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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. 9,724,310
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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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`Qualifications................................................................................................ 1
`I.
`Scope of Work .............................................................................................. 5
`II.
`III. Overview of the ’310 Patent ......................................................................... 6
`IV. File History of the ’310 Patent ...................................................................... 9
`V.
`Legal Standards .......................................................................................... 25
`VI. Level of Ordinary Skill and Relevant Time ................................................. 28
`VII. Claim Construction ..................................................................................... 29
`A. About ................................................................................................ 30
`B.
`Coat Weight ...................................................................................... 32
`C.
`Flux .................................................................................................. 34
`D.
`Therapeutically Effective Amount .................................................... 36
`VIII. The State of the Art ..................................................................................... 36
`IX. The Asserted References Disclose or Suggest the Claimed Features of
`the ’310 Patent ............................................................................................ 50
`A.
`Brief Overview of the Asserted References ...................................... 50
`i. Mueller .......................................................................................... 50
`ii. Vivelle-Dot® Label ........................................................................ 60
`iii. Kanios ........................................................................................ 63
`iv.
`Chien .......................................................................................... 66
`Detailed Analysis of the Claims ........................................................ 69
`GROUND 1. Mueller Anticipates Claims 1-2, 8, and 10-15. ................. 69
`i. Claim 1 .......................................................................................... 69
`ii. Claim 2 .......................................................................................... 77
`iii. Claim 8 ...................................................................................... 78
`iv.
`Claims 10-14 .............................................................................. 79
`v. Claim 15 ........................................................................................ 84
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`B.
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`GROUND 2. The Teachings of Mueller and the Vivelle-Dot®
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`Label Render Claims 1- 2 and 8-15 Obvious. ......................................... 85
`i. Claims 1 and 2 ............................................................................... 85
`ii. Claim 8 .......................................................................................... 93
`iii. Claim 9 ...................................................................................... 95
`iv.
`Claims 10-14 .............................................................................. 96
`v. Claim 15 ........................................................................................ 99
`Kanios Render Claims 3-7 Obvious. .................................................... 100
`i. Claims 3 and 5 ............................................................................. 101
`ii. Claims 4 and 6 ............................................................................. 110
`iii. Claim 7 .................................................................................... 112
`Kanios, and Chien Render Claims 1-15 Obvious. ................................ 117
`X.
`Concluding Statements ............................................................................. 129
`XI. Appendix – List Of Exhibits ..................................................................... 131
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`GROUND 3. The Teachings of Mueller, Vivelle-Dot® Label, and
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`GROUND 4: The Teachings of Mueller, Vivelle-Dot® Label,
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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. 9,724,310 to
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`Mantelle (“the ’310 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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`’310 patent. I have reviewed the ’310 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 No. 9,730,900. EX1035. I cite in this declaration other documents that
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`I have reviewed and considered in arriving at my opinions. For convenience,
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`documents cited in this declaration are listed in the 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 ’310 PATENT
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`14. The ’310 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,” “Applicants,” or “Patent Owner”). The patent states at the front page that
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`the ’310 patent was filed on September 12, 2013 as U.S. Application No.
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`14/024,985 (“the ’985 application”). The ’985 application is a continuation of U.S.
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`Application No. 13/553,972 (“the ’972 application”), that was filed on July 20,
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`2012, and issued as U.S. Patent No. 9,730,900. See EX1035 (File History of the
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`’900 patent); EX1036 (“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 ’310 patent is
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`July 10, 2008.
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`15. The claims of the ’310 patent are directed to a transdermal drug
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`delivery system for estradiol. Claim 1 of the ’310 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 about 10 mg/cm2 and includes greater than 0.156 mg/cm2
`estradiol, and the system achieves an estradiol flux of from about
`0.0125 to about 0.05 mg/cm2/day, based on the active surface area.
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`EX1001, 15:50-16:3 (claim 1).
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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 16:4-7
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`(claim 2); see also id. at 9:57-59.
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`18.
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`I note that the ’310 patent claims encompass using a polymer blend
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`that may contain polymers that are immiscible. Id. at 10:27-33. 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 ’310 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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`16:8-14. Claims 4-7 depend from dependent claim 3 and, thereby, from claim 1. Id.
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`at 16:15-25. Claims 4 and 5 respectively recite that the penetration enhancer
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`comprises oleyl alcohol and dipropylene glycol. Id. at 16:15-19. 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 16:19-21. 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 16:22-25.
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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 16:26-32. The ’310 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 11:64-12:3. 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 16:33-37.
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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 about 0.0125 mg/cm2/day, about 0.0133
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`mg/cm2/day, about 0.015 mg/cm2/day, about 0.0167 mg/cm2/day, and about 0.0175
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`mg/cm2/day. Id. at 16:38-52. Claim 15 recites that the adhesive polymer matrix of
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`claim 1 comprises “about 1.6% by weight estradiol, based on the total dry weight
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`of the adhesive polymer matrix.” Id. at 16:53-56.
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`IV. FILE HISTORY OF THE ’310 PATENT
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`22. As noted above, the ’310 patent issued from the ’985 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 ’985 application, Applicants filed a
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`preliminary amendment amending the claims to specify that the transdermal drug
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`delivery system is a “monolithic” system “for estradiol,” “consisting of (i) a
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`backing layer, (ii) a single polymer matrix layer,” and “optionally, (iii) a release
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`liner.” EX1004, 0051-52. The claims were also amended to specify that the “single
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`polymer matrix layer comprises…estradiol as the only drug.” Id. Claim 1 was
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`additionally amended to specify that the estradiol dose and flux limitations applied
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`to the “polymer matrix layer.” Id.
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`24. A non-final rejection was mailed on May 20, 2015 rejecting 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, 0097-
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`99. 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 ’985 application claims. Id. at 0097.
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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 ’985 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 0098-99.
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`25. The Examiner also rejected the pending claims for double patenting in
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`view of U.S. Patent No. 8,231,906 (id. at 0100-02), as well as under 35 U.S.C.
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`§103(a) as obvious in further view of U.S. Patent Application Publication No.
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`2009/0041831 to Miller et al. (published February 12, 2009) (EX1032, “Miller”).
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`EX1004, 0099-0100. The Examiner stated that Miller teaches silicone-based
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`transdermal delivery systems in which the cast composition has a coat weight of
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`90-110 g/m2. Id.
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`26. Applicants responded on June 12, 2015 by amending the independent
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`claims to clarify that the single polymer matrix layer was a single “adhesive”
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`polymer matrix layer and that “the adhesive polymer matrix layer has a coat weight
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`of greater than about 10 mg/cm2.” Id. at 0117-18.
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`27. Applicants also provided a summary of a June 10, 2015 Examiner
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`interview. Id. at 0119. Applicants also stated they “were surprised by the discovery
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`that increasing the amount of estradiol per unit area resulted an increased rate of
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`drug delivery per unit area[.]” Id. at 0120. Applicants also incorrectly asserted that
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`“coat weight was thought to provide delivery over a longer period of time, but it
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`was not known that increasing the amount of drug per unit area could increase the
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`drug delivery rate.” Id. Applicants stated that “[t]he invention is important because
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`it permits the development of smaller transdermal drug delivery systems,” which
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`“improve patient satisfaction and patient compliance, reduces the area of skin
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`subject to occlusion and irritation, and reduces manufacturing costs.” Id.
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`Applicants reiterated their mistaken assertion that “coat weight is typically selected
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`to control the duration of drug delivery, but was not understood to impact delivery
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`rate (e.g., daily dose delivered).” Id.
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`28. Finally, Applicants 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 “the prior art Vivelle-Dot® products deliver only
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`about 22% of their drug content over their intended period of use…Since the
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`systems already include a large excess of drug than is delivered over the intended
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`delivery period, it was unexpected that increasing the amount of drug per unit area
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`would impact drug delivery rate.” Id. at 0120-21. I note here that Applicants
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`expressly identify the Vivelle-Dot® product as prior art.
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`29.
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`I further note that Applicants interchangeably used the phrases
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`“estradiol per unit area” and “coat weight.” In fact, 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 ’310 patent, Applicants 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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`30.
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`I note that the above arguments are similar to arguments made by
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`Applicants during prosecution of the application which issued as the related ’900
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`patent. For example, Applicants argued that the advantage of this allegedly
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`“unexpected discovery” was that the size of a patch could be decreased while
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`maintaining the amount of drug delivered by increasing coat weight and thereby
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`increasing the flux (the rate of drug delivery). Id. at 0170. Applicants also stated
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`that the specification identifies a “system according to the invention can be only
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`60% the size of a prior art composition that includes only 0.156 mg/cm2 estradiol
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`and yet achieve comparable, therapeutically effective drug flux, such as a drug flux
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`of greater than 0.01 mg/cm2/day.” Id.
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`31. Despite the Applicants’ 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”). Thus, Applicants’
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`assertions that these results were unexpected are not correct in view of the
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`teachings of those of ordinary skill in the art prior to 2008.
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`32.
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`In response to the first Office Action, Applicants also discussed that
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`the pre-existing product sold as Vivelle-Dot® provided a series of increased doses
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`via patches increasing in size. EX1004, 0121. As discussed below, flux, dose, and
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`patch size are all directly related. Thus, the skilled artisan would have understood
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`from the art as a whole that increasing patch size is just one way to increase the
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`dose administered by a transdermal delivery system. As understood by those in the
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`art 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.
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`33. Moreover, Applicants admitted Kanios ’528 teaches “matrix-type
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`transdermal drug delivery systems,” but argued that neither Kanios ’528 nor
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`Nuwayser teach every limitation recited in the claims and asserted that Nuwayser
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`is directed towards reservoir-type systems, which contained liquid compositions
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`rather than polymer matrix-type systems. EX1004, 0122-24. Applicants further
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`argued that Miller was not applicable because it taught systems comprising
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`fentanyl, rather than estradiol. Id. Applicants also filed a terminal disclaimer to
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`address the double patenting rejection. Id.
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`34. Following filing a second summary of the June 10, 2015 interview, on
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`June 15, 2015 (id. at 0146-47), the Examiner mailed a Notice of Allowance on
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`October 2, 2015. Id. at 0149-55.
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`35. On December 18, 2015, Applicants submitted an Amendment after
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`Allowance, attempting to change the estradiol dose per unit area limitation in the
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`independent claims from “greater than 0.156 mg/cm2” to “from about 0.195 to
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`about 0.260 mg/cm2” as well as to change the estradiol flux limitation from
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`“greater than 0.01 mg/cm2/day” to “from about 0.0125 to about 0.0167 mg
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`/cm2/day.” Id. at 0166-69. A Request for Continued Examination (RCE) on
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`December 31, 2015 was also filed, asserting:
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`[P]aragraph
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`[0016] of
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`the
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`specification as
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`filed…discloses
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`embodiments having “about 1.25, 1.33, 1.5, [or] 1.67” times the
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`amount of estradiol per unit area as the Vivelle-Dot® product, which
`is taught in this paragraph to have 0.156 mg/cm2 estradiol, and so
`discloses embodiments having from about 0.195 to about 0.260
`mg/cm2 estradiol. That is, the low end of the recited range is disclosed
`by 1.25 x 0.156 mg/cm2 = 0.195 mg/cm2 estradiol and the upper end
`of the recited range is disclosed by 1.67 x 0.156 mg/cm2 = 0.260
`mg/cm2 estradiol. In parallel, this paragraph discloses embodiments
`that achieve an estradiol flux that is “about 1.25, 1.33, 1.5, [or] 1.67 ...
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`times the flux of the Vivelle-Dot® products,” which is taught in this
`paragraph to be 0.01 mg/cm2/day, and so discloses embodiments that
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`achieve an estradiol flux of from about 0.0125 to about 0.0167
`mg/cm2/day.
`Id. at 0178.
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`36. Applicants further argued that the criticality of the endpoints was
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`taught in the Examples disclosed in the specification, as well as in Figure 1, stating
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`“both compositions…achieved an estradiol flux greater than that of the Vivelle-
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`Dot® product…and within the range of from about 0.0125 to about 0.0167
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`mg/cm2/day recited in the amended claims.” Id. at 0179.
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`37. The Examiner issued an office action January 5, 2016 disapproving
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`the December 18, 2015 amendments, stating that they constituted new matter and
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`changed the scope of the claims. Id. at 0186-87. The Examiner stated that “[t]here
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`is no support for the ranges or for the criticality of the endpoints selected.” Id. at
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`0187.
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`38. The Examiner issued a Non-Final Office Action on May 5, 2016
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`rejecting all claims except for claim 13, under 35 U.S.C. §112 (a) stating that the
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`claims contained new matter. Id. at 0219-24. The Examiner stated that the
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`disclosure in the specification is limited to describing the estradiol per unit area as
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`“greater than the 0.156 mg/cm2 estradiol of the Vivelle-Dot® products.” Id. at
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`0222-23. The Examiner further stated that the specification disclosed “coat weight
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`that is about 1.25, 1.33, 1.5, 1.67, 1.75, 2, or 3 times the coat weight of the Vivelle-
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`Dot® products,” however, this statement was not a teaching of the estradiol per
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`unit area. Id. at 0223 (internal quotations omitted). The Examiner further stated
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`that the specification does not teach the flux range recited in the amended claims
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`and that disclosure of “discrete points” is “not a range” since the range “includes
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`values…that are not disclosed in the originally filed specification.” Id.
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`Furthermore, the Examiner stated that “there is no disclosure…that the newly
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`claimed amounts of estradiol achieve the newly claimed flux.” Id.
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`39. An applicant-initiated interview summary was filed on July 7, 2016
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`providing a summary of an interview that took place on June 28, 2016, stating that
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`an amendment to the flux to “0.0125-0.05 mg/cm2/day” was suggested, but no
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`agreement was reached on the estradiol dose. Id. at 0237-38.
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`40. Applicants responded on August 2, 2016, reverting the estradiol dose
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`back to “greater than 0.156 mg/cm2” and amending the estradiol flux to recite that
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`“the system” achieves an estradiol flux from about 0.0125 to about 0.05
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`mg/cm2/day. Id. at 0241. Applicants also cancelled pending claim 13, adding
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`dependent claims 21-25 (now issued claims 10-14), which each respectively recite
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`that the system achieves estradiol flux values of “about 0.0125 mg/cm2/day,”
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`“about 0.0133 mg/cm2/day,” “about 0.015 mg/cm2/day,” “about 0.0167
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`mg/cm2/day,” and “about 0.0175 mg/cm2/day.” Id. at 0242. I note that all of these
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`flux values fall within the broader range of “about 0.0125 to about 0.05
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`mg/cm2/day” recited in claim 1. I also note that Applicants erroneously introduced
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`claims 21-25 (now issued claims 10-14) to as depending from “[t]he method of
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`claim 1,” despite the fact that claim 1 does not recite a method, but rather a
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`“transdermal drug delivery system.”
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`41. A Notice of Allowance was mailed on September 15, 2016. Id. at
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`0253, 0257-60. The Examiner noted that authorization was given for an examiner’s
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`amendment to specify that claims 21-25 (now issued claims 10-14) depend from
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`“transdermal drug delivery system” claims rather than “method” claims. Id. at
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`0258-59, 0261.
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`42. Thereafter, issuance of the ’310 patent was delayed by over 9 months
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`by a series of RCEs filed together with information disclosure statements (“IDSs”)
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`or claim amendments. Id. at 0276-81, 0316-21, 0365-72, 0408. I note none of these
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`IDS, or any other IDS in the file history, mentions Chien (EX1009), Kim
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`(EX1010), or Ghosh (EX1014), discussed in this declaration.
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`43. Following a Notice of Allowance mailed on April 26, 2017 (EX1004,
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`0322), Applicants filed an RCE on June 6, 2017, adding a new claim to recite “the
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`adhesive polymer matrix comprises about 1.6% by weight estradiol, based on the
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`total dry weight of the adhesive polymer matrix.” EX1004, 0371. An applicant-
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`initiated interview summary was filed on June 14, 2017 regarding a June 8, 2017
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`interview. Id. at 0378-79. This summary states that “Applicant’s representative and
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`Dr. Guy explained how the included data supported the unexpected results that
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`increasing the coat weight of the drug-containing adhesive layer resulted in an
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`increased flux per unit area, and permitted the development of smaller transdermal
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`drug delivery systems that achieve comparable daily dosages.” Id. at 0379. An
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`outline for the June 8, 2017 Examiner Interview was also provided. Id. at 0381-
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`0403.
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`44. Applicants further filed a Supplemental Response and Declaration
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`under 37 C.F.R. § 1.132 of Dr. Richard H. Guy (“the Guy Declaration”) on June
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`15, 2017 along with an IDS. Id. at 0404-0523. The Guy Declaration asserts that the
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`prior art does not teach that increasing coat weight increases flux. Id. at 0415-16.
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`Dr. Guy also in