the flux profile
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`from a pseudo-zero-order to a first order delivery system, which is undesirable for
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`a TDS intended to deliver a uniform dose over an extended period of time.
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`EX2001, ¶¶56-58; EX2010, 415; see also EX1011, 40:66-41:3, 9-12; EX1033,
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`40:43-47, 53-56. These results illustrate the unpredictable effects of adjusting even
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`one parameter of a TDS, and also illustrate the delicate balance and tension
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`between increasing flux and sustaining flux. EX2001, ¶¶58, 62.
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`Increasing drug solubility has a similarly unpredictable impact on flux. For
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`example, when using soluble polyvinylpyrrolidone (“PVP”) to increase drug
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`solubility, the Miranda Patents cited by Petitioner report that even though
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`increasing amounts of PVP reduced crystal formation, the flux was “essentially the
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`same.” EX1011, 50:65-51:5; EX1033, 50:66-51:6. This indicates that an approach
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`that increases drug solubility will not necessarily impact flux. EX2001, ¶¶59-60.
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`Despite these express teachings in Petitioner’s own exhibits, Petitioner
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`inexplicably asserts that there was “a reasonable expectation of successfully
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`increasing the flux” by increasing PVP. Petition, 56.
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`Even the use of penetration enhancers is unpredictable, because the “best”
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`enhancer for a given composition depends on the drug being formulated, the
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`desired pharmacokinetic profile, and other components present in the composition.
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`EX2001, ¶61; EX1011, 38:3-60:40; EX1033, 37:54-60:54; EX2012, 9-10. “It is
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`difficult to select rationally a penetration enhancer for a given permeant…the level
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`of enhancement expected for these agents is unpredictable.” EX2001, ¶61 (quoting
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`EX2011, 248).
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`Further complicating the development process is that the components of a
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`polymer matrix can interact in unpredictable and undesirable ways. EX2001, ¶¶63-
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`64. Previous writings by Dr. Brain highlight this problem. See EX2013. For
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`example, Dr. Brain explains that when the drug is mixed with the adhesive (as it is
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`in a drug-containing polymer matrix), “the potential for interaction between drug
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`and adhesive, which can lead to either a reduction of adhesive effectiveness, or the
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`formation of a new chemical species, must be fully assessed.” EX2013, 339. He
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`also cautions that “residual monomers, catalysts, plasticizers, and resins may react
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`to give new chemical species,” and that “the excipients, including enhancers, or
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`their reaction products, may interfere with adhesive systems.” Id. He identifies
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`“three critical considerations in the selecti