UNITED STATES PATENT AND TRADEMARKOFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN TECHNOLOGIES, INC.
`Petitioner,
`
`v.
`
`NOVEN PHARMACEUTICALS, INC.
`Patent Owner.
`
`Patent No. 9,724,310
`
`Title: TRANSDERMAL ESTROGEN DEVICE AND DELIVERY
`
`Inter Partes Review No. IPR2018-00173
`
`
`DECLARATIONOF DR. ADRIAN C. WILLIAMS
`
`Noven Pharmaceuticals, Inc.
`EX2001
`Mylan Tech., Inc., v. Noven Pharma., Inc.
`IPR2018-00173
`
`0001
`
`

`

`TABLE OF CONTENTS
`
`IPR2018-00173
`USS. 9,724,310
`
`RCRD CANERTI ceded at cukeansdiiean ach daaeines ai niRha DRE DRAGS SHEA iil
`
`I.
`
`RSACSATT cos ox zaciapians tanataa ctatsigiscasags iantssanattaias apasiatanssosassiesaedisaadarntatnaesas l
`
`By, TTR CERIO, 0d < tuascs dochdsccesadensanccorsararoeshsaacste drei gansideueuadsutecsdehaysasasdeabazecseatuch ans 2
`
`IT.=Patent Law Standards ..0.........ccccccccccccccccccecsseessecueceseceseceseseesseesseesseeeseeeseeees 6
`
`IV.
`
`Level Of Skill In The Art 20.0... ccc ccc ccsecesscessceeeeeeseeeseecsueesseceseeeseeesees 10
`
`Wis
`
`TUS 3 RW) Patents 3.56 occcssecsecctacegesit------00-ccceccceeccencecncnensceesceesseesccesccnsaccesscteass 1]
`A.
`Brief Overview of the Claimed Invention..............0..00ccccceeeceeeseeeeteee 11
`B.—Brief Overview of the Prosecution History...........0000..cccceeseeeeeeeeeeteeeee 13
`
`Technological Background ........... ccc ceessceeessececsssceceesseecessncecsessececssneeeesnseees 16
`VI.
`A.—Transdermal Drug Delivery and Drug Flux ...........0..ccccceeeeeeeeeseeees 16
`B.|Developing Transdermal Drug Delivery Systems..............000...000000+ 25
`C.
`Coat Weight Was Not Known To Impact Flux.............000cceeeeeeeeees 32
`i,
`Bin (ROT O1O) soo cadge est hart eee eae hia aes 33
`iz.
`hasty (Eel OT), 2: cscorccs cccen, sdees cast vnc pecsatedial neapoleeeees aaa lied44
`3.
`Bronaigh (EX W026) sissies ceccvevesetecvcdies stickies cdcestdeec tata tates cas 48
`4.
`CTviein (ER UOOOY ccs ceca net eens ease anebaagGaabapcaaiveo a Sia SERVES49
`5:
`Dineller CEXIQOS). 5, i2) susnecassecercvaniaroncanentaany Sas wecteadescuaddansvanades 52
`6.
`WHORE CEN O2S oso sist retractor lodenlestepdeshshis echin decd vuasintaniriiovensind 54
`D.—Estradiol Transdermal Drug Delivery Systems ......................0....:000065 55
`
`VIL, Claim Constrincitotts. 5. si ccccc ccs seccccassasapsisan dais cninsmas tins stoeecahapanaiebndvapiniaaicivacanss 59
`A.—_Legal Standard............cccececcceccecccccceesescecececeesesececessssseeceeesssseeeeesesees 59
`Bes©PUROUAD cpces sca vzatzed os as zn soaeds picasa sds a dcsnasa ste paas wade n dasa Auda vaus ia eau tana FUROR 60
`Ci,
`MOSWHEE ccc gtcctes vsceeass days ncovunoccascdenisieiecmatans suagasanaseeeeiaoantens 60
`De RRs ciitencetvaret avis ctatens Wis oleae dlp el eon Seiad 62
`E..
`“Therapeutically Effective Amount” «0. :ccccccccsscessecescsswezasseisocerecndos snd 65
`
`VIM, Grounds of Unpatentabng lity icc cccccc ced csekes cesanvenes cpa secesdpvscesecaudcccerasvscedsueesed 66
`A.—Cited References... ccecccecceeccccceeeesseceseeeeessececeeeessssceeeesnsseeeeeeeesees 66
`1.
`AMC Sr ENS )), sss. consyasctvdcastinyeus depionssdanscebiesne Saaseiactbsacecdeted 66
`2
`Vivelle-Dot® Label (EX 1006) 2.3 .:::2:c0sccccssccsscassucezsscnecsscasensces 69
`3. BoE OOTce nd eneee cerceenshoce eS 70
`4 SRRAW 2 oft a2 os oo ee eines me cekt hen de tala teh ea, 74
`
`1
`
`0002
`
`

`

`IPR2018-00173
`USS. 9,724,310
`GRP, Ts os.n erates eters stb hih tects RA ENA dsb iccaGike eee tapanp goed noes ere 74
`L:,
`Claims1, 2, 8, and 10-15 are Not Taught By Mueller............. 74
`Be
`Mueller Does Not Show That Example 3 Achieved The
`Clamed Bstiadinl! PR: ..iiccscscciscshscioatenasitlecccoven co ed tavsecenereiss 75
`Petitioner’s Use of Mueller Fig. 3 is Scientifically Invalid......81
`3.
`GSEOMTIN as iscccst2ahdi co ogse lesa sacsseartivanbiansadatvel paassocinedcseiadessbiassaiians teecesinansds 82
`E
`Claims 1-2 and 8-15 are not suggested by Mueller and
`the Vivelle-Dot® Label. 2000.00.00... ceeccccccceeseecccceeeensseeeeeeeeees 82
`RRO Foto vancdoececieacspcceter Sacapes shes auctercepaacori asian ease eseceeet: 83
`ie
`Claims3-7 are not suggested by Mueller, the Vivelle-
`Dot® Label and Kamios..... .....ic.::-ccceccecsncossncrestneneencntsnanenenceaeais 83
`ARRON te cit ci Re AN atI ee tn ate 92
`he
`Claims 1-15 are not suggested by Mueller, the Vivelle-
`Dat® Label, Keantos, ‘anil: CHien.,,...v.ccecccesnerciapancenserececessheceaveres 92
`
`il
`0003
`
`

`

`LIST OF CITED EXHIBITS
`
`Patent Owner Exhibits
`
`Ex #
`
`Description
`
`IPR2018-00173
`USS. 9,724,310
`
`2002|Curriculum Vitae of Dr. Adrian C. Williams
`
`Minivelle® Product Label
`2003
`
`
`
`
`
`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)
`
`J. Hadgraft, Passive enhancement strategiesin topical and
`
`2005
`
`transdermal drug delivery, 184 INT’L J. PHARMACEUTICS 1-6 (1999)
`
`B. Barry, Transdermal Drug Delivery, in AULTON’S PHARMACEUTICS
`
`2006|— 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
`2007|penetration enhancersin human skin, 36 INT’L J. PHARMACEUTICS
`
`43-50 (1989)
`
`
`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)
`
`ill
`0004
`
`

`

`Ex #
`
`Description
`
`2009
`Esclim® Product Label
`
`
`J. Mantelle, e¢ al., Effect ofSilicone/Acrylic PSA Blendson Skin
`
`Permeation, 26 PROCEEDINGS OF THE INTERNATIONAL SYMPOSIUM ON
`
`2010
`
`CONTROLLED RELEASE OF BIOACTIVE MATERIALS 415-16 (Rev. July
`
`1999) (“the Mantelle Article’’)
`
`IPR2018-00173
`US. 9,724,310
`
` 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, The enhancement index concept applied to
`
`2012
`
`terpene penetration enhancersfor human skin and modellipophilic
`
`(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)
`
`iv
`0005
`
`

`

`IPR2018-00173
`US. 9,724,310
`
`Ex #
`
`Description
`
`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=200S5&sciodt=0,5&hl=en
`
`
`
`
`
`A. Ghoshet al., Current Pharmaceutical Design on Adhesive Based
`2015|Transdermal Drug Delivery Systems, 21 CURR. PHARM. DESIGN
`
`2016|U.S. Patent No. 8,029,820
`
`
`2771-2783 (2015)
`
`B. Godin & E. Touitou, Transdermalskin delivery: Predictions for
`
`2017|humansfrom in vivo, ex vivo and animal models, 59(11) ADV. DRUG
`
`DELIV. REVIEWS 1152-1161 (2007)
`
`
`2018|utility ofhairless mouse skin, 93(1) J. INVEST. DERMATOL. 87-91
`
`R. Hinz et al., In vitro percutaneouspenetration: evaluation ofthe
`
`(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)
`
`0006
`
`

`

`IPR2018-00173
`US. 9,724,310
`
`Ex #
`
`Description
`
`R. Subediet al., Influence offormulation variable in transdermal
`2020|drug delivery system containing zolmitriptan, 419 INT’L J.
`
`PHARMACEUTICS 209-214 (2011)
`
`
`
`
`
`
`R. Subedi ef al., Formulation and in vitro evaluation oftransdermal
`drug delivery system for donezil, 42 J. PHARMA. INVEST. 1-7 (2012)
`
`5091
`
`J. Mantelle, DOT Matrix® Technology, in MODIFIED RELEASE DRUG
`
`2022|DELIVERY TECHNOLOGY405-14 (Rathboneefa/. eds., 2d ed. 2008)
`
`(“the Mantelle Chapter’)
`
`J. van de Sandtet al., In vitro predictions ofskin 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. 9,724,310 (“the ’310 Patent”)
`
`1002|Declaration of Dr. Keith Brain
`
`1004|File history of U.S. Patent No. 9,724,310
`
`Vi
`0007
`
`

`

`Ex #
`
`1005
`
`Description
`
`U.S. Patent Application Publication No. US 2003/0099695
`
`(“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’”’)
`
`1009|U.S. Patent No. 5,145,682 (“Chien”)
`
`IPR2018-00173
`US. 9,724,310
`
`
`
`
`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 Mirandaefal.
`
`1012|PCT Application Publication WO 1996/0031 19 (“Fotinos”)
`
`1013.|U.S. Patent No. 5,919,477 (“Bevan”)
`
`Vil
`0008
`
`

`

`IPR2018-00173
`US. 9,724,310
`
`Ex #
`
`Description
`
`Ghoshet al., Development ofa Transdermal Patch of Methadone:In
`
`1014
`
`Vitro Evaluation Across Hairless Mouse and Human CadaverSkin, |
`
`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.lmg Transdermal System
`
`1016|(Watson Laboratories) 04/05/2002 Approval Letter and Final
`
`Labeling — FOI Document # 5210490A (“Alora® Label”)
`
`
`1018|US. Patent No. 5,902,602 (“Miiller’”)
`
`1019|U.S. Patent No. 6,156,335 (“Rovati’”)
`
`1020|U.S. Patent No. 6,521,250 (“Meconi”)
`
`
` magazines/noven-pharmaceuticals-inc (last accessed: June 29, 2017)
`
`Dinger, E., Noven Pharmaceuticals, Inc. ENCYCLOPEDIA.COM (2006)
`http://www.encyclopedia.com/books/politics-andbusiness-
`
`1023
`
`(“Dinger’’)
`
`Vill
`0009
`
`

`

`IPR2018-00173
`US. 9,724,310
`
`Ex #
`
`Description
`
`Butschli, J., Ziny 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, fundamentalsand applications. CRC Press,
`
`Boca Raton, Florida (1991) 85—114 (“Bronaugh’’)
`
`1027|U.S. Patent No. 5,352,457 (“Jenkins”)
`
`
`1028|U.S. Patent No. 5,603,947 (“Wong”)
`
`1030|U.S. 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|U.S. Patent No. 9,730,900
`
`1X
`0010
`
`

`

`IPR2018-00173
`USS. 9,724,310
`
`
`
`Ex # Description
`
`1036|File history of U.S. Patent No. 9,730,900
`
`
`x
`
`0011
`
`

`

`IPR2018-00173
`US. 9,724,310
`
`1.
`
`INTRODUCTION
`
`l.
`
`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 /nter Partes
`
`Review of U.S. Patent No. 9,724,310 filed by Mylan Technologies, Inc. (I[PR2018-
`
`00173) (the “Petition”). My opinions and analysis are set forth below, and are
`
`based on my review of U.S. Patent No. 9,724,310 (“the ’310 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 ’310 Patent, the
`
`purported prior art cited by Petitioner, and the opinions of Dr. Keith Brain stated in
`
`the Declaration of Keith Brain, Ph.D. (the “Brain Declaration”) (EX 1002).
`
`Evidence underlying my opinionsand analysis includes certain documentscited 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 wayon the outcomeofthis
`
`proceeding.
`
`0012
`
`

`

`IPR2018-00173
`US. 9,724,310
`
`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 developmentof
`
`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 commonskin
`
`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 companyin Reading.
`
`6.
`
`Iam 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
`
`

`

`IPR2018-00173
`USS. 9,724,310
`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 Pharmacy in 2011, and then Research Dean for Health in
`
`JOT:
`
`Be
`
`During my academic career, I 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 skin since |
`
`began my Ph.D. research and have published papers on this 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.; F7-Raman microscopic study ofdrug distribution in
`
`a transdermal drug delivery device, VIBRATIONAL SPECTROSCOPY,1996, 11, 105-
`
`9
`113.; Skin delivery ofoestradiolfrom deformable and traditional liposomes:
`
`0014
`
`

`

`IPR2018-00173
`USS. 9,724,310
`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
`
`THEORY TO CLINICAL PRACTICE. In 2013, I was asked to write the chapter Topical
`
`and Transdermal Drug Delivery for the well-known standard 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.
`
`I have 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 various aspects of pharmaceutics and drugdelivery,
`
`including “Oestradiol permeation through humanskin,silastic and snake
`
`membranes; effects of supersaturation and binary co-solvent systems” and
`
`“Promotion of oestradiol permeation through humanskin”.
`
`0015
`
`

`

`IPR2018-00173
`USS. 9,724,310
`I have also been invited to give presentations and to chair sessionsat
`
`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 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 Dermal Minisymposium,
`
`Paris, France, October 2012.
`
`12.
`
` Icurrently 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 memberof the
`
`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
`
`

`

`IPR2018-00173
`USS. 9,724,310
`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.
`
`My research and standingin 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 myelection as a Fellow
`
`of the UK Academyof 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 experiencein the area of transdermal drug delivery systems over
`
`the past 30 plus years.
`
`Il.
`
`PATENT LAW STANDARDS
`
`17.
`
`I have been informed by counselthat the claims of a patent are
`
`interpreted as a person of skill in the art would have understood them in the
`
`relevant time period, which I understandis the earliest filing date accorded to the
`
`patent. I understand that the ’310 Patent benefits fromafiling date of July 10,
`
`2008. Accordingly, my comments, opinions, and analysis herein refer to the
`
`0017
`
`

`

`IPR2018-00173
`USS. 9,724,310
`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 counselthat a claim 1s anticipated (.e.,
`
`deemed not novel) only if each and every elementas set forth in the claim is found,
`
`either expressly or inherently described, in a single prior art reference. I understand
`
`that the fact that a certain result or characteristic may occur or be present in the
`
`priorart 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 obviousif the
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`differences between the claimed invention and the 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 of the 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 deemedto have knowledgeofall relevantpriorart
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`at the time ofthe 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.
`
`I also understandthat patentability is not negated by the mannerin
`
`whichthe invention was made.
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`IPR2018-00173
`USS. 9,724,310
`Ihave been informed by counsel that when assessing obviousness one
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`21.
`
`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 inventionin 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 mapfor selecting and
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`combining itemsofprior art. I have been informed and understandthat 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 by the 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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`0019
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`IPR2018-00173
`USS. 9,724,310
`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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`[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 ofits
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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 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 theart.
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`24.
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`Further, I have been informed and understandthat 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 orneedin theart, 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 whenthe 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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`IPR2018-00173
`USS. 9,724,310
`show invalidity by a preponderance ofthe 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
`
`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 twoto 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 andinterpret the references discussed in the
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`field.” Petition, 15; EX1002, 962-63.
`
`27.
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`Lhave adopted Petitioner’s opinion for the purpose ofthis analysis
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`with the clarification that a POSA who doesnot 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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` Asreflected in my curriculum vitae (EX2002), I have the scientific
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`background andtechnical expertise to provide opinionsand 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 ’310 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 theart.
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`10
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`

`IPR2018-00173
`US. 9,724,310
`
`Vv.
`
`THE ’310 PATENT
`
`A.
`
`Brief Overview of the Claimed Invention
`
`29.
`
`[have read and understandthe specification and claimsof the ’310
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`Patent. The claims of the ’310 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 ’310 Patent, the TDSs of the ’310 Patent have a smaller active
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`surface area than the prior art Vivelle-Dot® productline, 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. EX1001, 4:3-23. Indeed, the Minivelle® products for which
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`the °310 Patent is an Orange Book-listed patent are only about 60%the size of the
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`Vivelle-Dot® products but deliver the same daily doses of estradiol. EX2003, 16;
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`EX1006, 12.
`
`30.
`
`As discussed in the ’310 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, 3:54-67. As explained in the 310
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`Patent and as I discuss in more detail below,this result was surprising “because
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`1]
`0022
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`IPR2018-00173
`USS. 9,724,310
`coat weightis typically selected to control the duration of delivery, but 1s not
`
`generally understood to impact delivery rate.” Jd. That is, as explained in the °310
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`Patent and as I discuss 1n 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
`
`permit the development of a smaller system while maintaining daily dosage.” Jd. It
`
`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.
`
`31.
`
`The TDSs claimed in the ’310 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 (i) a backing layer; (11) a drug-in-adhesive polymer matrix
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`layer, and, optionally,(111) a release liner that is removedprior to use. EX1001,
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`Claim |. The claims recite that the adhesive polymer matrix has a coat weight of
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`greater than about 10 mg/cm’ andincludes greater than 0.156 mg/cm’ ofestradiol,
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`and that the TDS achievesanestradiol flux of from about 0.0125 to about 0.05
`
`mg/cm’/day, based onthe active surface area of the system. Jd.
`
`32.
`
`The ’310 patent has 15 claims, with independent Claim | being the
`
`sole independentclaim. Claim | of the ’310 patentrecites:
`
`12
`0023
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`IPR2018-00173
`USS. 9,724,310
`A monolithic transdermal drug delivery system for estradiol,
`
`consisting of (i) a backing layer, (i1) a single adhesive polymer
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`matrix layer defining an active surface area and, optionally, (111)
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`a release liner, wherein the single adhesive polymer matrix
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`layer comprises
`
`an adhesive polymer matrix comprising
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`estradiol as the only drug, wherein the adhesive polymer matrix
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`layer has a coat weight of greater than about 10 mg/cm’ and
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`includes greater than 0.156 mg/cm” estradiol, and the system
`
`achieves an estradiol flux of from about 0.0125 to about 0.05
`
`mg/cm” /day, basedonthe active surface area.
`
`33.
`
`For the purposesofthis declaration, I have focused primarily on
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`independent claim | and dependent claim 3 of the ’310 patent.
`
`B.
`
`Brief Overview of the Prosecution History
`
`34.
`
`U.S. Application No. 14/024,985 (“the 985 application”), which
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`issued as the 7310 Patent, was filed on September 12, 2013, and is a continuation
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`of U.S. patent application no. 13/553,972 (now U.S. 9,730,900) (EX1036), which
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`was a continuation of U.S. patent application no. 12/216,811 (now U.S. 8,231,906)
`
`(EX1004), which I understand has been andis the subjectoflitigation. Paper 5, 2.
`
`35.
`
`During prosecution of the ’985 application, the claims were rejected
`
`as allegedly obvious over U.S. Patent No. 6,638,528 (EX1030; “Kanios °528”); in
`
`13
`0024
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`IPR2018-00173
`USS. 9,724,310
`view of U.S. Patent No. 4,624,665 (EX1031; “Nuwayser”); and allegedly obvious
`
`over Kanios °528 and Nuwayserfurther in view of U.S. Patent Application
`
`Publication No. 2009/0041831 (EX1032; “Miller”). EX1004, 94-103.
`
`36.
`
`Patent Owner overcamethese rejections with arguments and
`
`clarifying claim amendments. The Examiner subsequently allowed the claims in
`
`the Notice of Allowance mailed September 15, 2016, which included an
`
`Examiner’s amendmentto correct a typographical error in the preamble of the
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`claims. EX1004, 253-260.
`
`37.
`
`Following receipt of the September 2016 Notice of Allowance, Patent
`
`Ownerfiled a Request for Continued Examination (“RCE”) in order to obtain
`
`consideration of information disclosure statements (“IDSs”). EX1004, 276-281,
`
`316-321. After consideration of each IDS, the Examinerissued a Notice of
`
`Allowance with similar reasons for allowance. /d., 288-294, 322-328. With the
`
`final RCE, Patent Owner presented a new dependent claim that was granted as
`
`claim 15. /d., 365-372.
`
`38.
`
`After the final RCE, Patent Owner conducted an interview with the
`
`Examiner and submitted the Declaration Under 37 CFR § 1.132 of Dr. Richard H.
`
`14
`0025
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`

`

`IPR2018-00173
`USS. 9,724,310
`Guy (the “Guy Declaration”)'. EX1004, 378-380, 409-437. 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 transdermalpatch” and that noneofthe art of record “suggests that
`
`increasing coat weight would increase flux.” EX1004, 435-436. Dr. Guy also
`
`attested that the only predictable way to increase drug flux from a TDSis to
`
`increase the size of the TDS. /d., 436. 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
`
`estradiol TDSincreased flux. /d., 423-432.
`
`39.
`
`Thereafter, the Examinerissued the final Notice of Allowance.
`
`EX1004, 526-533. The Examiner explained that “[t]he prior art does not teach nor
`
`'Dr. Guy is a professor of Pharmaceutical Sciences at the University of Bath (UK)
`
`in the Department of Pharmacy & Pharmacology and has more than 30 years’
`
`research experiencein the field of topical and transdermal drug delivery, including
`
`the study of drug absorption into and through the skin. He has co-authored more
`
`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.
`
`15
`0026
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`

`

`IPR2018-00173
`USS. 9,724,310
`reasonably suggest the claimed monolithic transdermal drug delivery system,” and
`
`separately noted that “Applicant’s arguments of unexpected results...are
`
`persuasive.” /d., 531-532.
`
`VI. TECHNOLOGICAL BACKGROUND
`
`A.
`
`Transdermal Drug Delivery and Drug Flux
`
`40.
`
`As noted above, the ’310 Patent generally relates to TDSs for the
`
`delivery of estradiol, methods of administering estradiol to a patient using the
`
`claimed transder