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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,
`
`v.
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`NOVEN PHARMACEUTICALS, INC.,
`Patent Owner.
`
`_____________________________
`
`Patent No. 9,730,900
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`_____________________________
`
`
`DECLARATION OF KEITH BRAIN, PH.D.
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`
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`MYLAN - EXHIBIT 1002
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`

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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 ’900 Patent ........................................................................ 6
`IV. File History of the ’900 Patent ....................................................................10
`V.
`Legal Standards ..........................................................................................30
`VI. Level of Ordinary Skill and Relevant Time .................................................33
`VII. Claim Construction .....................................................................................34
`A. About ................................................................................................35
`B.
`Coat Weight ......................................................................................37
`C.
`Flux ..................................................................................................39
`D.
`Therapeutically Effective Amount ....................................................41
`VIII. The State of the Art .....................................................................................41
`IX. The Asserted References Disclose or Suggest the Claimed Features of the
`’900 Patent ..................................................................................................55
`A.
`Brief Overview of the Asserted References ......................................55
`i.
`Mueller ...................................................................................55
`Vivelle-Dot® Label .................................................................65
`ii.
`iii. Kanios.....................................................................................68
`iv. Chien ......................................................................................71
`B. Detailed Analysis of the Claims ........................................................74
`GROUND 1. Mueller Anticipates Claims 1-2, 8, 10-16, and 18-23. ......74
`i.
`Claim 1 ...................................................................................74
`ii.
`Claim 2 ...................................................................................82
`iii. Claim 8 ...................................................................................83
`iv. Claims 10-14 ..........................................................................83
`v.
`Claim 15 .................................................................................89
`vi. Claim 16 .................................................................................89
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`vii. Claims 18-22 ..........................................................................93
`viii. Claim 23 .................................................................................94
`GROUND 2. The Teachings of Mueller and the Vivelle-Dot® Label
`Render Claims 1-2 and 8-23 Obvious. ...................................................94
`i.
`Claims 1, 2, and 16 .................................................................95
`ii.
`Claim 8 ................................................................................. 103
`iii. Claim 9 ................................................................................. 105
`iv. Claims 10-14 and 18-22 ........................................................ 106
`v.
`Claims 15 and 23 .................................................................. 110
`vi. Claim 17 ............................................................................... 111
`GROUND 3. The Teachings of Mueller, Vivelle-Dot® Label, and Kanios
`Render Claims 3-7 Obvious. ................................................................ 113
`i.
`Claims 3 and 5 ...................................................................... 114
`ii.
`Claims 4 and 6 ...................................................................... 123
`iii. Claim 7 ................................................................................. 125
`GROUND 4: The Teachings of Mueller, Vivelle-Dot® Label, Kanios, and
`Chien Render Claims 1-23 Obvious. .................................................... 130
`Concluding Statements ............................................................................. 143
`X.
`XI. Appendix – List Of Exhibits ..................................................................... 145
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`I, Keith Brain, declare as follows:
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`I.
`
`QUALIFICATIONS
`
`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
`
`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. 9,730,900 to
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`Mantelle (“the ’900 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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`’900 patent. I have reviewed the ’900 patent and sections of its file history from the
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`United States Patent and Trademark Office. EX1004. I cite in this declaration other
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`documents that I have reviewed and considered in arriving at my opinions. For
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`convenience, documents cited in this declaration are listed in the Appendix in
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`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 ’900 PATENT
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`14. The ’900 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 ’900 patent was filed on July 20, 2012 as U.S. Application No. 13/553,972
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`(“the ’972 application”). The patent states that the ’972 application is a
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`continuation of U.S. Application No. 12/216,811, now U.S. Patent No. 8,231,906,
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`which was filed on July 10, 2008. The earliest claimed priority date on the face of
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`the ’900 patent is July 10, 2008.
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`15. The claims of the ’900 patent are directed to a method of
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`administering estradiol using a transdermal drug delivery device and a method of
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`making said device. Claim 1 of the ’900 patent recites the following:
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`1. A method for administering estradiol, comprising applying to the
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`skin or mucosa of a subject in need thereof a monolithic transdermal
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`drug delivery system consisting of (i) a backing layer and (ii) a single
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`adhesive polymer matrix layer defining an active surface area and
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`comprising an adhesive polymer matrix comprising estradiol as the
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`only drug, wherein the polymer matrix has a coat weight of greater
`than about 10 mg/cm2 and includes greater than 0.156 mg/cm2
`estradiol and the system achieves an estradiol flux of from about
`0.0125 to about 0.05 mg/cm2/day, based on the active surface area.
`EX1001, 15:49-59 (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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`Claim 2 recites that the adhesive polymer matrix of claim 1 “comprises a polymer
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`blend comprising an acrylic adhesive, a silicone adhesive, and soluble PVP,”
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`wherein PVP stands for polyvinylpyrrolidone. Id. at 15:60-63; see also id. at 9:57-
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`79. I note that the ’900 patent claims encompass using a polymer blend that may
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`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 ’900 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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`17. 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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`15:64-16:2. Claims 4-7 depend from dependent claim 3 and, thereby, from claim 1.
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`Id. at 16:3-13. Claims 4 and 5 respectively recite that the penetration enhancer
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`comprises oleyl alcohol and dipropylene glycol. Id. at 16:3-6. Claim 6 recites that
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`the penetration enhancer comprises both oleyl alcohol and dipropylene glycol in
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`combination. Id. at 16:7-8. Claim 7 recites that the ratio of acrylic adhesive and
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`silicone adhesive in the polymer matrix is “from about 1:2 to about 1:6, based on
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`the total weight of the acrylic and silicone adhesives.” Id. at 16:9-12.
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`18. 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 16:13-19. The ’900 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 16:20-23.
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`19. 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 16:24-38. 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 16:39-41.
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`20.
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`Independent claim 16 of the ’900 patent is directed to a method of
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`making an estradiol transdermal delivery device and recites claim elements similar
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`to those recited in claim 1. Id. at 16:42-55. In addition to the backing layer and
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`single adhesive polymer matrix layer recited in claim 1, claim 16 also recites an
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`optional third layer – a release liner. Id. Independent claim 16 also recites the
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`elements recited in claim --that the adhesive polymer matrix is made of a blend of
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`acrylic adhesive, a silicone adhesive, and soluble PVP. Id. Independent claim 16
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`recites the same numerical parameters as claim 1, including the coat weight, the
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`estradiol dose, and the estradiol flux. Id.
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`21. Claims 17-23 each depend from claim 16. Id. at 16:56-17:9. Claim 17
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`recites that the transdermal patch has an active surface area that is 60% of the size
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`selected from the group consisting of 2.5, 3.75, 5.0, 7.5, and 10 cm2. Id. at 16:56-
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`58. Claims 18-22 and 23 mirror dependent claims 10-14 and 15, respectively. Id. at
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`16:59-17:9.
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`IV. FILE HISTORY OF THE ’900 PATENT
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`22. As noted above, the ’900 patent issued from the ’972 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 ’972 application, Applicants filed a
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`preliminary amendment amending the claims to recite a transdermal drug delivery
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`system, a method for administering estradiol transdermally via said system, as well
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`as a method for making said system, wherein the system is “monolithic,” and
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`comprises “a single polymer matrix layer,” comprising “estradiol as the only
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`drug.” EX1004, 0050-52. Claims were additionally amended to specify that the
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`estradiol dose and/or flux limitations applied to the “polymer matrix layer.” Id.
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`24.
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`In response to a Restriction Requirement, Applicants elected to pursue
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`claims drawn to methods of administering estradiol over claims directed to the
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`delivery system itself and methods of making the same. Id. at 0080-84. I note
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`withdrawn claims were amended alongside elected claims in subsequent office
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`action responses.
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`25. A non-final rejection was mailed on May 9, 2013, rejecting claims as
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`indefinite under 35 U.S.C. §112(b) or as anticipated under 35 U.S.C. §102(b) by
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`U.S. Patent Application Publication No. 2006/0078601 to Kanios et al. (published
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`April 13, 2006) (EX1029, “Kanios ’601”). EX1004, 0097-0100. As explained by
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`the Examiner, Kanios ’601 teaches a “transdermal drug delivery system”
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`comprising a polymer matrix layer. Id. at 0099. Moreover, the polymer matrix
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`layer taught by Kanios ’601 comprises pressure-sensitive adhesive polymers
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`including acrylic-based polymers, silicone-based polymers, polyvinylpyrrolidone
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`(PVP), and estradiol. Id. at 0099. The Examiner additionally noted that although
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`Kanios ’601 did not recite a “soluble PVP,” “the solubility of the material is an
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`inherent property.” Id. The Examiner further stated that Kanios ’601 discloses
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`systems with greater than 0.156 mg/cm2 estradiol and that achieve estradiol flux
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`that is greater than 0.01 mg/cm2/day, as recited in the ’972 application claims. Id.
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`26. The Examiner also noted that Kanios ’601 discloses estradiol delivery
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`systems which have a coat weight “from about 2.5 mg/cm2 to about 15 mg/cm2,”
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`and deliver estradiol over a period of 3.5 days, at a rate of 0.096 mg/day. Id. at
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`0100. I note here that in their response to these rejections, Applicants did not refute
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`the Examiner’s arguments that 0.096 mg/day satisfies the 0.1 mg/day flux claim
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`element.
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`27. The Examiner also rejected the claims of the ’972 application as
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`obvious over Kanios ’601 in view of U.S. Patent No. 6,638,528 to Kanios (issued
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`October 28, 2003) (EX1030, “Kanios ’528” ). Id. at 0101-02. As explained by the
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`examiner, Kanios ’601, in combination with Kanios ’528, teaches the specific
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`amounts and ratios of acrylic adhesive, silicone adhesive, penetration enhancer
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`(oleyl alcohol and dipropylene glycol), estradiol, and soluble PVP, recited in the
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`claims of the ’972 application. Id.
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`28. The Examiner additionally rejected the ’972 application claims as
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`obvious over Kanios ’601 in view of U.S. Patent No. 4,624,665 to Nuwayser
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`(issued November 25, 1986) (EX1031, “Nuwayser”). EX1004, 0102-03. As
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`explained by the examiner, Kanios ’601, in combination with Nuwayser, teaches a
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`2.4 cm2 estradiol patch, which is about 60% of 3.75 cm2, as recited in the ’972
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`application claims. Id. The Examiner also rejected the pending claims for double
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`patenting in view of U.S. Patent No. 8,231,906. Id. at 0103-04.
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`29. A summary of an applicant-initiated interview was filed on November
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`5, 2013, outlining Applicants’ arguments to the claim rejections, as well as
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`potential claims amendments discussed during an October 31, 2013 interview. Id.
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`at 0115-16.
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`30. Soon thereafter, on November 14, 2013, Applicants amended the
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`claims to recite that the transdermal system “consist[ed] of (i) a backing layer,
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`[and] (ii) a single polymer matrix layer” and that the method in withdrawn claim
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`16 included systems, which “consist[ed] of (i) a backing layer, (ii) a single
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`polymer matrix layer and, optionally, (iii) a release liner.” Id. at 0120-22 (emphasis
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`added).
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`31.
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`In response to the prior art-based rejections, Applicants argued that
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`Kanios ’601 does not teach monolithic transdermal drug delivery systems, and
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`instead teaches multilayer systems. Id. at 0126. Applicants further argued that
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`Kanios ’601 teaches a system wherein the estradiol dose is 0.1 mg/cm2 (2% of a
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`coat weight of 5 mg/cm2). Id. Applicants acknowledged Kanios ’601 uses “the
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`prior art Vivelle-Dot® product discussed in the instant application” as a control. Id.
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`32. Applicants also argued that neither Kanios ’528 nor Nuwayser in
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`combination with Kanios ’601 teach “monolithic transdermal drug delivery
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`systems for estradiol consisting of (i) a backing layer and (ii) a single polymer
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`matrix layer comprising greater than 0.156 mg/cm2 estradiol that achieves an
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`estradiol flux that is greater than 0.01 mg/cm2/day.” Id. at 0127. Applicants
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`additionally filed a terminal disclaimer to address the double patenting rejection.
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`Id.
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`33. On March 5, 2014, the Examiner issued a Final Office Action
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`maintaining the existing §102(b) and §103 rejections. Id, 0146-52. The Examiner
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`reasserted that Kanios ’601 teaches transdermal drug delivery systems that could
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`be monolithic, with a coat weight that is “greater than the instantly claimed coat
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`weight.” Id. at 0151-52.
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`34. An interview summary filed on May 19, 2014 for a May 14, 2014
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`interview notes discussions regarding “the background of the invention,” including
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`the coat weight of estradiol and pending rejections. Id. at 0156-57. Despite these
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`discussions, the Examiner noted that “[n]o agreement was reached.” Id. at 0157.
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`35. On May 23, 2014, Applicants submitted remarks which echoed
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`previously asserted arguments regarding the pending rejections. Id. at 0165-71.
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`Again, Applicants asserted that Kanios ’601 does not teach monolithic transdermal
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`drug delivery systems consisting of a backing layer and a single polymer matrix
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`layer defining the active surface area, with an optional release liner. Id. at 0166.
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`Applicants argued the “backing layer” taught by Kanios ’601 was not a “backing
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`material and a polymeric non-drug containing coating layer,” insisting that treating
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`the polymeric non-drug containing coating layer as part of the backing layer was
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`“inconsistent with how that term is used in the art, inconsistent with how that term
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`is used in the specification, and inconsistent with claims.” Id. at 0166-68.
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`36. Applicants also reasserted that Kanios ’601 did not teach the claimed
`
`estradiol dose per unit area and that, unlike the ’972 application, Kanios ’601
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`focused on “adjusting the coat weight of the non-drug containing polymer layer to
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`control drug delivery.” Id. at 0169. Moreover, Applicants argued that they
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`“surprisingly discovered that increasing the coat weight of the drug-containing
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`adhesive layer resulted in an increased flux per unit area” thus allowing for the
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`development of bioequivalent dosages that were smaller in size. Id. Applicants
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`incorrectly asserted that “[t]his result was surprising because coat weight…is not
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`generally understood to impact delivery rate.” Id. Applicants further explained that
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`“it is apparent from the specification as a whole that the inventors understood these
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`surprising and unexpected results to relate to the amount of estradiol per unit area,
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`and used the coat weight of the drug-containing adhesive layer as a proxy for that
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`parameter.” Id.
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`37. Applicants argued that the advantage of this allegedly “unexpected
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`discovery” was that the size of a patch could be decreased while maintaining the
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`amount of drug delivered by increasing coat weight and thereby increasing the flux
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`(the rate of drug delivery). Id. at 0170. Applicants also stated that the specification
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`identifies a “system according to the invention can be only 60% the size of a prior
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`art composition that includes only 0.156 mg/cm2 estradiol and yet achieve
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`comparable, therapeutically effective drug flux, such as a drug flux of greater than
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`0.01 mg/cm2/day.” Id.
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`38. 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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`-15-
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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 skill in the art prior to 2008.
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`39. Furthermore, Applicants stated that neither the combination of Kanios
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`’601 and Kanios ’528 nor the combination of Kanios ’601 and Nuwayser taught
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`the subject matter recited in the independent claims. EX1004, 0171.
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`40. After receipt of an Advisory Action from the Patent Office,
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`Applicants attempted to support their argument by relying on the Declaration of
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`Viet Nguyen (“the Nguyen Declaration”). Id. at 0185-0202. The Nguyen
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`Declaration echoed arguments previously presented by Applicants -- that Kanios
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`’601 does not describe monolithic systems, that the amount of estradiol per unit
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`area disclosed in Kanios ’601 does not meet the requirements of the ’972
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`application claims, and that the relationship between the amount of estradiol per
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`unit area, and estradiol flux was unknown in the art. Id. at 0192-94, 0199-0202.
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`41. On February 9, 2015, Applicants amended claims and requested Track
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`I expedited review of the ’972 application. Id. at 0212-17. The Patent Office
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`granted the Track I request on March 25, 2015. Id. at 0244-46.
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`42. A non-final rejection was mailed on May 5, 2015 rejecting claims
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`under 35 U.S.C. §103(a) as obvious over Kanios ’528 and Nuwayser. Id. at 0251-
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`53. 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 ’972 application claims. Id. at 0251.
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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 ’972 application claims. Id. The Examiner further
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`stated that Nuwayser teaches that increasing the concentration of a drug modulates
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`estradiol flux. Id. at 0252. In addition, Nuwayser teaches an estradiol patch that is
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`about 60% of 3.75 cm2. Id.
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`43. 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 0254-56), 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, 0253-54. 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. at 0254.
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`44. 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 polymer matrix has a coat weight of greater
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`than about 10 mg/cm2.” Id. at 0265-68.
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`45. Applicants also provided a summary of a June 10, 2015 Examiner
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`interview. Id. at 0268-69. Once again, Applicants incorrectly argued that
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`increasing estradiol per unit area to increase drug flux per unit area was unknown
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`in the prior art, again mistakenly characterising the prior art as teaching that it was
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`only thought that “increasing coat weight…provide[d] delivery over a longer
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`period of time.” Id. at 0269. Applicants stated that “[t]he invention is important
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`because it permits the development of smaller transdermal drug delivery systems,”
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`which “improve patient satisfaction and patient compliance, reduces the area of
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`skin subject to occlusion and irritation, and reduces manufacturing costs.” Id.
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`Finally, Applicants provided a chart of the percent of estradiol comprised by the
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`prior art Vivelle-Dot® transdermal estradiol delivery system that is delivered
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`transdermally, stating “the prior art Vivelle-Dot® products deliver only about 22%
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`of their drug content over their intended period of use…Since the systems already
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`include a large excess of drug than is delivered over the intended delivery period, it
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`was unexpected that increasing the amount of drug per unit area would impact drug
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`delivery rate.” Id. at 0270. I note here that Applicants expressly identify the
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`Vivelle-Dot® product as prior art.
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`46. As discussed above, however, Applicants’ statements fail to account
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`for the teachings of the prior art discussed herein. As described in further detail
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`below in Section VIII and Section IX, one of ordinary skill in the art at the time of
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`the invention was well aware of the advantages of reducing patch size to patient
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`compliance. See, e.g., U.S. Patent No. 5,919,477 to Bevan et al. (issued July 6,
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`1999) (EX1013, “Bevan”), 1:28-33, 2:66-3:9, 3:27-39; PCT Application
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`Publication WO 1996/003119 to Fot