`
`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—01 1 19
`
`
`DECLARATION OF DR. ADRIAN C. WILLIAMS
`
`Noven Pharmaceuticals, Inc.
`EX2001
`
`Mylan Tech., Inc., V. Noven Pharma, Inc.
`IPR2018-01119
`
`0001
`
`
`
`TABLE OF CONTENTS
`
`IPR2018-01119
`
`US. 9,833,419
`
`Introduction ...................................................................................................... l
`
`II.
`
`Qualifications ...................................................................................................2
`
`III.
`
`Patent Law Standards ...................................................................................... 6
`
`IV.
`
`Level Of Skill In The Art .............................................................................. 10
`
`The ’419 Patent .............................................................................................. 11
`
`A.
`
`B.
`
`Brief Overview of the Claimed Invention ........................................... 11
`
`Brief Overview of the Prosecution History ......................................... 14
`
`VI.
`
`Technological Background ............................................................................ 16
`
`A.
`
`B.
`
`C.
`
`Transderrnal Drug Delivery and Drug Flux ........................................ 16
`
`Developing Transdennal Drug Delivery Systems .............................. 26
`
`Coat Weight Was Not Known To Impact Flux ................................... 33
`
`l.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`Kim(EX1010) ........................................................................... 34
`
`Ghosh (EX1014) .......................................................................43
`
`Wong (EX1028) ........................................................................46
`
`Bronaugh (EX1026) .................................................................. 51
`
`Benson (EX1039) ...................................................................... 52
`
`Chien (EX1009) ........................................................................ 53
`
`Mueller (EX 1 005) ..................................................................... 56
`
`D.
`
`Estradiol Transdermal Drug Delivery Systems .................................. 58
`
`VII.
`
`Claim Construction ........................................................................................ 63
`
`A.
`
`B
`
`C.
`
`D
`
`Legal Standard ..................................................................................... 63
`
`“About” ................................................................................................ 63
`
`“Coat Weight” ..................................................................................... 64
`
`“F lux” .................................................................................................. 66
`
`1
`
`0002
`
`
`
`E.
`
`“Therapeutically Effective Amount” .................................................. 69
`
`VIII. Grounds of Unpatentability ........................................................................... 69
`
`A-
`
`Cited References .................................................................................. 69
`
`IPR2018-01119
`
`US. 9,833,419
`
`l.
`
`2.
`
`3.
`
`4.
`
`Mueller (EXIOOS) ..................................................................... 69
`
`Vivelle-D0t® Label (EX1006) ................................................. 72
`
`Kanios (EX1007) ...................................................................... 73
`
`Chien (EX1009) ........................................................................ 77
`
`B.
`
`Ground 1 .............................................................................................. 77
`
`1.
`
`2.
`
`Claims 1, 2, 8, and 10-15 are Not Taught By Mueller ............. 77
`
`Mueller Does Not Show That Example 3 Achieved The
`
`Claimed Estradiol Flux ............................................................. 78
`
`3.
`
`Petitioner’s Use of Mueller Fig. 3 is Scientifically Invalid ...... 85
`
`C.
`
`Ground 2 .............................................................................................. 86
`
`1.
`
`Claims 1-2 and 8-15 are not suggested by Mueller and
`
`the Vivelle-Dot® Label. ........................................................... 86
`
`D.
`
`Ground 3 .............................................................................................. 87
`
`1.
`
`Claims 3—7 are not suggested by Mueller, the Vivelle—
`
`Dot® Label and Kanios. ........................................................... 87
`
`E.
`
`Ground 4 .............................................................................................. 95
`
`1.
`
`Claims 1-15 are not suggested by Mueller, the Vivelle-
`
`Dot® Label, Kanios, and Chien. ............................................... 95
`
`ii
`0003
`
`
`
`LIST OF CITED EXHIBITS
`
`IPR2018-01119
`
`US. 9,833,419
`
`Patent Owner Exhibits
`
`
`Ex #
`
`Description
`
`2002
`
`Curriculum Vitae of Dr. Adrian C. Williams
`
`2003
`Minivelle® Product Label
`
`
`J. Hadgrafi and R. Guy, Feasibilily Assessment in Topical and
`
`2004
`
`Transdermal Delivery, in TRANSDERMAL DRUG DELIVERY 3-4 (R.
`
`Guy & J. Hadgrafi eds., 2d ed. 2003)
`
`2005
`
`J. Hadgraft, Passive enhancement .s-lralegies in (apical and
`tram'dermal drug delivery, 184 INT’L J. PHARMACEUTICS 1-6 (1999)
`
`B. Barry, Transdermal Dmg Delivery, in AULTON’S PHARMAC EUTICS
`
`2006
`
`— THE. DESIGN AND MANUFACTURE OF MEDICINES 565, 571-72, 577
`
`(M. Aulton 6d, 3d ed. 2007)
`
`
`
`
`
`A. Williams & B. Barry, Urea analogues in propylene glycol as
`
`2007
`
`penetration enhancers in human skin, 36 INT’L J. PHARMACEUTICS
`
`43—50 (1989)
`
`
`iii
`0004
`
`
`
`US. 9,833,419
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`IPR2018-01119
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`Ex #
`
`Description
`
`K. Brain & R- Chilcott, Physicachemical Factors Aflecting Skin
`
`2008
`
`Absorption, in PRINCIPLES AND PRACTICE OF SKIN TOXICOLOGY 83-92
`
`(R. Chilcott and S. Price eds., 2008)
`
`2009
`
`Esclim® Product Label
`
`A. Williams & B. Barry, (.‘hemicai Permeation Enhancement, in
`
`2011
`
`ENHANCEMENT IN DRUG DELIVERY 233, 248-50 (E. Touitou & B.
`
`Barry eds., 2007)
`
`A. Williams & B. Barry, The enhancement index concept applied to
`
`2012
`
`terpene penetration enhancersfor human skin and mode! itpophilic
`(oestradioi) and hydrophiiic (Sffluoronracil) drugs, 74 INT’L J.
`
`PHARMACEUTICS 157—168 (1991)
`
`
`
`
`
`K. Walters & K. Brain, Dematalogical F()rmaiaiian and Transdermai
`
`2013
`
`systems; in DEMATOLOGICAL AND TRANSDERMAL FORMULATIONS
`
`338-43 (K. Walters, ed., 2002)
`
`Google Scholar search results obtained March 7, 2018 — citations of
`
`Kim et al., Penetration Enhancement (ffi2-Seiective Agonist,
`
`2014
`
`Tulabuterol, Across Hairless Mouse Skin, J. Pharm. Invest. 33: 79-84
`
`(2003), available online at https://sch01ar.g00gle.com/sch01ar?cites=
`
`790345 3726087495 818&as_sdt=2005&sci0dt=0,5&hl=en
`
`
`iv
`0005
`
`
`
`US. 9,833,419
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`IPR2018-01119
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`Ex #
`
`Description
`
`A. Ghosh et al., Current Pharmaceutical Design on Adhesive Based
`
`2015
`
`Nansdermal Drug Delivery systems, 21 CURR. PHARM. DESIGN
`
`2771-2783 (2015)
`
`2016 US Patent No. 8,029,820
`
`B. Godin & E. Touitou, Transdermal skin delivery: Predictionsfor
`
`2017
`
`humansfi‘om in viva, ex vivo and animal models, 59(1 1) ADV. DRUG
`
`DELIV. REVIEWS 1152-1161 (2007)
`
`R- Hinz et al., In vitro pereutaneous penetration: evaluation of the
`
`2018
`
`utility ofhairless mouse skin, 93(1) J. INVEST. DERMATOL. 87-91
`
`(1989)
`
`J. Bond & B. Barry, Hairless mouse skin is limited as a modelfor
`
`2019
`
`assessing the effects ofpenetration enhancers in human skin, 90(6) J.
`
`INVEST. DERMATOL. 810-813 (1988)
`
`R. Subedi et al., Influence offbrmulation variable in transdermal
`
`2020
`
`drug delivery system containing zolmitriptan, 419 INT’L J.
`
`PHARMACEUTICS 209-214 (201 1)
`
`
`
`
`
`2021
`
`R. Subedi et al., Formulation and in vitro evaluation oftransdermal
`drug delivery system for donezil, 42 J. PHARMA. INVEST. 1-7 (2012)
`
`
`0006
`
`
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`US. 9,833,419
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`IPR2018-01119
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`Ex #
`
`2023
`
`
`
`
`
`Description
`
`J. van de Sandt et (11., In vitro predictions ofskin absorption of
`
`caffeine, testosterone, and benzoic acid: a ntulti-centre comparison
`
`study, 39 REG. TOXICOL. PHARMACOL 271—281 (2004)
`
`
`
`Petitioner Exhibits
`
`
`
`
`EX # Description
`
`1001
`
`US. Patent No. 9,833,419 (“the ”419 Patent”)
`
`Declaration of Dr. Keith Brain
`1002
`
`
`
`
`
`1004
`
`File history of US. Patent No. 9,833,419
`
`1005
`
`US. Patent Application Publication No. US 2003/0099695
`
`(“Mueller”)
`
`Vivelle—Dot-ca Transdermal System ('Novartis) 05/03/2002
`
`1006
`
`Supplemental Approval [Label Revisions] — PD] Document #
`
`5236149B (2006) (“Vivelle-Dotrs Label”)
`
`1007
`
`US. Patent Application Publication No. US 2006/0078602
`
`(“Kanios”)
`
`
`
`vi
`0007
`
`
`
`US. 9,833,419
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`IPR2018-01119
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`Ex #
`
`Description
`
`1009
`US. Patent No. 5,145,682 (“Chien”)
`
`
`Kim et ai., Penetration Enhancement (Jffl2-Selective Agonisi,
`
`1010
`
`Tulabuterol, Across Hairless Mouse Skin, 33 J. PHARM. INVEST-
`
`(2003) 79—84 (“Kim”)
`
`1011
`
`US. Patent No. 5,656,286 to Miranda e! a}.
`
` (Watson Laboratories) 04/05/2002 Approval Letter and Final
`
`
`
`
`1012
`PCT Application Publication WO 1996/003119 (“Fotinos”)
`
`
`1013
`
`US. Patent No. 5,919,477 (“Bevan”)
`
`Ghosh et a1., Developmeni (21%: Transdermal Patch ofMeihadone: In
`
`1014
`
`Vitro Evaluation Across Hairless Mouse and Human Cadaver Skin, 1
`
`PHARM. DEV. TECH. (1996) 285—91 (“Ghosh”)
`
`Climara 0.025mg Transdermal System (Berlex Laboratories)
`
`1015
`
`04/05/2001 Supplemental Approval Letter and Final Labeling — FOI
`
`Document # 5243107A (“Climaraaio Label”)
`
`Alora 0.025mg, 0.05mg, 0.075mg, 0.1mg Transdermal System
`
`1016
`
`Labeling — F01 Document # 5210490A (“Aloracro Label”)
`
`vii
`0008
`
`
`
`US. 9,833,419
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`IPR2018-01119
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`Ex #
`
`Description
`
`US. Patent No. 5,902,602 (“Muller”)
`1013
`
`
`1019 US Patent No. 6,156,335 (“Rovati”)
`
`1020
`
`US. Patent No. 6,521,250 (“Meccni”)
`
`
`
`
`
`Dinger, E., Noven Pharmaceuticals, Inc. ENCYCLOPEDIACOM (2006)
`
`1023
`
`http://www.encyclopedia.com/books/politics-andbusiness-
`magazines/noven—pharmaceuticals-inc (last accessed: June 29, 2017)
`
`(“Dinger”)
`
`
`Butschli, J ., Tiny Patch ‘Dois ’ Pharmaccaiicai Landscape,
`
`PACKAGING WORLD (1999)
`
`1024
`
`https://www.packw0rld.coIII/article/machinery/inspect1011/checkweig
`
`hers/tiny-patch-dots-pharmaceutical-landscape (last accessed: June
`
`29, 2017) (“Butschli”)
`
`Bronaugh R.L., Maibach H.l. (eds), In vitro percutaneoas
`
`1026
`
`absorption: Principles, fundameniais and applications. CRC Press,
`
`Boca Raton, Florida (1991) 85—1 14 (“Bronaugh”)
`
`
`1027
`
`US. Patent No. 5,352,457 (“Jenkins”)
`
`1028
`
`US. Patent No. 5,603,947 (“Wong”)
`
`viii
`0009
`
`
`
`US. 9,833,419
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`IPR2018-01119
`
`Ex #
`
`Description
`
`US. Patent No. 6,638,528 (“KaniOS “528”)
`1030
`
`
`1031
`
`U.S. Patent NO. 4,624,665 (“Nuwayser”)
`
`1032
`
`US. Patent Application Publication No. US 2009/0041831 (“Miller”)
`
`1033
`
`US. Patent NO. 6,024,976 to Miranda e! 02.
`
`1035
`
`File History Of US. Patent NO. 9,730,900
`
`1037
`
`US. Patent No. 9,724,310 to Mantelle
`
`1038
`
`File History of US. Patent NO. 9,724,310
`
`
`
`
`
`1039
`
`Benson, Transdermal Drug Delivery: Penetration Enhancement
`
`Techniques, 2 CURRENT DRUG DELIVERY 23-33 (2005).
`
`J. Mantelle, el.’ (11., Effect quilz'cone/Acrylic PSA Blends 0n Skin
`
`1040
`
`Permeation, 26 PROCEEDINGS OF THE INTERNATIONAL SYMPOSIUM ON
`CONTROLLED RELEASE OF BIOACTIVE MATERIALS 415—16 (Rev. July
`
`1999) (“Mantelle 1999”)
`
`ix
`0010
`
`
`
`US. 9,833,419
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`IPR2018-01119
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`
`
`Ex #
`
`1041
`
`1042
`
`
`
`Description
`
`J. Mantelle, DOTMatriin) Technology, in MODIFIED RELEASE DRUG
`
`DELIVERY TECHNOLOGY 405-14 (Rathbone er al. eds., 2d ed. 2008)
`
`(“Mantelie 2008”)
`
`Foreign Application Number DE10012908 to Mflller
`
`
`
`0011
`
`
`
`lPR2018-01119
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`I.
`
`INTRODUCTION
`
`1.
`
`l have been retained by Noven Pharmaceuticals, Inc. (Patent Owner)
`
`t0 seive as an expert in the field of transdermal drug delivery systems (TDSs) and
`
`transdeimal drug delivery.
`
`2.
`
`I have been asked by Noven Pharmaceuticals, Inc. (Patent Owner) to
`
`provide my opinions and analysis of issues raised in the Petition for Inter Partes
`
`Review of US. Patent No. 9,833,419 filed by Mylan Technologies, Inc- (IPRZOI 8—
`
`01119) (the “‘Petition”). My opinions and analysis are set forth below, and are
`
`based on my review of US. Patent No. 9,833,419 (“the ’419 Patent”) and its
`
`prosecution history, the state of scientific and technical knowledge regarding the
`
`claimed subject matter on or before the priority date of the ’4 l 9 Patent, the
`
`purported prior art cited by Petitioner, and the opinions of Dr. Keith Brain stated in
`
`the Declaration of Keith Brain, PhD. (the “Brain Declaration”) (EX1002).
`
`Evidence underlying my opinions and analysis includes certain documents cited in
`
`the Petition and Brain Declaration and additional evidence listed in the List of
`
`Cited Exhibits above-
`
`3.
`
`I am being compensated for my time at my customary rate of £350 per
`
`hour. My compensation does not depend in any way on the outcome of this
`
`proceeding.
`
`0012
`
`
`
`lPR2018-Ol 119
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`US. 9,833,419
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`11.
`
`QUALIFICATIONS
`
`4.
`
`l have over 30 years“ research experience in transdermal and topical
`
`drug delivery as well as in other areas of drug delivery science including
`
`pharmaceutical materials characterization and novel drug delivery systems using
`
`polymers. My work has covered understanding of the fundamental skin barrier,
`
`strategies to increase topical and transdermal drug delivery and the development of
`
`novel drug delivery formulations.
`
`5.
`
`During my academic career I have taught most aspects of
`
`pharmaceutical formulation to undergraduate pharmacy students, from basic
`
`principles of physical chemistry relevant to drug delivery through to more
`
`specialized courses on topical formulations and the treatment of common skin
`
`conditions. In addition, I have also taught Masters students on topics related to skin
`
`and formulation development and have provided expert teaching on external
`
`courses for Qualified Person qualifications at the University of Brighton and for
`
`RSSL, a company in Reading.
`
`6.
`
`I am currently Professor of Pharmaceutics in the School of Pharmacy
`
`at the University of Reading (UK) and am also the University of Reading Research
`
`Dean for Health. I obtained a B.Sc. (Hons) in 1987 and then began a PhD.
`
`program under the supervision of Professor Brian Barry at the University of
`
`Bradford (UK), entitled “Terpenes and Urea Analogues as Penetration Enhancers
`
`0013
`
`
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`lPR2018-01119
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`US. 9,833,419
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`for Human Skin”. 1 was then appointed as lecturer in pharmaceutical technology in
`
`the Bradford School of Pharmacy where I stayed, progressing from lecturer to
`
`Professor of Biophysical Pharmaceutics. l was appointed as Professor of
`
`Pharmaceutics at the University of Reading in 2004, and held this position whilst
`
`progressing to be appointed Head of Pharmacy in 2008, then Head of the School of
`
`Chemistry, Food and Pharmacy in 2011, and then Research Dean for Health in
`
`2015.
`
`7.
`
`During my academic career, I have authored or co—authored 100
`
`original peer—reviewed research articles in addition to nine review articles and 30
`
`chapters in books. I have studied estradiol delivery through human skin since I
`
`began my PhD. research and have published papers on this topic including: The
`
`enhancement index concept applied to terpene penetration enhancersfor human
`
`skin and model lipoplzilic (oestradiol) and hydrophilic (Stfluorouracil) drugs, INT.
`
`J. PHARM, 1991, 74, 157-168.; Oestradiol permeation through human. skin and
`
`silastic membrane: eflects ofpropylene glycol and supensaturation, J. CONTROL-
`
`RELEASE, 1995, 36, 277-294.; Oestradiol permeation across human skin, silastic
`
`and snake skin membranes: the effects ofetl’ianol/water co—solvent systems, INT. J.
`
`PHARM, 1995, 1 16, 101—112.; FYLRaman microscopic study ofde distribution in
`
`a transdermal drug delivery device, VIBRATIONAL SPECTROSCOPY, 1996, 11, 105—
`
`1 13.; Skin delivery ofoestradiolfrom deformable and traditional liposomes:
`
`0014
`
`
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`mechanistic studies, J. PHARM. PHARMACOL, 1999, 51, 1 123-1 134.; Skin hydration
`
`and possible shunt route penetration in controlled estradiol deliveryfi'om
`
`deformable and standard liposomes, J. PHARM. PHARMACOL, 2001, 53, 1311-
`
`1322.
`
`8.
`
`I wrote a textbook in 2003 that was published by the Pharmaceutical
`
`Press (London) entitled TRANSDERMAL AND TOPICAL DRUG DELIVERY; FROM
`
`THEORY T0 CLINICAL PRACTICE. In 2013, I was asked to write the chapter Topical
`
`and Trcmsdermal Drug Delivery for the well—known standard pharmaceutics
`
`textbook used by many UK Pharmacy students AULTON’S PHARMACEUTICS, and
`
`have subsequently updated this in future editions of the book.
`
`9.
`
`To date, my publications have been cited over 11,200 times by other
`
`researchers.
`
`10.
`
`I have supervised 50 PhD. students and seven post—doctoral
`
`researchers who have worked on projects variously funded by competitively won
`
`research grant awards, by commercial sponsorship or from overseas fiinding.
`
`Projects have spanned various aspects of pharmaceutics and drug delivery,
`
`including “‘Oestradiol permeation through human skin, silastic and snake
`
`membranes; effects of supersaturation and binary co-solvent systems” and
`
`“Promotion of oestradiol permeation through human skin”.
`
`0015
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`1 1.
`
`I have also been invited to give presentations and to chair sessions at
`
`national and international conferences. Examples of such presentations include:
`
`“Maximising the bioavailability of topical drugs”, Introductory Course on the
`
`Biology of the Skin, Fitzwilliam College, Cambridge, 1998.; “Patchy responses to
`
`transdermal delivery”, British Pharmaceutical Conference, Manchester, September
`
`2008.; “Controlled release transdermal therapeutic systems — current trends and
`
`future directions”, Controlled Release Society, Istanbul, Turkey, May 2005.; “Do
`
`corneocytes leak?” Session chair & debate leader, Gordon Research Conference on
`
`the Barrier Function of Mammalian Skin, Newport, Rhode Island, Aug 2007-;
`
`“Formulation issues of dermal products”, CiToxLAB Denna] Minisymposium,
`
`Paris, France, October 2012.
`
`12.
`
`I currently act as a reviewer for grant awarding bodies including the
`
`Commonwealth Scholarship Commission, the UK Medical Research Council, the
`
`UK Engineering and Physical Sciences Research Council and the UK
`
`Biotechnology and Biological Sciences Research Council. I also regularly review
`
`articles submitted to international scientific journals and I am a member of the
`
`editorial board for the Journal of Pharmacy and Pharmacology and a member of
`
`the editorial advisory board for the Journal of Pharmaceutical Sciences.
`
`13.
`
`Throughout my research career I have worked with numerous
`
`pharmaceutical companies, either by providing expect lectures, working on joint
`
`0016
`
`
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`IPR2018-01119
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`research projects or through consultancy. For example, I provided a lecture on
`
`“Strategies for improving transdermal drug delivery”, to Unilever Research, Port
`
`Sunlight (UK) in 1996, and in 2016 1 was a consultant for Pfizer, Jersey City, NJ,
`
`on their Topical Pain Advisory Board.
`
`14. My research and standing in the field has been recognized by my
`
`election as a Fellow of the Royal Society of Chemistry in 1992, being awarded a
`
`Fellow of the UK Higher Education Academy in 2007, and my election as a Fellow
`
`of the UK Academy of Pharmaceutical Sciences in 2013.
`
`15.
`
`A copy of my curriculum vitae, which includes my education
`
`background, work and research history, and a list of selected publications and
`
`presentations, is attached to this declaration as Exhibit 2002.
`
`16.
`
`The analysis set forth in this declaration is based on my education,
`
`knowledge and experience in the area of transdermal drug delivery systems over
`
`the past 30 plus years.
`
`111.
`
`PATENT LAW STANDARDS
`
`17.
`
`I have been informed by counsel that the claims of a patent are
`
`interpreted as a person of skill in the alt would have understood them in the
`
`relevant time period, which I understand is the earliest filing date accorded to the
`
`patent. I understand that the ’419 Patth benefits from a filing date of July 10,
`
`2008. Accordingly, my comments, Opinions, and analysis herein refer to the
`
`0017
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`
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`lPR2018-01119
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`US. 9,833,419
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`knowledge and understanding in the field of transdermal drug delivery systems and
`
`transdermal drug delivery as of July 10, 2008.
`
`18.
`
`I have been informed by counsel that a claim is anticipated (118.,
`
`deemed not novel) only if each and every element as set forth in the claim is found,
`
`either expressly or inherently described, in a single prior 2111 reference- I understand
`
`that the fact that a certain result or characteristic may occur or be present in the
`
`prior art is not sufficient to establish the inherency of that result or characteristic.
`
`Rather, the feature at issue must necessarily be present in the thing described.
`
`19.
`
`I have been informed by counsel that a claim is obvious if the
`
`differences between the claimed invention and the prior alt are such that the
`
`claimed invention as a whole would have been obvious to a person having ordinary
`
`skill in the art to which the claimed invention pettains (a “POSA”) as of the earliest
`
`filing date of the patent. I understand that a person of ordinary skill in the art is a
`
`hypothetical person or persons deemed to have knowledge of all relevant prior art
`
`at the time of the earliest filing date of the patent (here, July 10, 2008)- I also
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`understand that a POSA is considered to possess ordinary creativity- My discussion
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`herein of a POSA refers to such a person as of July 10, 2008.
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`20.
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`I also understand that patentability is not negated by the manner in
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`which the invention was made.
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`21.
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`I have been informed by counsel that when assessing obviousness one
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`must determine: (1) the scope and content of the prior art; (2) the differences
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`between the claimed invention of the patent and the prior art; (3) the level of
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`ordinary skill in the art at the time the invention was made; and (4) any secondary
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`considerations of non—obviousness. I understand that such secondary or objective
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`evidence of nonobviousness can include evidence that an invention achieved a
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`surprising or unexpected result and evidence of commercial success of the
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`invention. I understand that such evidence must have a nexus, or causal
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`relationship, to the claimed invention in order to be relevant to the nonobviousness
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`of the claim.
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`22.
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`I also have been informed and understand that when analyzing the
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`question of obviousness, it is improper to use hindsight to reconstruct the
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`invention, and that one cannot use the patent as a road map for selecting and
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`combining items of prior art. I have been informed and understand that the relevant
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`question is what a POSA would have understood without the benefit of the
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`disclosure of the patent- I have been informed and understand that an obviousness
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`inquiry can be based on a combination of multiple prior alt references; however,
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`the references must either be from the same field of endeavor as the claimed
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`invention or reasonably pertinent to the problem faced by the inventor, in that it
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`would logically commend itself to the inventor’s attention in considering his or her
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`problem. I further understand that the obviousness inquiry considers whether a
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`POSA would have had a reason to attempt to select, combine and modify the
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`references in the manner asserted for obviousness, and a reasonable expectation of
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`success in doing so.
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`23.
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`I am further informed and understand that a claim composed of
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`several elements is not proved obvious merely by demonstrating that each of its
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`elements was independently known in the prior art. There must have been an
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`apparent reason to select and combine the known elements in the fashion claimed,
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`a reasonable expectation of success in doing so, and the results must have been
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`predictable to one of ordinary skill in the aft.
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`24.
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`Further, I have been informed and understand that claims can be
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`found invalid under an “obvious to try” theory only if, at the time of the invention,
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`there was a recognized problem or need in the an, a finite number of identified,
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`predictable potential solutions to the recognized need or problem, and a POSA
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`could have pursued the known potential solutions with a reasonable expectation of
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`success. I also have been informed and understand that even then,
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`secondary/objective evidence of nonobviousness must be considered.
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`25.
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`Further, I understand that when the validity of a patent is challenged
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`in a USPTO inter partes review proceeding, the burden falls on the Petitioner to
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`0020
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`show invalidity by a preponderance of the evidence, e.g., by evidence showing that
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`invalidity is more likely than not.
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`IV. LEVEL OF SKILL IN THE ART
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`26.
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`Petitioner alleges that the person of ordinary skill in the alt (“POSA”)
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`would have “an advanced degree, for example a Ph.D., in pharmaceutical
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`chemistry, physical chemistry, bioengineering, or a drug delivery related disciple”
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`or, altematively, “a bachelor’s degree plus two to five years“ experience in the
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`transdermal delivery industry.” Petitioner also asserts that a POSA “would likely
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`have familiarity with formulation of drugs for transdermal administration and
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`would have been able to understand and interpret the references discussed in the
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`field.” Petition, 15; EXIOOZ, 11152—53.
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`27.
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`l have adopted Petitioner’s opinion for the purpose of this analysis
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`with the clarification that a POSA who does not have an advanced degree in the
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`listed fields would have a bachelor’s degree in a field related to drug delivery.
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`28.
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`As reflected in my curriculum vitae (EX2002), l have the scientific
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`background and technical expertise to provide opinions and analysis from the
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`perspective of a person of ordinary skill in the art as of the July 10, 2008 priority
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`date of the ’4 1 9 Patent. Moreover, as of that date, I met or exceeded the above
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`qualifications of a hypothetical person of ordinary skill in the art.
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`V.
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`THE ’419 PATENT
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`A.
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`Brief Overview of the Claimed Invention
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`29.
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`I have read and understand the specification and claims of the ’419
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`Patent. The claims of the ’419 Patth are generally directed to estradiol transderma]
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`drug delivery systems (cg, transdermal “patches,” referred to herein as “TDSs”).
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`As described in the ’419 Patent, the TDSs of the ’419 Patth have a smaller active
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`surface area than the prior art Vivelle—Dot® product line, but achieve daily dosages
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`that are about equal to or greater than the Vivelle-Dot® products, meaning that
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`they achieve daily dosages that are about equal to a Vivelle-Dot® product in a
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`smaller sized system. EXIOOI, 3266-4: 16. Indeed, the Minivelle® products for
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`which the ’4 l 9 Patth is an Orange Book-listed patent are only about 60% the size
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`of the Vivelle—Dot® products but deliver the same daily doses of estradiol.
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`EX2003, 16; EX1006, 12.
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`30.
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`As discussed in the ”419 Patent, “the ability to provide a smaller
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`system without sacrificing daily dosage represents a significant advance,” and was
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`made possible by the surprising discovery that “increasing the coat weight of the
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`drug-containing adhesive layer resulted in an increased flux per unit area, and thus
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`permitted the development of smaller transdermal drug delivery systems that
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`achieve comparable daily dosages.” EXlOOl, 3:50-63. As explained in the ’419
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`Patent and as I discuss in more detail below, this result was surprising “because
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`1 1
`0022
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`coat weight is typically selected to control the duration of delivery, but is not
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`generally understood to impact delivery rate.”1d. That is, as explained in the ’419
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`Patent and as I discuss in more detail below, “while it is known in the art to
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`increase coat weight to provide delivery over a longer period of time, it was not
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`known that increasing coat weight could increase delivery rate or flux, and thus
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`permit the development of a smaller system while maintaining daily dosage.” 10’. It
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`is this unexpected discovery that permitted the development of Patent Owner’s
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`FDA—approved Minivelle® product line, which offers women the same therapeutic
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`efficacy as Vivelle—Dot® products in much smaller sized patches. EX2003, 16;
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`EX1006, 12.
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`3].
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`The TDSs claimed in the “419 Patent are “monolithic” ding—in—
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`adhesive systems, meaning that they have a single drug-containing polymer matrix
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`layer and consist of (i) a backing layer; (ii) a drug-in—adhesive polymer matrix
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`layer, and, optionally, (iii) a release liner that is removed prior to use. EX1001,
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`Claim 1. The claims recite that the adhesive polymer matrix has a coat weight of
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`greater than about 10 mg/cm2 and includes greater than 0.156 mg/cm2 of estradiol,
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`and that the TDS achieves an estradiol flux of from 0.0125 to about 0.05
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`mg/cmz/day, based on the active surface area of the system. 1d.
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`32.
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`The ’419 Patent has 15 claims, with independent Claim 1 being the
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`sole independent claim. Claim 1 of the ’419 Patent recites:
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`12
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`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
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`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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`33.
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`For the purposes of this declaration, I have focused primarily on
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`independent claim 1 and dependent claim 3 of the ”419 Patent.
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`34.
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`The ’419 Patth is a continuation of the ’310 and ’900 Patents, for
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`which I previously provided declaration testimony in lPR2018-00173 and
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`lPR2018—00174, which were denied institution. 1 note that independent claim 1 of
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`the ’419 Patth differs from independent claim 1 of the ”310 Patent only by one
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`word (“‘about” is not recited in one instance of claim 1 of the ’41 9 Patent).
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`Dependent claims 10 and 11 of the ’419 Patent are each similarly missing a single
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`instance of the term “about” that is recited in dependent claims 10 and 11 of the
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`’310 Patent, but claims 1-15 of the ’419 Patent are otherwise identical to claims 1-
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`13
`0024
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`15 of the ’310 Patent. I also note that Petitioner’s asserted Grounds of
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`unpatentability for the ’419 Patent are the same as Petitioner’s previously asserted
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`Grounds of unpatentability for the ’3 10 and ’900 Patents.
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`B.
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`Brief Overview of the Prosecution History
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`35. US. Application No. 14/870,574 (“the ’574 application”), which
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`issued as the ”419 Patent, was filed on September 30, 2015, and is a continuation
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`of US. patent application no. 14/738,255 (pending), which was a continuation of
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`U.S. patent application no. 14/024,985 (now US. 9,724,310), which was a
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`continuation of US. patent application no. 13/553,972 (now US. 9,730,900),
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`which was a continuation of US. patent application no. 12/216,81 1 (now US.
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`8,231,906) (EX1004). I understand that the ”419, ’310 Patent and “900 Patents
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`have been and are the subject of litigation. Paper 4, l—2-
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`36.
`
`During prosecution of the ’574 application, the claims were rejected
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`as allegedly obvious over US. Patent No. 6,638,528 (EX1030; “Kanios ’528”); in
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`view of US. Patent No. 4,624,665 (EX1031; “Nuwayser”). EX1004, 129-133.
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`37.
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`Patent Owner overcame these rejections with arguments and
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`clarifying claim amendments. EX1004, 183-193.
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`38.
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`Patent Owner also conducted an interview with the Examiner and
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`submitted the Declaration Under 37 CFR § 1.132 of Dr. Richard H. Guy (the “Guy
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`14
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`US. 9,833,419
`Declaration”)1. EX1004, 138, 159-181, 200-306. In his declaration, Dr. Guy
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`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, 207, 227. 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., 227. 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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`increasing the coat weight of the drug—containing polymer matrix of the monolithic
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`estradiol