UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN TECHNOLOGIES, INC.
`
`Petitioner,
`
`V-
`
`NOVEN PHARMACEUTICALS, INC.
`
`Patent Owner.
`
`Patent No. 9,730,900
`
`Title: TRANSDERMAL ESTROGEN DEVICE AND DELIVERY
`
`Inter Parley Review No. IPR2018-00174
`
`
`DECLARATION OF DR. ADRIAN C. WILLIAMS
`
`Noven Pharmaceuticals, Inc-
`EX2001
`
`Mylan Tech., Inc., v. Noven Pharma, Inc.
`IPR2018-00174
`
`0001
`
`

`

`TABLE OF CONTENTS
`
`1PR201 8—00174
`
`US. 9,730,900
`
`List Of Cited Exhibits .............................................................................................. iii
`
`1.
`
`Introduction ...................................................................................................... 1
`
`II.
`
`Qualifications ................................................................................................... 2
`
`III.
`
`Patent Law Standards ...................................................................................... 6
`
`IV.
`
`Level Of Skill In The Art .............................................................................. 10
`
`V.
`
`The ’900 Patth .............................................................................................. 11
`
`A.
`
`B.
`
`Brief Overview of the Claimed Invention ........................................... 11
`
`Brief Overview of the Prosecution History ......................................... 14
`
`VI.
`
`Technological Background ............................................................................ 17
`A.
`Transdermal Drug Delivery and Drug Flux ........................................ 17
`B.
`Developing Transdermal Drug Delivery Systems .............................. 27
`C.
`Coat Weight Was Not Known To Impact Flux ................................... 34
`1.
`Kim(EX1010) ........................................................................... 35
`2.
`Ghosh (EX 1 014) .......................................................................46
`3.
`Bronaugh (EX1026) .................................................................. 50
`4.
`Chien (EX1009) ........................................................................ 51
`5.
`Mueller (EXIOOS) ..................................................................... 54
`6.
`Wong (EX1028) ........................................................................ 56
`Estradiol Transdermal Drug Delivery Systems .................................. 57
`
`D.
`
`V11. Claim Construction ........................................................................................ 61
`
`A.
`B.
`
`C.
`D.
`
`E.
`
`Legal Standard ..................................................................................... 61
`“About” ................................................................................................ 62
`
`“Coat Weight” ..................................................................................... 62
`“Flux” .................................................................................................. 64
`
`“Therapeutically Effective Amount” .................................................. 67
`
`VIII. Grounds of Unpatentability ........................................................................... 68
`A.
`Cited References .................................................................................. 68
`
`1.
`2.
`3.
`4
`
`Mueller (EXlOOS) ..................................................................... 68
`Vivelle-Dot® Label (EX1006) ................................................. 71
`Kanios (EX1007) ...................................................................... 72
`Chien (EX1009) ........................................................................ 76
`
`i
`
`0002
`
`

`

`IPR201 8—00174
`
`US. 9,730,900
`
`Ground 1 .............................................................................................. 76
`
`1.
`
`2.
`
`3.
`4.
`
`Claims I, 2, 8, 10-16 and 18-23 are Not Taught
`By Mueller ................................................................................ 76
`Mueller Does Not Show That Example 3 Achieved The
`Claimed Estradiol Flux ............................................................. 77
`
`Petitioner’s Use of Mueller Fig. 3 is Scientifically Invalid ...... 83
`Mueller Does Not Disclose Applying Its Example 3 TDS
`To A Person In Need Thereof ................................................... 84
`
`Ground 2 .............................................................................................. 86
`
`1.
`
`Claims 1-2 and 8-23 are not suggested by Mueller and
`the Vivelle—Dot® Label ............................................................ 86
`
`Ground 3 .............................................................................................. 87
`
`1.
`
`Claims 3—7 are not suggested by Mueller, the Vivelle—
`Dot® Label and Kanios ............................................................ 87
`
`Ground 4 .............................................................................................. 96
`
`1.
`
`Claims 1-23 are not suggested by Mueller, the Vivelle-
`D0t® Label, Kanios, and Chien ................................................ 96
`
`ii
`
`0003
`
`

`

`Minivelle® Product Label
`2003
`
`
`IPR201 8—00174
`
`US. 9,730,900
`
`LIST OF CITED EXHIBITS
`
`Patent Owner Exhibits
`
`Description
`
`Curriculum Vitae of Dr. Adrian C. Williams
`
`J. Hadgrafi and R- Guy, Feasibiliiy Assessment in Topical and
`
`Transderma/ Delive
`
`, in TRANSDERMAL DRUG DELIVERY 3-4 (R.
`
`Guy & J. Hadgraft eds., 2d ed. 2003)
`
`J. Hadgrafi, Passive enhancemeni siraiegies in (apical and
`
`(ransdermai drug delivery, 1 84 INT’L J. PHARMACEUTICS 1—6 (1999)
`
`B. Barry, Transderma/ Drug Delivery, in AULTON’S PHARMACEUTICS
`
`— THE DESIGN AND MANUFACTURE OF MEDICINES 565, 571—72, 577
`
`(M. Aulton ed-, 3d ed. 2007)
`
`A. Williams & B. Barry, Urea analogues in propylene glycoi as
`
`penetration enhancers in human skin, 36 INT’L J. PHARMACEUTICS
`
`
`
`Ex #
`
`2002
`
`2004
`
`2005
`
`2006
`
`2007
`
`
`
`43—50 (1989)
`
`
`K. Brain & R. Chilcott, Physicochemical Factors Affecting Skin
`
`Absorption, in PRINCIPLES AND PRACTICE OF SKIN TOXICOLOGY 83-92
`
`2008
`
`(R. Chilcott and S. Price eds., 2008)
`
`
`iii
`
`0004
`
`

`

`U.S. 9,730,900
`
`IPR201 8—00174
`
`Ex#
`
`Description
`
`2009
`Esclim® Product Label
`
`
`J. Mantelle, ei al. , Effect (ngilicone/Aerylic PSA Blends 0n Skin
`
`2010
`
`Permeaiion, 26 PROCEEDINGS OF THE INTERNATIONAL SYMPOSIUM ON
`
`CONTROLLED RELEASE OF BIOACTIVE MATERIALS 415-16 (Rev. July
`
`1999) (“the Mantelle Article”)
`
` K. Walters & K. Brain, Demato/ogical F()rmuiaiion and Transderma/
`
`
`
`A. Williams & B. Barry, Chemical 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 enhancers for human skin and modef lipophilic
`
`(oesiradinl) and hydrophilic (57flu0muraeif) drugs, 74 INT’LJ.
`
`PHARMACEUTICS 157-168 (1991)
`
`2013
`
`Sysiems; in DEMATOLOGICAL AND TRANSDERMAL FORMULATIONS
`
`338-43 (K. Walters, ed., 2002)
`
`iv
`
`0005
`
`

`

`
`
`US. Patent No. 8,029,820
`2016
`
`
`B. Godin & E. Touitou, Transdermal skin delivery.“ Predictionsfor
`
`humansfrom in vivo, ex vivo and animal models, 59(1 1) ADV. DRUG
`
`2017
`
`DELIV. REVIEWS 1 152-1 161 (2007)
`
`
`U.S. 9,730,900
`
`IPR201 8—00174
`
`Ex #
`
`Description
`
`Google Scholar search results obtained March 7, 2018 — citations of
`
`Kim et al. , Penetration Enhancement of,62-5eleetive Agonist,
`
`Tulobuterol, Across Hairless Mouse Skin, J. Pharm. Invest. 33: 79-84
`
`(2003), available online at https:llscholar.g00gle.com/scholar?cites=
`
`7903453 7260874958 1 8&as_sdt=2005&sci0dt=0,5&hl=en
`
`A. Ghosh et al., Current Pharmaceutical Design on Adhesive Based
`
`Transdermal Drug Delivery iSjtstems, 21 CURR. PHARM. DESIGN
`
`2771—2783 (2015)
`
`2014
`
`2015
`
`2018
`
`2019
`
`R. Hinz et al., In vitro percutaneous penetration: evaluation ofthe
`
`utility ofhairless mouse skin, 93(1) J. INVEST. DERMATOL. 87—91
`
`(1989)
`
`J. Bond & B. Barry, Hairless mouse skin is limited as a modeljor
`
`assessing the effects ofpenetration enhancers in human skin, 90(6) J.
`
`INVEST. DERMATOL. 810-813 (1988)
`
`0006
`
`
`
`

`

`US. 9,730,900
`
`IPR201 8—00174
`
`
`
`Ex #
`
`2020
`
`202]
`
`2022
`
`Description
`
`R. Subedi ei aL, Influence offiirmuiaiion variabie in iransderma!
`
`dmg delivery system containing zoimitripian, 419 INT’L J.
`
`PHARMACEUTICS 209—2 14 (201 1)
`
`R. Subedi ei al., Formulation and in vitro evaluation ofiran.s'dermal
`
`drug delivery .sysiemfor donezil, 42 J. PHARMA. INVEST. 1-7 (2012)
`
`J. Mantelle, DOT Mairix® Technoiogy, in MODIFIED RELEASE DRUG
`
`DELIVERY TECHNOLOGY 405-14 (Rathbone ei al. eds., 2d ed. 2008)
`
`(“the Mantelle Chapter”)
`
`
`
`
`
`
`J. van de Sandt ei (.11., In vitro predictions of'skin absorption of
`
`cafleine, iesiosierone, and benzoic acid: a main-centre comparison
`
`2023
`
`snidy, 39 REG. TOXICOL. PHARMACOL 271—281 (2004)
`
`
`Petitioner Exhibits
`
`Ex #
`
`Description
`
`1001
`
`US. Patent No. 9,730,900 (“the ’900 Patent”)
`
`
`
`
`1002
`
`Declaration of Dr. Keith Brain
`
`1004
`
`File history of US. Patent No. 9,730,900
`
`vi
`
`0007
`
`

`

`US. 9,730,900
`
`1PR201 8—00174
`
`Ex #
`
`1005
`
`1006
`
`1007
`
`1009
`
`1010
`
`1011
`
`1012
`
`
`
`Description
`
`US. Patent Application Publication No. US 2003/0099695
`
`Vivelle-Dot-a'a Transdermal System (Novartis) 05/03/2002
`
`Supplemental Approval [Label Revisions] — F01 Document #
`
`52361493 (2006) (“Vivelle—Dotaa Label”)
`
`US. Patent Application Publication No. US 2006/0078602
`
`(“Kanios”)
`
`US. Patent No. 5,145,682 (“Chien”)
`
`Kim et 0]., Penetration Enhancement Qffi2—Seleetz've Agonist,
`
`Tulobnteroi, Across Hairless Mouse Skin, 33 J. PHARM. INVEST.
`
`(2003) 79—84 (“Kim”)
`
`US. Patent N0. 5,656,286 to Miranda et a1.
`
`PCT Application Publication WO 1996/003119 (“Fotinos”)
`
`
`
`(“Mueller”)
`
`
`us. Patent N0. 5,919,477 (“Bevan”)
`1013
`
`
`vii
`
`0008
`
`

`

`US. 9,730,900
`
`1PR201 8—00174
`
`Description
`
`Ex #
`
`1014
`
`1015
`
`Ghosh e! a/., Deveiapmeni ofa Transderma/ Pate/1 anet/zadane.‘ In
`
`Vitm Evaluation Across Hair/(ass Mouse and Human Cadaver Skin, 1
`
`PHARM. DEV. TECH. (1996) 285-91 (“Ghosh”)
`
`Climara 0.025mg Transdermal System (Berlex Laboratories)
`
`04/05/2001 Supplemental Approval Letter and Final Labeling — FOI
`
`
`
` magazines/noven—pharmaceuticals-inc (last accessed: June 29, 2017)
`
`Document # 5243107A (“Climaraia Label”)
`
`
`Alora 0.025mg, 0.05mg, 0.075mg, 0.1mg Transdermal System
`
`1016
`
`(Watson Laboratories) 04/05/2002 Approval Letter and Final
`
`Labeling — F01 Document # 5210490A (“Alma-a Label”)
`
`
`1018
`
`1019
`
`1020
`
`1023
`
`US. Patent No. 5,902,602 (“Mtiller”)
`
`US. Patent N0. 6,156,335 (“Rovati”)
`
`US. Patent N0. 6,521,250 (“Meconi”)
`
`Dinger, E., Naven Pharmaceuticals, Inc. ENCYCLOPEDIACOM (2006)
`
`http://www.encyclopediacom/books/politics—andbusiness-
`
`(“Dinger”)
`
`
`viii
`
`0009
`
`

`

`US. 9,730,900
`
`IPR201 8—00174
`
`Ex #
`
`1024
`
`1026
`
`Description
`
`Butschli, 1., Tiny Patch ‘Dots ’ Pharmaceutical Landscape,
`
`PACKAGING WORLD (1999)
`
`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), In vitro percui‘aneous
`
`absorption: Prineiples, fundamentals and applications. CRC Press,
`
`Boca Raton, Florida (1991) 85—1 14 (“Bronaugh”)
`
`1027
`US. Patent No. 5,352,457 (“Jenkins”)
`
`
`1028
`
`1029
`
`US. Patent No. 5,603,947 (“Wong”)
`
`US. Patent Application Publication No. US 2006/0078601
`(“Kanios ’601”)
`
`
`
`
`
`1030
`US. Patent No. 6,638,528 (“Kanios ’528”)
`
`
`1031
`
`US. Patent No. 4,624,665 (“Nuwayser”)
`
`1032
`US. Patent Application Publication No. us 2009/0041831 (“Miller”)
`
`
`US. Patent No. 6,024,976 to Miranda et al.
`1033
`
`
`ix
`
`0010
`
`

`

`1PR201 8—00174
`
`US. 9,730,900
`
`I.
`
`INTRODUCTION
`
`1.
`
`I have been retained by Noven Pharmaceuticals, Inc. (Patent Owner)
`
`to serve as an expert in the field oftransdennal 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 Inter Parties
`
`Review of US. Patent No. 9,730,900 filed by Mylan Technologies, Inc. (IPR2018-
`
`00174) (the “‘Petition”). My opinions and analysis are set forth below, and are
`
`based on my review of US Patent No. 9,730,900 (“the ’900 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 “900 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”) (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.
`
`0011
`
`

`

`1PR201 8—00174
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`US. 9,730,900
`
`II.
`
`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.
`
`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
`
`0012
`
`

`

`IPR201 8—00174
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`US. 9,730,900
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`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 201 1, 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 enhancers.for human
`
`.skin and model lipophilic (oestradiol) and hydrophilic (57fluorouracil) drugs, INT.
`
`J. PHARM, 1991, 74, 157—168-; ()esiradiol permeation through human skin and
`
`silastic membrane: effects ofpropylene glycol and supersaturation, J. CONTROL.
`
`RELEASE, 1995, 36, 277—294.; ()estradiol permeation across human skin, silasiic
`
`and snake skin membranes: the effects ofethanol/water co-solvent .s‘ystems, INT. J.
`
`PHARM, 1995, 1 16, 101-112.; FT—Raman microscopic study ofdrug distribution in
`
`a transdermal drug delivery device, VIBRATIONAL SPECTROSCOPY, 1996, 11, 105—
`
`1 13.; Skin delivery of'oestradiollfrom deformable and traditional liposomes.‘
`
`0013
`
`

`

`1PR201 8—00174
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`US. 9,730,900
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`mechanistic studies, J. PHARM. PHARMACOL, 1999, 51, 1123—1 134.; Skin hydration
`
`and possible shunt route penetration in controlled estradiol deliveryfrom
`
`deformable and standard liposomes, J. PHARM. PHARMACOL, 2001, 53, 13 l l—
`
`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 updated this in future editions of the book.
`
`9.
`
`To date, my publications have been cited over 1 1,200 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 funding.
`
`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”.
`
`0014
`
`

`

`1PR201 8—00174
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`U.S. 9,73 0,900
`
`l 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
`
`transderrnal 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
`
`comeocytes 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 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
`
`0015
`
`

`

`1PR201 8—00174
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`US. 9,730,900
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`research projects or through consultancy. For example, I provided a lecture on
`
`“Strategies for improving transderrnal 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 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.
`
`[I].
`
`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 art 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 ’900 Patth benefits from a filing date of July 10,
`
`2008. Accordingly, my comments, opinions, and analysis herein refer to the
`
`0016
`
`

`

`1PR201 8—00174
`
`US. 9,730,900
`
`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 (£16.,
`
`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 art 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 art 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 pertains (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
`
`understand that a POSA is considered to possess ordinary creativity. My discussion
`
`herein of a POSA refers to such a person as of July 10, 2008.
`
`20.
`
`1 also understand that patentability is not negated by the manner in
`
`which the invention was made.
`
`0017
`
`

`

`1PR201 8—00174
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`US. 9,730,900
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`21.
`
`I have been informed by counsel that when assessing obviousness one
`
`must determine: (1) the scope and content of the prior art; (2) the differences
`
`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 reconstmct 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 art 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 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 “obvious to fly” theory only if, at the time of the invention,
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`there was a recognized problem or need in the art, 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 interpartes review proceeding, the burden falls on the Petitioner to
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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 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’ 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 intelpret the references discussed in the
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`field.” Petition, 15; EX1002, 111177—78.
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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), I 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 ’900 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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`10
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`US. 9,730,900
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`V.
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`THE ”900 PATENT
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`A.
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`Brief Overview of the Claimed Invention
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`29.
`
`l have read and understand the specification and claims of the ’900
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`Patent. The claims of the ’900 Patth are generally directed to methods for
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`administering estradiol using transdermal drug delivery systems (eg, transdermal
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`“patches,” referred to herein as “TDSs”) and methods of making such TDSS. As
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`described in the ”900 Patent, the TDSS of the ’900 Patent 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. EX 1 001, 4:3-23. Indeed, the Minivelle® products for which
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`the ”900 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, I6;
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`EX1006, 12.
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`30.
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`As discussed in the ’900 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.” EX 1 001, 2:5 8—32. As explained in the ’900
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`11
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`Patent and as I discuss in more detail below, this result was surprising “because
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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.” Id. That is, as explained in the ’900
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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.” Id. 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.
`
`31.
`
`The TDSs claimed in the ’900 Patent are “monolithic” drug-in-
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`adhesive systems, meaning that they have a single drug—containing polymer matrix
`
`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. EXlOOl ,
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`Claims 1, 16. The claims recite that the adhesive polymer matrix has a coat weight
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`of greater than about 10 mg/cm2 and includes greater than 0.156 mg/cm2 of
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`estradiol, and that the TDS achieves an estradiol flux of from about 0.0125 to
`
`about 0.05 mg/cmZ/day, based on the active surface area of the system. Id.
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`12
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`0022
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`32.
`
`The ”900 patent has 23 claims, including independent claims 1 and 16.
`
`Claim 1 of the ”900 patent recites:
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`1PR201 8—00174
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`US. 9,730,900
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`A method for administering estradiol, comprising applying to
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`the skin or mucosa of a subject in need thereof a monolithic
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`transdermal drug delivery system consisting of (i) a backing
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`layer and (ii) a single adhesive polymer matrix layer defining an
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`active surface area and comprising an adhesive polymer matrix
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`comprising estradiol as the only drug, wherein the polymer
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`matrix has a coat weight of greater than about 10 mg/cm2 and
`
`includes greater than 0.156 mg/cm2 estradiol, and the system
`
`achieves an estradiol flux of from about 00125 to about 0.05
`
`mg/cmZ/day, based on the active surface area.
`
`33.
`
`Claim 16 of the ’900 patent recites:
`
`A method of making a monolithic transdermal drug delivery
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`system for administering estradiol consisting of (i) a backing
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`layer,
`
`(ii)
`
`a
`
`single adhesive polymer matrix layer and,
`
`optionally, (iii) a release liner, comprising forming an adhesive
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`polymer matrix comprising estradiol as the only drug and a
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`polymer blend comprising an acrylic adhesive, a silicone
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`adhesive, and soluble PVP, and applying the adhesive polymer
`
`13
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`U.S. 9,730,900
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`matrix to a support layer to form a single adhesive polymer
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`matrix layer such that the adhesive polymer matrix layer has a
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`coat weight of greater than about 10 mg/cm2 and includes
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`greater
`
`than 0.156 mg/cm2 estradiol, wherein the system
`
`achieves an estradiol flux of from about 0.0125 to about 0.05
`
`mg/cmZ/day, based on the active surface area.
`
`34.
`
`For the purposes of this declaration, I have focused primarily on
`
`independent claims 1 and 16 and dependent claim 3 of the ’900 Patent.
`
`B.
`
`Brief Overview of the Prosecution History
`
`35.
`
`U.S. Application No. 13/553,972 (“the ”972 Application”), which
`
`issued as the ’900 Patent, was filed on July 20, 2012, and is a continuation of the
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`application that issued as U.S. Patent No. 8,231,906 (“the ”906 Patent”) (EX1004),
`
`which I understand has been and is the subject of litigation. Paper 4, 2.
`
`36. During prosecution of the ’972 Application, the claims were rejected
`
`as allegedly anticipated by U.S. Patent Application Publication No. 2006/0078601
`
`(EX1029; “Kanios ’601”); allegedly obvious over Kanios ’601 in View of U.S.
`
`Patent No. 6,638,528 (EX1030; “Kanios ’528”); allegedly obvious over Kanios
`
`“601 in view of U.S- Patent No. 4,624,665 (EX1031; “Nuwayser”); allegedly
`
`obvious over Kanios ’528 in view of Nuwayser; and allegedly obvious over Kanios
`
`14
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`0024
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`1PR201 8—00174
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`US. 9,730,900
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`’528 and Nuwayser further in View of US. Patent Application Publication No.
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`2009/0041831 (EX1032; “‘Miller”). EX1004, 99-103, 147-151, 251-254.
`
`37.
`
`Patent Owner overcame these rejections with arguments and
`
`clarifying claim amendments. As acknowledged by the Examiner in the Notice of
`
`Allowance mailed October 2, 2015 (EX1004, 296-303), “[t]he prior art does not
`
`teach nor reasonably suggest a method for administering estradiol with the claimed
`
`monolithic transdermal drug delivery system. Further, the prior art does not teach
`
`nor reasonably suggest a method for making the claimed monolithic transderrnal
`
`drug delivery system.” Id., 302.
`
`38.
`
`Following receipt of the October 2015 Notice of Allowance, Patent
`
`Owner filed an Amendment Under 37 CFR § 1.312 seeking to amend the allowed
`
`claims to recite specific embodiments with regard to the amount of estradiol per
`
`unit area and flux. EX1004, 314—3 19. When the Examiner would not enter the
`
`amendments after final, Patent Owner filed a requests for continued examination
`
`(“RCE”) to pursue similar claim amendments. Id., 330-331. Once agreement was
`
`reached on revised