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
`
`
`DECLARATIONOF DR. ADRIAN C. WILLIAMS
`
`Noven Pharmaceuticals, Inc.
`EX2001
`Mylan Tech., Inc., v. Noven Pharma., Inc.
`IPR2018-01119
`
`0001
`
`

`

`TABLE OF CONTENTS
`
`IPR2018-01119
`U.S. 9,833,419
`
`PSVERECUITION oo Lay's choc: cesdengcacicegesanztencaceeerecqans assed apesesppenseneasionyzspeacescecesseansensesapeds ]
`
`IL.
`
`RATER OART of wn sd cas toaa pase sash acs ua owecte ahawewastea'gey sapnrverdsosuniescacetsasieaecnteaedaeoeeeo ee2
`
`HI.
`
`Pateteh Law Standard 5, ss ccsvscezasincssxasenssvsisarsvviscsainsatarscesinotaved danisiens covniseveisaets 6
`
`IV.
`
`Level Of Skill In The Art 200.0... cece ceceececeececnecceseceecenseeseseeesesenseeeees 10
`
`PHS TTS PAGING, cisasccivwsesccestyspceccousczcces co is ovekasandin iw evatsesaasiesiseitaseee ene eeintoe 1]
`
`A.
`
`Brief Overview of the Claimed Invention.................00..:ccceeeceeeeeeeeeeee 11
`
`B._Brief Overview of the Prosecution History...........0....00.cccceesceeeseeeeeeee 14
`
`VI.
`
`Pechnescal BAGeeOATS25 a. vis ccs adcisearsntarigeesederessyeeres tecatieret peep etadinieest 16
`
`A.—Transdermal Drug Delivery and Drug Flux....0....000..000cccceeeceeeeeeeeeee 16
`
`B.|Developing Transdermal Drug Delivery Systems................0.....:0:0+ 26
`
`C.
`
`Coat Weight Was Not Known To Impact Flux.........0...0..0cccccceeeeees 33
`
`1.
`
`2
`
`3
`
`Rima (BAPG 3622 caccnriiinaiiivistiteiapaiiea asa casa 34
`
`Ghosh (EXO) castascauscad ania naa ieausaanaies43
`
`WOMEEPOZaNis cibscedeeiedaiinte Rh Haedetesegamie hide asedeemeira iets46
`
`4. Brora (EX GOO) «c-20zctccacssdoscedgnseadscbeaczet seach osocetddecheoscends act: 51
`
`5
`
`6
`
`7
`
`FSGS CEES SD)sa aie sec sais Sone casa dans catia case cevocatcapanixapadcapanse 52
`
`Cater CBA NDO9) ve. sccsveaassaswansenacasssaassocasrssdends saevadcasebsansssanssincesas 53
`
`Muciler (EX TOUS) scocsce sc ciasieaiircaatia ma eiturcimeetiaeieee 56
`
`D.—Estradiol Transdermal Drug Delivery Systems...................eeeeeeeees 58
`
`VIL.
`
`Claim Construction ...........cccccceseesceseesceescesecesecaeeeeeesesseeseceeseeeeaeeaesaeeeeeeaeens 63
`
`Ac©TRBOaE Sanat ccs ct oecees kn ibise hood teeta acd lee tenet cache thes! 63
`
`B
`
`PPURMOMELSco: cheat anecdote sasacansaezorsesetactceadeceedaseccacbpicectcass teeatteniendadeasct cen eee! 63
`
`Gi CE WettA a ssiec cad cecdias es ba Leas cca ssesdsuasivasveay et siesbcviey eaeisasoasadsdaatasseanebns 64
`
`De ER oeeasa davemeceevacceveteaiatcerssts AN SLE CAN CG Iola deer ae idatiateeniaeed es 66
`
`i
`0002
`
`

`

`IPR2018-01119
`U.S. 9,833,419
`““Therapeutically EMechive Amount”..:;.cc:sccc:icsgacsbiscgessageslicesidessiiacs 69
`
`BE.
`
`Vilk.. reinds of Unpatentabilisy, ..4.s:winicianirausneinaunianawouweaiah 69
`
`As
`
`RettCGHdesi cirasiiatisttsatisSuistasuesaicavaladiaatasreantbias 69
`
`1.
`
`2.
`
`3.
`
`4.
`
`WMieHer (EOS): ctsesss sasvsacerstsasabinsiescdsesssnarsguenasdetazsarscansssasans 69
`
`Vivelle-Dot® Label (EX1006).............cccc ct ceecssescesssescneessseeees 72
`
`Kanios (EX1007) ooo... eccccecccecessescececeenseeececessssseceeeesessseees 73
`
`Chien (EX1009) oo...cece ce cceceeeceeceeseeeneeenseensecesseesseeeseeeseees 77
`
`Bl GU 1 one cece cece ceeecesecesecensceeseceseeeseecsececseecnsecnseenseeesesenseeeees 77
`
`n
`
`ze.
`
`2.
`
`Claims 1, 2, 8, and 10-15 are Not Taught By Mueller............. 77
`
`Mueller Does Not Show That Example 3 Achieved The
`
`Clatmed Estradiol PIX .0...c..cccescccecscceeasesessecseaavvarsteenscvecastessaens 78
`
`Petitioner’s Use of Mueller Fig. 3 is Scientifically Invalid......85
`
`Oe RNR te cat extn Zac ate goaadhocen SY i secatesaesbugczagtesevccaatbeh otene teeta 86
`
`P.
`
`Claims 1-2 and 8-15 are not suggested by Mueller and
`
`thie Vivelle-Dote) Gael sce cccasicccees ac cecsd cs dese daesas cand coceernvas onal 86
`
`DY, CGB D is 2a55 205.2 cescrentse nsdn teavitenet dene dav Wiad deal Monde eases tee bites 87
`
`1.
`
`Claims 3-7 are not suggested by Mueller, the Vivelle-
`
`POOTE LG) ate TEATIOS: a: sasssiconsscavasdceansdsahsieeas sdebsocteacicess sosnntar’ 87
`
`Be,|UGSROMMREICE FT ccapssncecoscartsseatensovenseceatasterencgansaconsnscensagrerseresezeapceseazepceesatens 95
`
`b:
`
`Claims 1-15 are not suggested by Mueller, the Vivelle-
`
`Dot® Label, Kanios, and Chien...0....0.0000.....cceceeeeeeeeseeceeeeeeeeeeees 95
`
`il
`0003
`
`

`

`LIST OF CITED EXHIBITS
`
`IPR2018-01119
`U.S. 9,833,419
`
`Patent Owner Exhibits
`
`
`Ex #
`
`Description
`
`2002|Curriculum Vitae of Dr. Adrian C. Williams
`
`2003|Minivelle® Product Label
`
`
`J. Hadgraft and R. Guy, Feasibility Assessment in Topical and
`2004|Transdermal Delivery, in TRANSDERMAL DRUG DELIVERY3-4 (R.
`
`Guy & J. Hadgraft eds., 2d ed. 2003)
`
`
` 43-50 (1989)
`
`
`J. Hadgraft, Passive enhancement strategiesin topical and
`transdermaldrug delivery, 184 INT’L J. PHARMACEUTICS1-6 (1999)
`
`5005
`
`2006|—THE DESIGN AND MANUFACTUREOF MEDICINES 565, 571-72, 577
`
`B. Barry, Transdermal Drug Delivery, in AULTON’S PHARMACEUTICS
`
`(M. Aulton ed., 3d ed. 2007)
`
`A. Williams & B. Barry, Urea analoguesin propylene glycol as
`2007|penetration enhancersin human skin, 36 INT’L J. PHARMACEUTICS
`
`ill
`0004
`
`

`

`Ex #
`
`Description
`
`K. Brain & R. Chilcott, Physicochemical Factors Affecting Skin
`
`2008
`
`Absorption, in PRINCIPLES AND PRACTICE OF SKIN TOXICOLOGY 83-92
`
`(R. Chilcott and S. Price eds., 2008)
`
`2009
`
`Esclim® Product Label
`
`IPR2018-01119
`U.S. 9,833,419
`
`
` K. Walters & K. Brain, Dematological Formulation and Transdermal
`
`
`A. Williams & B. Barry, Chemical Permeation Enhancement, in
`
`2011
`
`ENHANCEMENTIN DRUG DELIVERY 233, 248-50 (E. Touitou & B.
`
`Barry eds., 2007)
`
`A. Williams & B. Barry, Zhe enhancement index concept applied to
`
`terpene penetration enhancersfor human skin and modellipophilic
`
`2012
`
`(oestradiol) and hydrophilic (5-fluorouracil) drugs, 74 INT’L J.
`
`PHARMACEUTICS 157-168 (1991)
`
`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 off2-Selective Agonist,
`
`2014
`
`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
`
`1V
`0005
`
`

`

`IPR2018-01119
`U.S. 9,833,419
`
`Ex #
`
`Description
`
`A. Ghosh et al., Current Pharmaceutical Design on Adhesive Based
`2015|Transdermal Drug Delivery Systems, 21 CURR. PHARM. DESIGN
`
`2771-2783 (2015)
`
`2016|U.S. Patent No. 8,029,820
`
`B. Godin & E. Touitou, Transdermal skin delivery: Predictionsfor
`2017|humansfrom in vivo, ex vivo and animal models, 59(11) ADV. DRUG
`
`DELIV. REVIEWS 1152-1161 (2007)
`
`
`
`
`
`R. Subedi e/ al., Formulation andin vitro evaluation oftransdermal
`drug delivery system for donezil, 42 J. PHARMA. INVEST. 1-7 (2012)
`
`R. Hinz ef al., In vitro percutaneouspenetration: 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 enhancersin humanskin, 90(6)J.
`
`INVEST. DERMATOL. 810-813 (1988)
`
`R. Subedi e/ al., Influence offormulation variable in transdermal
`2020|drug delivery system containing zolmitriptan, 419 INT’L J.
`
`PHARMACEUTICS 209-214 (2011)
`
`5091
`
`Vv
`
`0006
`
`

`

`Ex #
`
`Description
`
`IPR2018-01119
`
`U.S. 9,833,419
`
`
`
`J. van de Sandtef al., In vitro predictionsofskin absorption of
`2023|caffeine, testosterone, and benzoic acid: a multi-centre comparison
`
`study, 39 REG. TOXICOL. PHARMACOL 271-281 (2004)
`
`Petitioner Exhibits
`
`
`
`
`
`Ex # Description
`
`1001|U.S.Patent No. 9,833,419 (“the ’419 Patent”)
`
`Declaration of Dr. Keith Brain
`1002
`
`
`1004|File history of U.S. Patent No. 9,833,419
`
`U.S. Patent Application Publication No. US 2003/0099695
`
`1005
`
`
`
`
`
`
`(“Mueller”)
`
`Vivelle-Dot# Transdermal System (Novartis) 05/03/2002
`1006|Supplemental Approval [Label Revisions] — FOI Document #
`
`5236149B (2006)(“Vivelle-Dot» Label”)
`
`U.S. Patent Application Publication No. US 2006/0078602
`
`1007
`
`(“Kanios”)
`
`v1
`0007
`
`

`

`Ex #
`
`Description
`
`1009|US. Patent No. 5,145,682 (“Chien”)
`
`
`Kim et al., Penetration Enhancement off2-Selective Agonist,
`1010|Tulobuterol, Across Hairless Mouse Skin, 33 J. PHARM. INVEST.
`
`(2003) 79-84 (“Kim”)
`
`1011|U.S. Patent No. 5,656,286 to Mirandaet al.
`
`1012|PCT Application Publication WO 1996/003119 (“Fotinos”)
`
`
`1013|US. Patent No. 5,919,477 (“Bevan”)
`
`IPR2018-01119
`U.S. 9,833,419
`
` (Watson Laboratories) 04/05/2002 Approval Letter and Final
`
`
`
`
`Ghoshef al., Development ofa Transdermal Patch ofMethadone:In
`
`1014
`
`Vitro Evaluation Across Hairless Mouse and Human Cadaver Skin, |
`
`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 (“Climara® Label”’)
`
`Alora 0.025mg, 0.05mg, 0.075mg, 0.1mg Transdermal System
`
`1016
`
`Labeling — FOI Document # 5210490A (“Alora® Label’)
`
`Vii
`0008
`
`

`

`IPR2018-01119
`U.S. 9,833,419
`
`Ex #
`
`Description
`
`1018|U.S. Patent No. 5,902,602 (“Miiller’’)
`
`
`1019|U.S. Patent No. 6,156,335 (“Rovati’)
`
`1020|U.S. Patent No. 6,521,250 (“Meconi’”’)
`
`Dinger, E., Noven Pharmaceuticals, Inc. ENCYCLOPEDIA.COM (2006)
`http://www.encyclopedia.com/books/politics-andbusiness-
`magazines/noven-pharmaceuticals-inc (last accessed: June 29, 2017)
`
`
`
`
`
`1023
`
`(“Dinger’)
`
`
`Butschli, J., Tiny Patch ‘Dots’ Pharmaceutical Landscape,
`
`PACKAGING WORLD(1999)
`1024|https://www.packworld.com/article/machinery/inspection/checkweig
`
`hers/tiny-patch-dots-pharmaceutical-landscape (last accessed: June
`
`29, 2017) (“Butschli”)
`
`Bronaugh R.L., Maibach H.I. (eds.), /n vitro percutaneous
`1026|absorption: Principles, fundamentals and applications. CRC Press,
`
`Boca Raton, Florida (1991) 85—114 (“Bronaugh’’)
`
`
`1027|US.Patent No. 5,352,457 (“Jenkins”)
`
`1028|U.S. Patent No. 5,603,947 (“Wong”)
`
`Vill
`0009
`
`

`

`IPR2018-01119
`U.S. 9,833,419
`
`Ex #
`
`Description
`
`1030|US. Patent No. 6,638,528 (“Kanios 528”)
`
`
`1031|U.S. Patent No. 4,624,665 (“Nuwayser’’)
`
`1032
`
`U.S. Patent Application Publication No. US 2009/0041831 (“Miller”)
`
`1033|U.S. Patent No. 6,024,976 to Mirandaet al.
`
`1035|File History of U.S. Patent No. 9,730,900
`
`1037|U.S. Patent No. 9,724,310 to Mantelle
`
`1038|File History of U.S. Patent No. 9,724,310
`
` CONTROLLED RELEASE OF BIOACTIVE MATERIALS415-16 (Rev. July
`
`
`
`J. Mantelle, et al., Effect ofSilicone/Acrylic PSA Blends on Skin
`Permeation, 26 PROCEEDINGS OF THE INTERNATIONAL SYMPOSIUM ON
`
`1039
`
`Benson, 7ransdermal Drug Delivery: Penetration Enhancement
`Techniques, 2 CURRENT DRUG DELIVERY 23-33 (2005).
`
`rai
`
`1999) (““Mantelle 1999”)
`
`1X
`0010
`
`

`

`IPR2018-01119
`
`Ex #
`
`Description
`
`J. Mantelle, DOT Matrix® Technology, in MODIFIED RELEASE DRUG
`1041|DELIVERY TECHNOLOGY405-14 (Rathbonee/al. eds., 2d ed. 2008)
`
`
`
`U.S. 9,833,419
`
`(“Mantelle 2008”)
`
`1042|Foreign Application Number DE10012908 to Miiller
`
`x
`
`0011
`
`

`

`IPR2018-01119
`U.S. 9,833,419
`
`I.
`
`INTRODUCTION
`
`ie
`
`I have been retained by Noven Pharmaceuticals, Inc. (Patent Owner)
`
`to serve as an expert in the field of transdermal drug delivery systems (TDSs) and
`
`transdermal 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 /nier Partes
`
`Review of U.S. Patent No. 9,833,419 filed by Mylan Technologies, Inc. (IPR2018-
`
`01119) (the “Petition”). My opinions and analysis are set forth below, and are
`
`based on my review of U.S. Patent No. 9,833,419 (“the ’419 Patent’) andits
`
`prosecution history, the state of scientific and technical knowledge regarding the
`
`claimed subject matter on or before the priority date of the °419 Patent, the
`
`purported prior art cited by Petitioner, and the opinionsof Dr. Keith Brain stated in
`
`the Declaration of Keith Brain, Ph.D. (the “Brain Declaration”) (EX1002).
`
`Evidence underlying my opinions and analysis includes certain documentscited in
`
`the Petition and Brain Declaration and additional evidence listed in the List of
`
`Cited Exhibits above.
`
`3.
`
`1 am being compensated for my time at my customary rate of £350 per
`
`hour. My compensation does not depend in any way on the outcomeofthis
`
`proceeding.
`
`0012
`
`

`

`IPR2018-01119
`U.S. 9,833,419
`
`Il.
`
`QUALIFICATIONS
`
`4.
`
`I 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.
`
`a,
`
`During my academic career | have taught most aspects of
`
`pharmaceutical formulation to undergraduate pharmacystudents, 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 Ph.D.
`
`program underthe supervision of Professor Brian Barry at the University of
`
`Bradford (UK), entitled “Terpenes and Urea Analogues as Penetration Enhancers
`
`0013
`
`

`

`IPR2018-01119
`U.S. 9,833,419
`for Human Skin’. I 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. I 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 Pharmacyin 2011, and then Research Dean for Health in
`
`2015.
`
`ty
`
`During my academic career, | have authored or co-authored 100
`
`original peer-reviewed researcharticles in addition to nine review articles and 30
`
`chapters in books. I have studied estradiol delivery through human skinsinceI
`
`began my Ph.D. research and have published papers onthis topic including: 7he
`
`enhancement index concept applied to terpene penetration enhancersfor human
`
`skin and modellipophilic (oestradiol) and hydrophilic (5-fluorouracil) drugs, INT.
`
`J. PHARM., 1991, 74, 157-168.; Oestradiol permeation through human skin and
`
`silastic membrane:effects ofpropylene glycol and supersaturation, J. CONTROL.
`
`RELEASE, 1995, 36, 277-294.; Oestradiol permeation across humanskin, silastic
`
`and snake skin membranes:the effects ofethanol/water co-solvent systems, INT. J.
`
`PHARM., 1995, 116, 101-112.; #'7-Raman microscopicstudy ofdrug distribution in
`
`a transdermal drug delivery device, VIBRATIONAL SPECTROSCOPY, 1996, 11, 105-
`
`113.; Skin delivery ofoestradiolfrom deformable and traditional liposomes:
`
`0014
`
`

`

`IPR2018-01119
`U.S. 9,833,419
`mechanistic studies, J. PHARM. PHARMACOL., 1999, 51, 1123-1134.; Skin hydration
`
`and possible shunt route penetration in controlled estradiol deliveryfrom
`
`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
`
`THEORYTO CLINICAL PRACTICE. In 2013, I was asked to write the chapter Topical
`
`and Transdermal Drug Delivery for the well-knownstandard pharmaceutics
`
`textbook used by many UK Pharmacy students AULTON’S PHARMACEUTICS, and
`
`have subsequently updatedthis in future editions of the book.
`
`9.
`
`To date, my publications have been cited over 11,200 times by other
`
`researchers.
`
`10.
`
`Ihave supervised 50 Ph.D. 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 funding.
`
`Projects have spanned variousaspects of pharmaceutics and drug delivery,
`
`including “Oestradiol permeation through humanskin, silastic and snake
`
`membranes; effects of supersaturation and binary co-solvent systems” and
`
`“Promotion of oestradiol permeation through human skin”.
`
`0015
`
`

`

`IPR2018-01119
`U.S. 9,833,419
`[have also been invited to give presentations andto chair sessions at
`
`11.
`
`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 responsesto
`
`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
`
`cormeocytes 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 Dermal Minisymposium,
`
`Paris, France, October 2012.
`
`12.
`
`I currently act as a reviewerfor 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 memberofthe
`
`editorial board for the Journal of Pharmacy and Pharmacology and a memberof
`
`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
`
`

`

`IPR2018-01119
`U.S. 9,833,419
`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 I was a consultant for Pfizer, Jersey City, NJ,
`
`on their Topical Pain Advisory Board.
`
`14. Myresearch andstandingin 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. Acopy 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 experiencein the area of transdermal drug delivery systems over
`
`the past 30 plus years.
`
`II.
`
`PATENT LAW STANDARDS
`
`17.
`
`Ihave been informed by counsel that the claims of a patent are
`
`interpreted as a person of skill in the art would have understood them in the
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`relevant time period, which I understandis the earliest filing date accorded to the
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`patent. I understand that the ’419 Patent benefits from a filing date of July 10,
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`2008. Accordingly, my comments, opinions, and analysis herein refer to the
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`U.S. 9,833,419
`knowledge and understandingin the field of transdermal drug delivery systems and
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`transdermal drug delivery as of July 10, 2008.
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`18.
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`LI have been informed by counsel that a claim is anticipated (Z.e.,
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`deemednot novel) only if each and every elementas set forth in the claim is found,
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`either expressly or inherently described, in a single prior art reference. I understand
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`that the fact that a certain result or characteristic may occurorbe presentin the
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`priorart is not sufficient to establish the inherencyof that result or characteristic.
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`Rather, the feature at issue must necessarily be presentin the thing described.
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`19.
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`Ihave been informed by counsel that a claim is obviousif the
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`differences between the claimed invention andthe prior art are such that the
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`claimed invention as a whole would have been obviousto a person having ordinary
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`skill in the art to which the claimed invention pertains (a “POSA”)as ofthe earliest
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`filing date of the patent. I understand that a person of ordinary skill in the art is a
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`hypothetical person or persons deemed to have knowledgeofall relevant priorart
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`at the time of the earliest filing date of the patent (here, July 10, 2008). I also
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`understand that a POSAis considered to possess ordinary creativity. My discussion
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`herein of a POSArefers 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 mannerin
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`which the invention was made.
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`Ihave been informed by counsel that when assessing obviousness one
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`21.
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`must determine: (1) the scope and content of the priorart; (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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`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 cannotuse the patent as a road mapfor selecting and
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`combining itemsofpriorart. I have been informed and understand that the relevant
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`question is what a POSA would have understood withoutthe 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 art references; however,
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`the references musteither be from the samefield of endeavoras the claimed
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`invention or reasonably pertinent to the problem faced bythe inventor, in that it
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`would logically commenditself to the inventor’s attention in considering his or her
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`problem. I further understand that the obviousness inquiry considers whethera
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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 mannerasserted for obviousness, and a reasonable expectation of
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`success in doing so.
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`23.
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`Jam further informed and understand that a claim composed of
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`several elements is not proved obvious merely by demonstrating that eachofits
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`elements was independently knownin the prior art. There must have been an
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`apparent reason to select and combine the knownelements 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 art.
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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 “obviousto try” theory onlyif, at the time of the invention,
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`there was a recognized problem orneedin the art, a finite numberofidentified,
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`predictable potential solutions to the recognized need or problem, and a POSA
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`could have pursued the knownpotential 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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`show invalidity by a preponderanceof the evidence, e.g., by evidence showing that
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`invalidity is morelikely 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 art (“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, alternatively, “a bachelor’s degree plus two to five years’ experiencein 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 beenable to understand and interpret the references discussed in the
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`field.” Petition, 15; EX1002, 9952-53.
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`27.
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`Ihave adopted Petitioner’s opinion for the purpose ofthis analysis
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`with the clarification that a POSA whodoes not have an advanced degree in the
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`listed fields would have a bachelor’s degreein a field related to drug delivery.
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`28.
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`As reflected in my curriculum vitae (EX2002), I have the scientific
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`background andtechnical 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 °419 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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`
`Vv.
`
`THE ’419 PATENT
`
`A.
`
`Brief Overview of the Claimed Invention
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`29.
`
`Ihave read and understandthe specification and claimsof the ’419
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`Patent. The claims of the ’419 Patent are generally directed to estradiol transdermal
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`drug delivery systems(e.g., transdermal “patches,” referred to herein as “TDSs”).
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`As described in the ’419 Patent, the TDSs of the °419 Patent have a smaller active
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`surface area than the priorart 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® productin a
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`smaller sized system. EX1001, 3:66-4:16. Indeed, the Minivelle® products for
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`which the ’419 Patent 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 ofestradiol.
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`EX2003, 16; EX1006, 12.
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`30.
`
`As discussed in the ’419 Patent, “the ability to provide a smaller
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`system withoutsacrificing daily dosage represents a significant advance,” and was
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`madepossible 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 systemsthat
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`achieve comparable daily dosages.” EX1001, 3:50-63. As explained in the ’419
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`Patent and as I discuss in moredetail below,this result was surprising “because
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`0022
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`coat weightis typically selected to control the duration of delivery, but is not
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`generally understood to impact delivery rate.” /d. 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 theart to
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`increase coat weight to provide delivery over a longer period of time, it was not
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`knownthat 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.” /d.It
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`is this unexpected discovery that permitted the developmentof Patent Owner’s
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`FDA-approved Minivelle® productline, which offers womenthe same therapeutic
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`efficacy as Vivelle-Dot® products in much smaller sized patches. EX2003, 16;
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`EX1006,12.
`
`31.
`
`The TDSs claimed in the ’419 Patent are “monolithic” drug-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 (1) a backing layer; (11) a drug-in-adhesive polymer matrix
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`layer, and, optionally, (iii) a release liner that is removedprior to use. EX1001,
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`Claim 1. The claimsrecite that the adhesive polymer matrix has a coat weight of
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`greater than about 10 mg/cm’andincludesgreater than 0.156 mg/cm’ofestradiol,
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`and that the TDS achievesan estradiol flux of from 0.0125 to about 0.05
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`mg/em’/day, based on the active surface area of the system. /d.
`
`32.
`
`The ’419 Patent has 15 claims, with independent Claim 1 being the
`
`sole independentclaim. 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 (1) a backing layer, (11) 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/cm” and includes
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`greater than 0.156 mg/cm’estradiol, and the system achieves an
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`estradiol flux of from 0.0125 to about 0.05 mg/cm? /day, based
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`on the active surface area.
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`33.
`
`For the purposesofthis declaration, I have focused primarily on
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`independent claim | and dependentclaim 3 of the ’419 Patent.
`
`34.
`
`The ’419 Patentis a continuation of the °310 and ’900 Patents, for
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`which I previously provided declaration testimony in IPR2018-00173 and
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`IPR2018-00174, which were deniedinstitution. I note that independent claim 1 of
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`the °419 Patent 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 ’419 Patent).
`
`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
`
`unpatentability for the ’419 Patent are the same as Petitioner’s previously asserted
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`IPR2018-01119
`U.S. 9,833,419
`
`Groundsof unpatentability for the °310 and ’900 Patents.
`
`B.
`
`Brief Overview of the Prosecution History
`
`35.
`
`U.S. Application No. 14/870,574 (“the °574 application”), which
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`issued as the °419 Patent, was filed on September30, 2015, and is a continuation
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`of U.S. patent application no. 14/738,255 (pending), which wasa continuation of
`
`U.S. patent application no. 14/024,985 (now U.S. 9,724,310), which was a
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`continuation of U.S. patent application no. 13/553,972 (now U.S. 9,730,900),
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`which was a continuation of U.S. patent application no. 12/216,811 (now U.S.
`
`8,231,906) (EX1004). I understand that the 419, ’310 Patent and ’900 Patents
`
`have been and are the subjectof litigation. Paper 4, 1-2.
`
`36.
`
`During prosecution of the ’574 application, the claims were rejected
`
`as allegedly obvious over U.S. Patent No. 6,638,528 (EX1030; “Kanios *528”); in
`
`view of U.S. Patent No. 4,624,665 (EX1031; “Nuwayser”’). EX1004, 129-133.
`
`37.
`
`Patent Owner overcamethese rejections with arguments and
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`clarifying claim amendments. EX1004, 183-193.
`
`38.
`
`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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`Declaration”)'. EX1004, 138, 159-181, 200-306.In his declaration, Dr. Guy
`
`explained the state of the art and presented experimental data of unexpected
`
`results. Dr. Guy attested that “a person of ordinary skill in the art would not have
`
`thought of coat weight as a parameter to be adjusted to affect the flux of a drug
`
`from a transdermal patch” and that none of the art of record “suggests that
`
`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. /d., 227. Dr. Guy also presented experimental data
`
`showing the unexpected result embodied in the claimed subject matter, that
`
`increasing the coat weight of the drug-containing polymer matrix of the monolithic
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`estradiol TDSincreasedflux. /d., 214-224.
`
`39.
`
`The Examiner subsequently allowed the claims in the Notice of
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`Allowance mailed October 3, 2017. EX1004, 319-325. The Examiner explained
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`' Dr. Guyis 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 experiencein 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