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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`_____________________________
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`MYLAN TECHNOLOGIES INC.,
`Petitioner,
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`v.
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`NOVEN PHARMACEUTICALS, INC.,
`Patent Owner.
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`_____________________________
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`Patent No. 9,833,419
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`_____________________________
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`DECLARATION OF KEITH BRAIN, PH.D.
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`MYLAN - EXHIBIT 1002
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`TABLE OF CONTENTS
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`Page
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`I.Qualifications ....................................................................................................... 1
`II.Scope of Work .................................................................................................... 5
`III.Overview of the ’419 Patent ............................................................................... 6
`IV.File History of the ’419 Patent ......................................................................... 10
`V.Legal Standards ................................................................................................. 23
`VI.Level of Ordinary Skill and Relevant Time...................................................... 26
`VII.Claim Construction ......................................................................................... 27
`A. About ................................................................................................ 28
`B.
`Coat Weight ...................................................................................... 30
`C.
`Flux .................................................................................................. 31
`D.
`Therapeutically Effective Amount .................................................... 33
`VIII.The State of the Art ....................................................................................... 34
`’419 Patent .................................................................................................. 55
`A.
`Brief Overview of the Asserted References ...................................... 55
`i. Mueller .......................................................................................... 56
`ii. Vivelle-Dot® Label ........................................................................ 66
`iii. Kanios ........................................................................................... 68
`iv. Chien ............................................................................................. 72
`B.
`Detailed Analysis of the Claims ........................................................ 74
`GROUND 1. Mueller Anticipates Claims 1-2, 8, and 10-15. ................................ 74
`i. Claim 1 .......................................................................................... 74
`ii. Claim 2 .......................................................................................... 82
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`IX.The Asserted References Disclose or Suggest the Claimed Features of the
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`GROUND 2. The Teachings of Mueller and the Vivelle-Dot® Label Render
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`iii. Claim 8 .......................................................................................... 83
`iv. Claims 10-14 ................................................................................. 84
`v. Claim 15 ........................................................................................ 89
`Claims 1- 2 and 8-15 Obvious. .................................................................... 90
`i. Claims 1 and 2 ............................................................................... 90
`ii. Claim 8 .......................................................................................... 99
`iii. Claim 9 ........................................................................................ 101
`iv. Claims 10-14 ............................................................................... 102
`v. Claim 15 ...................................................................................... 105
`Render Claims 3-7 Obvious. ..................................................................... 106
`i. Claims 3 and 5 ............................................................................. 107
`ii. Claims 4 and 6 ............................................................................. 117
`iii. Claim 7 ........................................................................................ 119
`Chien Render Claims 1-15 Obvious. ......................................................... 124
`X.Concluding Statements.................................................................................... 136
`XI.Appendix – List Of Exhibits .......................................................................... 138
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`GROUND 3. The Teachings of Mueller, Vivelle-Dot® Label, and Kanios
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`GROUND 4: The Teachings of Mueller, Vivelle-Dot® Label, Kanios, and
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`I.
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`I, Keith Brain, declare as follows:
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`QUALIFICATIONS
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`1. My name is Keith Brain. I was appointed to a full-time tenured
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`position on faculty at the School of Pharmacy and Pharmaceutical Sciences of
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`Cardiff University in 1969 and retired as Reader in Dermatopharmaceutics (the
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`science of skin drug delivery) in 2011 after 42 years of continuous service. I was
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`awarded an Honorary Senior Research Fellowship at retirement and continued
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`research involvement with former colleagues. My career in research has covered a
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`number of topics, focusing primarily on aspects of dermal and transdermal drug
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`delivery. During the last 20-25 years of my research career, my work also focused
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`on molecular interactions between polymers. My work has covered both basic
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`science and translational and applied aspects of research.
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`2.
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`During my time at Cardiff, I was responsible for a number of B.
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`Pharm and M. Pharm courses including those on pharmaceutical chemistry,
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`pharmaceutical analysis, drug delivery (pharmaceutics), and quality assurance. I
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`also lectured externally for courses in the Diploma in Pharmaceutical Medicine and
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`Dermal Toxicology MSc program.
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`3.
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`I received my B. Pharm. from the University of Nottingham in 1966
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`and my Ph.D. in Pharmaceutical Science from the University of Bath in 1969.
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`4.
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`I have authored or co-authored over 100 peer-reviewed journal
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`articles, of which several articles present original research and data on transdermal
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`delivery of active agents across the skin from various drug delivery systems
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`including transdermal patches. In particular, I have co-authored an article on
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`transdermal estradiol drug delivery. I have also authored or co-authored 22 book
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`chapters, three books, 56 peer-reviewed papers in conference proceedings, and 140
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`conference abstracts, in addition to editing 22 books, including several editions of
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`Perspectives in Percutaneous Penetration. I am a regular reviewer for 11 high-
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`impact peer reviewed journals including Nature Biotechnology, the Journal of
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`Controlled Release, and the International Journal of Pharmaceutics.
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`5.
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`For the past 30 years, I have served as CEO of An-eX Analytical
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`Services Ltd. An-eX Analytical Services is an independent contract research and
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`development company that provides services in the development and evaluation of
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`pharmaceutical materials. An-eX Analytical Services has received global
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`recognition in the field of dermal pharmaceutics and has provided a range of
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`services to a wide range of international clients. Whilst most of this work has been
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`subject to Non-Disclosure Agreements, certain studies have been published at the
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`request of the Sponsor. These include collaborations with Organon, Mentholatum,
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`Biomarin, Clairol, Unilever Research, Proctor and Gamble, Cosmetic Toiletries
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`and Fragrance Association, Research Institute for Fragrance Materials and the
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`Center for Drug Evaluation and Research of the US Food and Drug
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`Administration.
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`6.
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`Together with the University of Regensburg, University of Padova,
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`Destiny Pharma, Waldmann AG, and Solvias AG, An-eX Analytical Services was
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`a member of the European Commission funded (EU 693,700) Development of a
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`Photodynamic Treatment to Eradicate and Control the Current Spread of Infections
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`Antibiotic Resistant Microorganisms in Man (“DYNAMICRO”) project.
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`7.
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`Together with Cardiff University, Waterford Institute of Technology,
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`and Eirgen Pharma, An-eX Analytical Services was also a member of the High
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`Potency Dermatologicals (“HIPODERM”) Consortium. HIPODERM focused on
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`innovative dermal drug delivery solutions for disease management. It was funded
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`(EU 838,363) by the European Union’s Marie Curie Programme under the
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`auspices of the Community Research and Development Information Service
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`(“CORDIS”) of the European Commission.
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`8.
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`I have also served on other boards and committees involved in
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`transdermal delivery. For example, I served as an expert panel member at the
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`Workshop on Dermal Absorption for Pesticide Risk Assessment in 2012. I served
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`as a member of the Planning Committee for the FDA/DIA Meeting on Improved
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`Development and Regulation of Transdermal Systems in 2011. I also served as a
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`member on the European Centre for Ecotoxicology and Toxicology of Chemicals
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`(“ECETOC”) Selection Team for the Human Exposure and Tiered Risk
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`Assessment Monitoring Team (“HETRA”) A2.3 International Workshop on
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`Dermal Exposure Modelling Meeting in 2003. I became a member of the Expert
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`Workshop on Percutaneous Absorption in 2005 and joined the Scientific Board for
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`the Society for Molecular Imprinting in 2006.
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`9.
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`I have participated in and been invited to speak at numerous
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`workshops and meetings pertaining to the field of drug delivery and dermal drug
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`delivery, including at the Predictive Modelling for Healthcare Technology through
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`Maths (“POEMs”) Workshop on Modelling of Skin Absorption in 2016, FDA/DIA
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`meeting on Improved Development and Regulation of Transdermal Systems in
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`2011, the Defense Threat Reduction Agency (“DTRA”) Dermal Toxicity
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`Workshop in 2010, the Gordon Research Conference on Barrier Function of
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`Mammalian Skin in 1999, 2001, 2005, 2007, and 2009, the American Association
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`of Pharmaceutical Scientists Annual Meeting in 2003-2004, the Perspectives in
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`Percutaneous Conference in 1999, 2004 and 2006, the AgChemForum Meeting in
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`2004, and the Workshop on Molecularly Imprinted Polymers (“MIP”) in 2004. I
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`am also a conference organiser for the Biennial International Perspectives in
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`Percutaneous Penetration Conference and Introductory Course on Percutaneous
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`penetration as well as the Biennial International Molecularly Imprinted Polymers
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`Workshop.
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`10. Academic research funding in excess of GBP 800,000 was obtained
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`from a wide variety of governmental, commercial, and charitable sources including
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`the Science and Engineering Research Council, Smith Kline Beecham,
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`Engineering and Physical Sciences Research Council, Reckitt and Colman,
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`Wellcome Trust, Biotechnology and Biological Sciences Research Council, World
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`Health Organisation, Home Office, Molecular Light Technology, Hadwen Trust,
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`and An-eX. Notably, I received the Sir Henry Wellcome Award for Innovative
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`Research in consecutive years for work on molecular interactions in polymers.
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`11.
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`I am submitting a copy of my CV as EX1003. My CV provides a
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`summary of my education, academic and industry experience, conference
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`attendance, committee membership, and publications.
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`II.
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`SCOPE OF WORK
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`12.
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`I understand that a petition is being filed with the United States Patent
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`and Trademark Office for Inter Partes Review of U.S. Patent No. 9,833,419 to
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`Mantelle (“the ’419 patent,” EX1001). I have been retained by the Petitioner as a
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`technical expert to provide my independent analysis and opinions regarding the
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`’419 patent. I have reviewed the ’419 patent and sections of its file history from the
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`United States Patent and Trademark Office (EX1004), as well as that of related
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`U.S. Patent Nos. 9,730,900 (EX1035) and related 9,724,310 (EX1037-38). I cite in
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`this declaration other documents that I have reviewed and considered in arriving at
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`my opinions. For convenience, documents cited in this declaration are listed in the
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`Appendix in Section XI.
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`13.
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`I am being compensated at the rate of $400/hour for my time in this
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`matter. I have no financial interest in the outcome of this matter.
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`III. OVERVIEW OF THE ’419 PATENT
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`14. The ’419 patent is entitled “Transdermal Estrogen Device and
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`Delivery” and is assigned to Noven Pharmaceuticals, Inc. (referred to herein as
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`“Noven,” “Applicant,” or “Patent Owner”). The patent states at the front page that
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`the ’419 patent was filed on September 30, 2015 as U.S. Patent Application No.
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`14/870,574 (“the ’574 application”). The ’574 application is a continuation of U.S.
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`Patent Application No. 14/738,255 (“the ’255 application”), prosecution of which
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`was suspended upon request by Applicant. The ’255 application is a continuation
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`of U.S. Patent Application No. 14/024,985 (“the ’985 application”), that was filed
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`on September 12, 2013, and issued as U.S. Patent No. 9,724,310. See EX1037
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`(’310 patent); EX1038 (file history of the ’310 patent). The ’985 application is a
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`continuation of U.S. Patent Application No. 13/553,972 (“the ’972 application”),
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`that was filed on July 20, 2012, and issued as U.S. Patent No. 9,730,900. See
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`EX1035 (File History of the ’900 patent). The ’972 application is a continuation of
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`U.S. Application No. 12/216,811, now U.S. Patent No. 8,231,906, which was filed
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`on July 10, 2008. The earliest claimed priority date on the face of the ’419 patent is
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`July 10, 2008.
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`15. The claims of the ’419 patent are directed to a transdermal drug
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`delivery system for estradiol. Claim 1 of the ’419 patent recites the following:
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`1. A monolithic transdermal drug delivery system for estradiol,
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`consisting of (i) a backing layer, (ii) a single adhesive polymer matrix
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`layer defining an active surface area and, optionally, (iii) a release
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`liner, wherein the single adhesive polymer matrix layer comprises an
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`adhesive polymer matrix comprising estradiol as the only drug,
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`wherein the adhesive polymer matrix layer has a coat weight of
`greater than 10 mg/cm2 and includes greater than 0.156 mg/cm2
`estradiol, and the system achieves an estradiol flux of from 0.0125 to
`about 0.05 mg/cm2/day, based on the active surface area.
`EX1001, 15:43-54 (claim 1). I note that claim 1 of the ’419 patent is almost
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`identical to claim 1 of the ’310 patent. Id; EX1037, 15:50-16:3. In contrast
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`to the ’419 patent, claim 1 of the ’310 patent recites “a coat weight of greater
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`than about 10 mg/cm2” and “an estradiol flux of from about 0.0125 to about
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`0.05 mg/cm2/day.” EX1037, 15:50-16:3 (emphasis added). The independent
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`claims are otherwise the same.
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`16.
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`I understand that claims 2-15 incorporate the subject matter of claim 1
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`and that claims 4-7 each additionally incorporate the subject matter of claim 3.
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`17. Claim 2 recites that the adhesive polymer matrix of claim 1
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`“comprises a polymer blend comprising an acrylic adhesive, a silicone adhesive,
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`and soluble PVP,” wherein PVP stands for polyvinylpyrrolidone. Id. at 16:1-4
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`(claim 2); see also id. at 9:51-53.
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`18.
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`I note that the ’419 patent claims encompass using a polymer blend
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`that may contain polymers that are immiscible. Id. at 10:21-27. The effect of using
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`immiscible polymers with a hydrophobic drug such as estrogen is to encapsulate
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`the drug and form microreservoirs of estrogen within the polymer blend in a single
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`polymer adhesive layer. This is supported by the ’419 patent, which states, “a
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`plurality of polymers including a soluble polyvinylpyrrolidone, which may have
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`different solubility parameters for the drug and which may be immiscible with
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`each other, may be selected to adjust the solubility of the drug in the polymer
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`matrix[.]” Id.
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`19. Claim 3 further recites the percent dry weight of polymers in the
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`adhesive polymer matrix (“about 2-25% by weight acrylic adhesive, about 45-70%
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`by weight silicone adhesive, about 2-25% by weight soluble PVP”), as well as
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`“about 5-15% [by weight] penetration enhancer, and about 0.1-10% by weight
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`estradiol, all based on the total dry weight of the adhesive polymer matrix.” Id. at
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`16:5-11. Claims 4-7 depend from dependent claim 3 and, thereby, from claim 1. Id.
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`at 16:12-23. Claims 4 and 5 respectively recite that the penetration enhancer
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`comprises oleyl alcohol and dipropylene glycol. Id. at 16:12-16. Claim 6 recites
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`that the penetration enhancer comprises both oleyl alcohol and dipropylene glycol
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`in combination. Id. at 16:17-19. Claim 7 recites that the ratio of acrylic adhesive
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`and silicone adhesive in the polymer matrix is “from about 1:2 to about 1:6, based
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`on the total weight of the acrylic and silicone adhesives.” Id. at 16:20-23.
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`20. Claim 8 recites that the “adhesive polymer matrix comprises an
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`amount of estradiol effective to deliver a therapeutically effective amount of
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`estradiol over a period of time selected from the group consisting of at least 1 day,
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`at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days and at
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`least 7 days.” Id. at 16:23-29. The ’419 patent states that “a therapeutically
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`effective amount of estradiol is from about 0.025-0.1 mg/day, including about
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`0.025 mg/day, about 0.0375 mg/day, about 0.05 mg/day, about 0.075 mg/day, or
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`about 0.1 mg/day, such as 0.025-0.1 mg/day, 0.025 mg/day, 0.0375 mg/day, 0.05
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`mg/day, 0.075 mg/day, and 0.1 mg/day.” Id. at 11:58-64. Claim 9 recites that the
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`transdermal estradiol delivery system “comprises an amount of estradiol effective
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`to deliver an amount of estradiol selected from the group consisting of about 0.025,
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`0.0375, 0.05, 0.075 and 0.1 mg/day.” Id. at 16:30-34.
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`21. Claims 10-14 respectively recite that the estradiol flux achieved by the
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`system based on the active surface area is “0.0125 mg/cm2/day,” “0.0133
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`mg/cm2/day,” “about 0.015 mg/cm2/day,” “about 0.0167 mg/cm2/day,” and “about
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`0.0175 mg/cm2/day.” Id. at 16:34-48. Claim 15 recites that the adhesive polymer
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`matrix of claim 1 comprises “about 1.6% by weight estradiol, based on the total
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`dry weight of the adhesive polymer matrix.” Id. at 16:49-52. I note that dependent
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`claims 2-9 and 12-15 of the ’419 patent are identical to those of the ’310 patent.
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`Id. at 16:34-39, 16:40-49; EX1037, 16:38-52. Claims 10 and 11 of the ’419 patent
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`differ from claims 10-11 of the ’310 patent in that they do not recite the word
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`“about” with respect to the estradiol flux values of 0.0125 mg/cm2/day and 0.0133
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`mg/cm2/day, respectively. EX1001, 16:34-39; EX1037, 16:38-52.
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`IV. FILE HISTORY OF THE ’419 PATENT
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`22. As noted above, the ’419 patent issued from the ’574 application and
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`claims the benefit of July 10, 2008 as its earliest effective filing date.
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`23. Following submission of the ’574 application, a restriction
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`requirement was mailed on September 7, 2016. EX1004, 0107. Applicant
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`responded on March 6, 2017 canceling original claims 1-20 and filing new claims
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`21-33 directed to a monolithic transdermal drug delivery system. Id. at 0113-17.
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`These new claims recited that “the coat weight of the adhesive polymer matrix
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`layer is adjusted such that the system includes greater than 0.156 mg/cm2” and
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`that the system “achieves an estradiol flux of from about 0.0125 mg/cm2/day to
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`about 0.05 mg/cm2/day[.]” Id (emphasis added). I note that dependent claims
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`directed to particular flux values (0.0125 mg/cm2/day, 0.0133 mg/cm2/day, 0.015
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`mg/cm2/day, 0.0167 mg/cm2/day, and 0.0175 mg/cm2/day) were preceded by the
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`term “about.” Id. at 0115.
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`24. A non-final rejection was mailed on June 15, 2017 rejecting claims
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`under 35 U.S.C. §112(a) for containing new matter and under 35 U.S.C. §112(b)
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`for being indefinite. Id. at 0126-28. With respect to new matter, the Examiner held
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`that “the instant specification does not teach that the coat weight of the adhesive
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`polymer matrix layer is adjusted” and that the application only disclosed that the
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`ratio of resin to polymer and the amount of acrylic versus silicone adhesives could
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`be adjusted. Id. at 0127. With respect to indefiniteness, the Examiner found that the
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`independent claim lacked antecedent basis for the term “the coat weight of the
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`adhesive polymer matrix layer.” Id. at 0128. The Examiner further rejected claims
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`under 35 U.S.C. §103(a) as obvious over U.S. Patent No. 6,638,528 to Kanios
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`(issued October 28, 2003) (EX1030, “Kanios ’528”) and U.S. Patent No. 4,624,665
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`to Nuwayser (issued November 25, 1986) (EX1031, “Nuwayser”). EX1004, 0130-
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`33. As explained by the Examiner, Kanios ’528 teaches matrix-type transdermal
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`estradiol delivery systems containing percentages of silicone adhesives,
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`polyacrylate adhesives, PVP, penetration enhancers (dipropylene glycol and oleyl
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`alcohol), and estradiol recited in the ’574 application claims. Id. at 0130.
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`Moreover, the monolithic estradiol delivery systems of Kanios ’528 comprise an
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`adhesive matrix layer, release liner, and a backing layer. Id. The Examiner
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`additionally stated that Kanios ’528 teaches the administration of estradiol over a
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`period of time recited in the ’574 application claims. Id. The Examiner further
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`stated Nuwayser teaches that increasing the concentration of a drug modulates
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`estradiol flux. Id. at 0131-33.
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`25. The Examiner also rejected the pending claims for double patenting
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`over co-pending U.S. Patent Application No. 14/738,255, in view of co-pending
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`U.S. Patent Application No. 14/024,985 (now U.S. Patent Nos. 9,724,310 and
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`8,231,906, respectively). Id. at 0134-36. An applicant-initiated interview summary
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`was filed on June 15, 2017 regarding a June 8, 2017 interview. Id. at 0138. This
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`summary states that “Applicant’s representative and Dr. Guy explained how the
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`included data supported the unexpected results that increasing the coat weight of
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`the drug-containing adhesive layer resulted in an increased flux per unit area, and
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`permitted the development of smaller transdermal drug delivery systems that
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`achieve comparable daily dosages,” and further states that a Declaration would
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`need to be filed on the record for the data to be considered. Id. An outline for the
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`June 8, 2017 Examiner Interview was also provided. Id. at 0159-81.
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`26. Applicant responded on August 29, 2017 by canceling all claims, and
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`submitting fifteen new claims nearly identical to those that issued in the ’310
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`patent. Id. at 0184-86. As in the prosecution of the application which led to the
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`’310 patent, Applicant argued that neither Kanios ’528 nor Nuwayser taught the
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`claimed systems with the claimed coat weight, estradiol per unit area, and achieved
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`flux per unit area. Id. at 0188.
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`27. Applicant admitted Kanios ’528 teaches “matrix-type transdermal
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`drug delivery systems,” but argued that neither Kanios ’528 nor Nuwayser teach
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`every limitation recited in the claims and asserted that Nuwayser is directed
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`towards reservoir-type systems, which contained liquid compositions rather than
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`polymer matrix-type systems. EX1004, 0189-90. Applicant also filed a terminal
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`disclaimer to address the double patenting rejection. Id. at 0192.
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`28. Applicant also provided a summary of the June 8, 2017 Examiner
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`interview. Id. at 0187-88. Applicant, citing the specification, stated they were
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`“surprised by the discovery that increasing the coat weight of the adhesive polymer
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`matrix layer ‘resulted in an increased flux per unit area[.]’” Id. at 0190. Also citing
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`the specification, Applicant incorrectly asserted that “[indeed], ‘while it is known
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`in the art to increase coat weight to provide delivery over a longer period of time, it
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`was not known that increasing coat weight could increase delivery rate or flux[.]’”
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`Id. at 0191. Applicant stated that “[t]he invention is important because it permits
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`the development of smaller transdermal drug delivery systems,” which “improves
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`patient satisfaction and patient compliance, reduces the area of skin subject to
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`occlusion and irritation, and reduces manufacturing costs.” Id. Applicant reiterated
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`their mistaken assertion that “coat weight is typically selected to control the
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`duration of drug delivery, but was not understood to impact delivery rate (e.g.,
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`daily dose delivered).” Id.
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`29. Finally, Applicant provided a chart of the percent of estradiol
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`comprised by the prior art Vivelle-Dot® transdermal estradiol delivery system that
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`is delivered transdermally, stating “as reflected in the Vivelle-Dot® product line,
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`the state of the art used the size of a system to predictably adjust drug flux, using
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`larger systems to provide higher daily doses[.]” Id.
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`30.
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`I further note that Applicant has previously interchangeably used the
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`phrases “estradiol per unit area” and “coat weight.” During prosecution of the ’972
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`patent application, which issued as the ’900 patent with a specification identical to
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`that of the ’419 patent, Applicant admitted that “it is apparent from the
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`specification as a whole that the inventors understood these surprising and
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`unexpected results to relate to the amount of estradiol per unit area, and used the
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`coat weight of the drug-containing adhesive layer as a proxy for that parameter.”
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`EX1035 (File History of the ’900 patent), 0169. Thus, “estradiol per unit area” and
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`“coat weight” can be interchangeably used when discussing the impact of these
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`parameters on the flux of estradiol from transdermal drug delivery systems.
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`31.
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`I note that the above arguments are similar to arguments made by
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`Applicant during prosecution of the applications which issued as the related ’900
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`and ’310 patents. For example, Applicant argued that the advantage of this
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`allegedly “unexpected discovery” was that the size of a patch could be decreased
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`while maintaining the amount of drug delivered by increasing coat weight and
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`thereby increasing the flux (the rate of drug delivery). Id. at 0170; EX1038, 0120.
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`Applicant also stated that the specification identifies a “system according to the
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`invention can be only 60% the size of a prior art composition that includes only
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`0.156 mg/cm2 estradiol and yet achieve comparable, therapeutically effective drug
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`flux, such as a drug flux of greater than 0.01 mg/cm2/day.” EX1035, 0170.
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`32. Despite the Applicant’s assertions that it was not described in the
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`prior art that one can increase the estradiol flux by increasing the coat weight (i.e.,
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`the amount of estradiol per unit area), various prior art publications, discussed in
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`more detail later on in this declaration, taught this exact principle. See, e.g., U.S.
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`Patent No. 5,145,682 to Chien et al. (issued September 8, 1992) (EX1009,
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`“Chien”); Kim et al., Penetration Enhancement of β2-Selective Agonist,
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`Tulobuterol, Across Hairless Mouse Skin, 33 J. KOR. PHARM. SCI. (2003) 79-84
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`(EX1010, “Kim”); Ghosh et al., Development of a Transdermal Patch of
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`Methadone: In Vitro Evaluation Across Hairless Mouse and Human Cadaver Skin,
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`1 PHARM. DEV. TECHNOL. (1996) 285-91 (EX1014, “Ghosh”); U.S. Patent No.
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`5,603,947 to Wong et al. (issued February 18, 1997) (EX1028, “Wong”). Thus,
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`Applicant’s assertions that these results were unexpected are not correct in view of
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`the teachings of those of ordinary skill in the art prior to 2008.
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`33. As described above, Applicant also discussed that the pre-existing
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`product sold as Vivelle-Dot® provided a series of increased doses via patches
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`increasing in size. EX1004, 0191. As discussed below, flux, dose, and patch size
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`are all directly related. Thus, the skilled artisan would have understood from the art
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`as a whole that increasing patch size is just one way to increase the dose
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`administered by a transdermal delivery system. As understood by those in the art
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`well-prior to 2008, patch size could also be held constant, while flux was
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`increased, to deliver an increased dose. Indeed, various methods of increasing dose
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`through increased flux were known prior to the time of filing, including by
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`increasing the coat weight of the polymer matrix within a transdermal patch. See,
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`e.g., EX1009 (Chien), FIGS. 3-5; EX1010 (Kim), 82; EX1014 (Ghosh), 288. I note
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`that no IDS in the file history mentions the Chien (EX1009), Kim (EX1010),
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`Ghosh (EX1014), or Wong (EX1028) publications and patents, discussed in this
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`declaration.
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`34. Applicant also filed a Declaration under 37 C.F.R. § 1.132 of Dr.
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`Richard H. Guy (“the Guy Declaration”) on August 29, 2017. Id. at 0200-0306.
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`The Guy Declaration asserts that the prior art does not teach that increasing coat
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`weight increases flux. Id. at 0206-07. Dr. Guy also includes that “[n]othing in
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`Fick’s 1st law indicates or predicts that increasing the coat weight (thickness) of a
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`polymer matrix would increase flux.” Id. I note that Fick’s Law does not exclude
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`or limit the scope of variables that may impact the flux of drugs administered
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`transdermally. Indeed, as discussed in more detail herein, those in the art
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`understood that increasing coat weight can increase occlusion, which provides
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`more water (a penetration enhancer) at the site of patch application, and can
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`thereby, increase drug flux through the skin barrier. See, e.g., EX1009 (Chien),
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`FIGS. 3-5; EX1010 (Kim), 82; EX1014 (Ghosh), 288; EX1028 (Wong), 9:64-
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`10:24 and FIG. 12-FIG. 13; Bronaugh R.L., Maibach H.I. (eds.), In vitro
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`percutaneous absorption: Principles, fundamentals and applications. CRC Press,
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`Boca Raton, Florida (1991) 85–114 (EX1026, “Bronaugh”), 86, 95, 105-08;
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`Benson et al., Transdermal Drug Delivery: Penetration Enhancement Techniques,
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`2 CURRENT DRUG DELIVERY (2005) 23-33 (EX1039, “Benson”), 28. In addition,
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`the Guy Declaration also indicates how Applicant calculated flux and states that
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`“[a]n illustration of the type of experimental data collected with this approach is
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`shown below for one particular formulation; the results are presented as the
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`average cumulative amounts of drug delivered, and the average drug flux, as a
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`function of time, with the corresponding standard deviations for 4 replicate Franz
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`diffusion cells.” EX1004, 0208. The experimental data is summarised in a table,
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`which is copied below:
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`Id. at 0209.
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`35. This table and the above statement were also made in a miscellaneous
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`internal document, which was discussed with the Examiner on June 8, 2017. Id. at
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`0161-62. Regarding the above table, Applicant stated that, “[t]hese results may be
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`plotted graphically as illustrated in the specification[.]” Id. at 0162. One of
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`ordinary skill in the art would, of course, be capable of understanding data values
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`plotted in a graph (e.g., EX1001, Figure 1, 15:1-40). I note that the Applicant, Dr.
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`Guy, and the specification of the ’419 patent, do not state how the estradiol flux
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`shown in Figure 1 of the ’419 patent is calculated from raw data. EX1001, Figure
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`1, 15:1-40. Thus, statements during prosecution regarding the above table
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`encompass at least one way by which the estradiol flux limitation in the claims of
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`the ’419 patent are calculated.
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`36. A person of ordinary skill in the art would understand from Dr. Guy’s
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`statements and the above table that Applicant obtains the estradiol flux by
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`calculating the slope at each data point. Such calculations are straightforward. For
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`example, to calculate the flux at 23.95 hours, the average amount of drug
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`accumulated at 9.92 hours (2.55 µg/cm2) is subtracted from that at 23.95 hours
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`(12.64 µg/cm2). This difference (10.09 µg/cm2) is then divided by the amount of
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`time that has passed between the two data points (23.95 hours – 9.92 hours = 14.03
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`hours). This provides the slope at 23.95 hours (10.09 µg/cm2/14.03 hours = 0.72
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`µg/cm2/hr), which is also the flux achieved at that time point. Such calculations can
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`be carried out at each time point, as shown below in Table 1. For simplicity, I have
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`eliminated the columns for standard deviation, however, the calculation of flux at
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`each time point described above may also be performed using the standard
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`deviation at each time point as well.
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`TABLE 1 – Calculation of Estradiol Flux in Pros