`
`
`
`
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`
`MYLAN TECHNOLOGIES INC.,
`Petitioner,
`
`v.
`
`NOVEN PHARMACEUTICALS, INC.,
`Patent Owner.
`
`_____________________________
`
`Patent No. 9,724,310
`
`_____________________________
`
`
`DECLARATION OF KEITH BRAIN, PH.D.
`
`
`
`
`
`MYLAN - EXHIBIT 1002
`
`
`
`TABLE OF CONTENTS
`
`
`
`
`
`
`
`Page
`
`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
`
`B.
`
`
`
`-i-
`
`
`
`GROUND 2. The Teachings of Mueller and the Vivelle-Dot®
`
`
`
`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
`
`GROUND 3. The Teachings of Mueller, Vivelle-Dot® Label, and
`
`GROUND 4: The Teachings of Mueller, Vivelle-Dot® Label,
`
`
`
`
`
`
`
`
`
`
`
`
`
`-ii-
`
`
`
`
`
`
`
`
`
`I.
`
`I, Keith Brain, declare as follows:
`
`QUALIFICATIONS
`
`1. My name is Keith Brain. I was appointed to a full-time tenured
`
`position on faculty at the School of Pharmacy and Pharmaceutical Sciences of
`
`Cardiff University in 1969 and retired as Reader in Dermatopharmaceutics (the
`
`science of skin drug delivery) in 2011 after 42 years of continuous service. I was
`
`awarded an Honorary Senior Research Fellowship at retirement and continued
`
`research involvement with former colleagues. My career in research has covered a
`
`number of topics, focusing primarily on aspects of dermal and transdermal drug
`
`delivery. During the last 20-25 years of my research career, my work also focused
`
`on molecular interactions between polymers. My work has covered both basic
`
`science and translational and applied aspects of research.
`
`2.
`
`During my time at Cardiff, I was responsible for a number of B.
`
`Pharm and M. Pharm courses including those on pharmaceutical chemistry,
`
`pharmaceutical analysis, drug delivery (pharmaceutics), and quality assurance. I
`
`also lectured externally for courses in the Diploma in Pharmaceutical Medicine and
`
`Dermal Toxicology MSc program.
`
`3.
`
`I received my B. Pharm. from the University of Nottingham in 1966
`
`and my Ph.D. in Pharmaceutical Science from the University of Bath in 1969.
`
`
`
`-1-
`
`
`
`
`
`4.
`
`I have authored or co-authored over 100 peer-reviewed journal
`
`articles, of which several articles present original research and data on transdermal
`
`delivery of active agents across the skin from various drug delivery systems
`
`including transdermal patches. In particular, I have co-authored an article on
`
`transdermal estradiol drug delivery. I have also authored or co-authored 22 book
`
`chapters, three books, 56 peer-reviewed papers in conference proceedings, and 140
`
`conference abstracts, in addition to editing 22 books, including several editions of
`
`Perspectives in Percutaneous Penetration. I am a regular reviewer for 11 high-
`
`impact peer reviewed journals including Nature Biotechnology, the Journal of
`
`Controlled Release, and the International Journal of Pharmaceutics.
`
`5.
`
`For the past 30 years, I have served as CEO of An-eX Analytical
`
`Services Ltd. An-eX Analytical Services is an independent contract research and
`
`development company that provides services in the development and evaluation of
`
`pharmaceutical materials. An-eX Analytical Services has received global
`
`recognition in the field of dermal pharmaceutics and has provided a range of
`
`services to a wide range of international clients. Whilst most of this work has been
`
`subject to Non-Disclosure Agreements, certain studies have been published at the
`
`request of the Sponsor. These include collaborations with Organon, Mentholatum,
`
`Biomarin, Clairol, Unilever Research, Proctor and Gamble, Cosmetic Toiletries
`
`and Fragrance Association, Research Institute for Fragrance Materials and the
`
`-2-
`
`
`
`
`
`
`
`Center for Drug Evaluation and Research of the US Food and Drug
`
`Administration.
`
`6.
`
`Together with the University of Regensburg, University of Padova,
`
`Destiny Pharma, Waldmann AG, and Solvias AG, An-eX Analytical Services was
`
`a member of the European Commission funded (EU 693,700) Development of a
`
`Photodynamic Treatment to Eradicate and Control the Current Spread of Infections
`
`Antibiotic Resistant Microorganisms in Man (“DYNAMICRO”) project.
`
`7.
`
`Together with Cardiff University, Waterford Institute of Technology,
`
`and Eirgen Pharma, An-eX Analytical Services was also a member of the High
`
`Potency Dermatologicals (“HIPODERM”) Consortium. HIPODERM focused on
`
`innovative dermal drug delivery solutions for disease management. It was funded
`
`(EU 838,363) by the European Union’s Marie Curie Programme under the
`
`auspices of the Community Research and Development Information Service
`
`(“CORDIS”) of the European Commission.
`
`8.
`
`I have also served on other boards and committees involved in
`
`transdermal delivery. For example, I served as an expert panel member at the
`
`Workshop on Dermal Absorption for Pesticide Risk Assessment in 2012. I served
`
`as a member of the Planning Committee for the FDA/DIA Meeting on Improved
`
`Development and Regulation of Transdermal Systems in 2011. I also served as a
`
`member on the European Centre for Ecotoxicology and Toxicology of Chemicals
`
`-3-
`
`
`
`
`
`
`
`(“ECETOC”) Selection Team for the Human Exposure and Tiered Risk
`
`Assessment Monitoring Team (“HETRA”) A2.3 International Workshop on
`
`Dermal Exposure Modelling Meeting in 2003. I became a member of the Expert
`
`Workshop on Percutaneous Absorption in 2005 and joined the Scientific Board for
`
`the Society for Molecular Imprinting in 2006.
`
`9.
`
`I have participated in and been invited to speak at numerous
`
`workshops and meetings pertaining to the field of drug delivery and dermal drug
`
`delivery, including at the Predictive Modelling for Healthcare Technology through
`
`Maths (“POEMs”) Workshop on Modelling of Skin Absorption in 2016, FDA/DIA
`
`meeting on Improved Development and Regulation of Transdermal Systems in
`
`2011, the Defense Threat Reduction Agency (“DTRA”) Dermal Toxicity
`
`Workshop in 2010, the Gordon Research Conference on Barrier Function of
`
`Mammalian Skin in 1999, 2001, 2005, 2007, and 2009, the American Association
`
`of Pharmaceutical Scientists Annual Meeting in 2003-2004, the Perspectives in
`
`Percutaneous Conference in 1999, 2004 and 2006, the AgChemForum Meeting in
`
`2004, and the Workshop on Molecularly Imprinted Polymers (“MIP”) in 2004. I
`
`am also a conference organiser for the Biennial International Perspectives in
`
`Percutaneous Penetration Conference and Introductory Course on Percutaneous
`
`penetration as well as the Biennial International Molecularly Imprinted Polymers
`
`Workshop.
`
`-4-
`
`
`
`
`
`
`
`10. Academic research funding in excess of GBP 800,000 was obtained
`
`from a wide variety of governmental, commercial, and charitable sources including
`
`the Science and Engineering Research Council, Smith Kline Beecham,
`
`Engineering and Physical Sciences Research Council, Reckitt and Colman,
`
`Wellcome Trust, Biotechnology and Biological Sciences Research Council, World
`
`Health Organisation, Home Office, Molecular Light Technology, Hadwen Trust
`
`and An-eX. Notably, I received the Sir Henry Wellcome Award for Innovative
`
`Research in consecutive years for work on molecular interactions in polymers.
`
`11.
`
`I am submitting a copy of my CV as EX1003. My CV provides a
`
`summary of my education, academic and industry experience, conference
`
`attendance, committee membership, and publications.
`
`II.
`
`SCOPE OF WORK
`
`12.
`
`I understand that a petition is being filed with the United States Patent
`
`and Trademark Office for Inter Partes Review of U.S. Patent No. 9,724,310 to
`
`Mantelle (“the ’310 patent,” EX1001). I have been retained by the Petitioner as a
`
`technical expert to provide my independent analysis and opinions regarding the
`
`’310 patent. I have reviewed the ’310 patent and sections of its file history from the
`
`United States Patent and Trademark Office (EX1004), as well as that of related
`
`U.S. Patent No. 9,730,900. EX1035. I cite in this declaration other documents that
`
`-5-
`
`
`
`
`
`
`
`I have reviewed and considered in arriving at my opinions. For convenience,
`
`documents cited in this declaration are listed in the Appendix in Section XI.
`
`13.
`
`I am being compensated at the rate of $400/hour for my time in this
`
`matter. I have no financial interest in the outcome of this matter.
`
`III. OVERVIEW OF THE ’310 PATENT
`
`14. The ’310 patent is entitled “Transdermal Estrogen Device and
`
`Delivery” and is assigned to Noven Pharmaceuticals, Inc. (referred to herein as
`
`“Noven,” “Applicants,” or “Patent Owner”). The patent states at the front page that
`
`the ’310 patent was filed on September 12, 2013 as U.S. Application No.
`
`14/024,985 (“the ’985 application”). The ’985 application is a continuation of U.S.
`
`Application No. 13/553,972 (“the ’972 application”), that was filed on July 20,
`
`2012, and issued as U.S. Patent No. 9,730,900. See EX1035 (File History of the
`
`’900 patent); EX1036 (“the ’900 patent”). The ’972 application is a continuation of
`
`U.S. Application No. 12/216,811, now U.S. Patent No. 8,231,906, which was filed
`
`on July 10, 2008. The earliest claimed priority date on the face of the ’310 patent is
`
`July 10, 2008.
`
`15. The claims of the ’310 patent are directed to a transdermal drug
`
`delivery system for estradiol. Claim 1 of the ’310 patent recites the following:
`
`1. A monolithic transdermal drug delivery system for estradiol,
`
`consisting of (i) a backing layer, (ii) a single adhesive polymer matrix
`
`layer defining an active surface area and, optionally, (iii) a release
`
`-6-
`
`
`
`
`
`
`
`liner, wherein the single adhesive polymer matrix layer comprises an
`
`adhesive polymer matrix comprising estradiol as the only drug,
`
`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.
`
`EX1001, 15:50-16:3 (claim 1).
`
`16.
`
`I understand that claims 2-15 incorporate the subject matter of claim 1
`
`and that claims 4-7 each additionally incorporate the subject matter of claim 3.
`
`17. Claim 2 recites that the adhesive polymer matrix of claim 1
`
`“comprises a polymer blend comprising an acrylic adhesive, a silicone adhesive,
`
`and soluble PVP,” wherein PVP stands for polyvinylpyrrolidone. Id. at 16:4-7
`
`(claim 2); see also id. at 9:57-59.
`
`18.
`
`I note that the ’310 patent claims encompass using a polymer blend
`
`that may contain polymers that are immiscible. Id. at 10:27-33. The effect of using
`
`immiscible polymers with a hydrophobic drug such as estrogen is to encapsulate
`
`the drug and form microreservoirs of estrogen within the polymer blend in a single
`
`polymer adhesive layer. This is supported by the ’310 patent, which states, “a
`
`plurality of polymers including a soluble polyvinylpyrrolidone, which may have
`
`different solubility parameters for the drug and which may be immiscible with
`
`each other, may be selected to adjust the solubility of the drug in the polymer
`
`matrix[.]” Id.
`
`-7-
`
`
`
`
`
`
`
`19. Claim 3 further recites the percent dry weight of polymers in the
`
`adhesive polymer matrix (“about 2-25% by weight acrylic adhesive, about 45-70%
`
`by weight silicone adhesive, about 2-25% by weight soluble PVP”), as well as
`
`“about 5-15% [by weight] penetration enhancer, and about 0.1-10% by weight
`
`estradiol, all based on the total dry weight of the adhesive polymer matrix.” Id. at
`
`16:8-14. Claims 4-7 depend from dependent claim 3 and, thereby, from claim 1. Id.
`
`at 16:15-25. Claims 4 and 5 respectively recite that the penetration enhancer
`
`comprises oleyl alcohol and dipropylene glycol. Id. at 16:15-19. Claim 6 recites
`
`that the penetration enhancer comprises both oleyl alcohol and dipropylene glycol
`
`in combination. Id. at 16:19-21. Claim 7 recites that the ratio of acrylic adhesive
`
`and silicone adhesive in the polymer matrix is “from about 1:2 to about 1:6, based
`
`on the total weight of the acrylic and silicone adhesives.” Id. at 16:22-25.
`
`20. Claim 8 recites that the “adhesive polymer matrix comprises an
`
`amount of estradiol effective to deliver a therapeutically effective amount of
`
`estradiol over a period of time selected from the group consisting of at least 1 day,
`
`at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days and at
`
`least 7 days.” Id. at 16:26-32. The ’310 patent states that “a therapeutically
`
`effective amount of estradiol is from about 0.025-0.1 mg/day, including about
`
`0.025 mg/day, about 0.0375 mg/day, about 0.05 mg/day, about 0.075 mg/day, or
`
`about 0.1 mg/day, such as 0.025-0.1 mg/day, 0.025 mg/day, 0.0375 mg/day, 0.05
`
`-8-
`
`
`
`
`
`
`
`mg/day, 0.075 mg/day, and 0.1 mg/day.” Id. at 11:64-12:3. Claim 9 recites that the
`
`transdermal estradiol delivery system “comprises an amount of estradiol effective
`
`to deliver an amount of estradiol selected from the group consisting of about 0.025,
`
`0.0375, 0.05, 0.075 and 0.1 mg/day.” Id. at 16:33-37.
`
`21. Claims 10-14 respectively recite that the estradiol flux achieved by the
`
`system based on the active surface area is about 0.0125 mg/cm2/day, about 0.0133
`
`mg/cm2/day, about 0.015 mg/cm2/day, about 0.0167 mg/cm2/day, and about 0.0175
`
`mg/cm2/day. Id. at 16:38-52. Claim 15 recites that the adhesive polymer matrix of
`
`claim 1 comprises “about 1.6% by weight estradiol, based on the total dry weight
`
`of the adhesive polymer matrix.” Id. at 16:53-56.
`
`IV. FILE HISTORY OF THE ’310 PATENT
`
`22. As noted above, the ’310 patent issued from the ’985 application and
`
`claims the benefit of July 10, 2008 as its earliest effective filing date.
`
`23. Following submission of the ’985 application, Applicants filed a
`
`preliminary amendment amending the claims to specify that the transdermal drug
`
`delivery system is a “monolithic” system “for estradiol,” “consisting of (i) a
`
`backing layer, (ii) a single polymer matrix layer,” and “optionally, (iii) a release
`
`liner.” EX1004, 0051-52. The claims were also amended to specify that the “single
`
`polymer matrix layer comprises…estradiol as the only drug.” Id. Claim 1 was
`
`-9-
`
`
`
`
`
`
`
`additionally amended to specify that the estradiol dose and flux limitations applied
`
`to the “polymer matrix layer.” Id.
`
`24. A non-final rejection was mailed on May 20, 2015 rejecting claims
`
`under 35 U.S.C. §103(a) as obvious over U.S. Patent No. 6,638,528 to Kanios
`
`(issued October 28, 2003) (EX1030, “Kanios ’528”) and U.S. Patent No. 4,624,665
`
`to Nuwayser (issued November 25, 1986) (EX1031, “Nuwayser”). EX1004, 0097-
`
`99. As explained by the Examiner, Kanios ’528 teaches matrix-type transdermal
`
`estradiol delivery systems containing percentages of silicone adhesives,
`
`polyacrylate adhesives, PVP, penetration enhancers (dipropylene glycol and oleyl
`
`alcohol), and estradiol recited in the ’985 application claims. Id. at 0097.
`
`Moreover, the monolithic estradiol delivery systems of Kanios ’528 comprise an
`
`adhesive matrix layer, release liner, and a backing layer. Id. The Examiner
`
`additionally stated that Kanios ’528 teaches the administration of estradiol over a
`
`period of time recited in the ’985 application claims. Id. The Examiner further
`
`stated Nuwayser teaches that increasing the concentration of a drug modulates
`
`estradiol flux. Id. at 0098-99.
`
`25. The Examiner also rejected the pending claims for double patenting in
`
`view of U.S. Patent No. 8,231,906 (id. at 0100-02), as well as under 35 U.S.C.
`
`§103(a) as obvious in further view of U.S. Patent Application Publication No.
`
`2009/0041831 to Miller et al. (published February 12, 2009) (EX1032, “Miller”).
`
`-10-
`
`
`
`
`
`
`
`EX1004, 0099-0100. The Examiner stated that Miller teaches silicone-based
`
`transdermal delivery systems in which the cast composition has a coat weight of
`
`90-110 g/m2. Id.
`
`26. Applicants responded on June 12, 2015 by amending the independent
`
`claims to clarify that the single polymer matrix layer was a single “adhesive”
`
`polymer matrix layer and that “the adhesive polymer matrix layer has a coat weight
`
`of greater than about 10 mg/cm2.” Id. at 0117-18.
`
`27. Applicants also provided a summary of a June 10, 2015 Examiner
`
`interview. Id. at 0119. Applicants also stated they “were surprised by the discovery
`
`that increasing the amount of estradiol per unit area resulted an increased rate of
`
`drug delivery per unit area[.]” Id. at 0120. Applicants also incorrectly asserted that
`
`“coat weight was thought to provide delivery over a longer period of time, but it
`
`was not known that increasing the amount of drug per unit area could increase the
`
`drug delivery rate.” Id. Applicants stated that “[t]he invention is important because
`
`it permits the development of smaller transdermal drug delivery systems,” which
`
`“improve patient satisfaction and patient compliance, reduces the area of skin
`
`subject to occlusion and irritation, and reduces manufacturing costs.” Id.
`
`Applicants reiterated their mistaken assertion that “coat weight is typically selected
`
`to control the duration of drug delivery, but was not understood to impact delivery
`
`rate (e.g., daily dose delivered).” Id.
`
`-11-
`
`
`
`
`
`
`
`28. Finally, Applicants provided a chart of the percent of estradiol
`
`comprised by the prior art Vivelle-Dot® transdermal estradiol delivery system that
`
`is delivered transdermally, stating “the prior art Vivelle-Dot® products deliver only
`
`about 22% of their drug content over their intended period of use…Since the
`
`systems already include a large excess of drug than is delivered over the intended
`
`delivery period, it was unexpected that increasing the amount of drug per unit area
`
`would impact drug delivery rate.” Id. at 0120-21. I note here that Applicants
`
`expressly identify the Vivelle-Dot® product as prior art.
`
`29.
`
`I further note that Applicants interchangeably used the phrases
`
`“estradiol per unit area” and “coat weight.” In fact, during prosecution of the ’972
`
`patent application, which issued as the ’900 patent with a specification identical to
`
`that of the ’310 patent, Applicants admitted that “it is apparent from the
`
`specification as a whole that the inventors understood these surprising and
`
`unexpected results to relate to the amount of estradiol per unit area, and used the
`
`coat weight of the drug-containing adhesive layer as a proxy for that parameter.”
`
`EX1035 (File History of the ’900 patent), 0169. Thus, “estradiol per unit area” and
`
`“coat weight” can be interchangeably used when discussing the impact of these
`
`parameters on the flux of estradiol from transdermal drug delivery systems.
`
`30.
`
`I note that the above arguments are similar to arguments made by
`
`Applicants during prosecution of the application which issued as the related ’900
`
`-12-
`
`
`
`
`
`
`
`patent. For example, Applicants argued that the advantage of this allegedly
`
`“unexpected discovery” was that the size of a patch could be decreased while
`
`maintaining the amount of drug delivered by increasing coat weight and thereby
`
`increasing the flux (the rate of drug delivery). Id. at 0170. Applicants also stated
`
`that the specification identifies a “system according to the invention can be only
`
`60% the size of a prior art composition that includes only 0.156 mg/cm2 estradiol
`
`and yet achieve comparable, therapeutically effective drug flux, such as a drug flux
`
`of greater than 0.01 mg/cm2/day.” Id.
`
`31. Despite the Applicants’ assertions that it was not described in the
`
`prior art that one can increase the estradiol flux by increasing the coat weight (i.e.,
`
`the amount of estradiol per unit area), various prior art publications, discussed in
`
`more detail later on in this declaration, taught this exact principle. See, e.g., U.S.
`
`Patent No. 5,145,682 to Chien et al. (issued September 8, 1992) (EX1009,
`
`“Chien”); Kim et al., Penetration Enhancement of β2-Selective Agonist,
`
`Tulobuterol, Across Hairless Mouse Skin, 33 J. KOR. PHARM. SCI. (2003) 79-84
`
`(EX1010, “Kim”); Ghosh et al., Development of a Transdermal Patch of
`
`Methadone: In Vitro Evaluation Across Hairless Mouse and Human Cadaver Skin,
`
`1 PHARM. DEV. TECHNOL. (1996) 285-91 (EX1014, “Ghosh”). Thus, Applicants’
`
`assertions that these results were unexpected are not correct in view of the
`
`teachings of those of ordinary skill in the art prior to 2008.
`
`-13-
`
`
`
`
`
`
`
`32.
`
`In response to the first Office Action, Applicants also discussed that
`
`the pre-existing product sold as Vivelle-Dot® provided a series of increased doses
`
`via patches increasing in size. EX1004, 0121. As discussed below, flux, dose, and
`
`patch size are all directly related. Thus, the skilled artisan would have understood
`
`from the art as a whole that increasing patch size is just one way to increase the
`
`dose administered by a transdermal delivery system. As understood by those in the
`
`art well-prior to 2008, patch size could also be held constant, while flux was
`
`increased, to deliver an increased dose. Indeed, various methods of increasing dose
`
`through increased flux were known prior to the time of filing, including by
`
`increasing the coat weight of the polymer matrix within a transdermal patch. See,
`
`e.g., EX1009 (Chien), FIGS. 3-5; EX1010 (Kim), 82; EX1014 (Ghosh), 288.
`
`33. Moreover, Applicants admitted Kanios ’528 teaches “matrix-type
`
`transdermal drug delivery systems,” but argued that neither Kanios ’528 nor
`
`Nuwayser teach every limitation recited in the claims and asserted that Nuwayser
`
`is directed towards reservoir-type systems, which contained liquid compositions
`
`rather than polymer matrix-type systems. EX1004, 0122-24. Applicants further
`
`argued that Miller was not applicable because it taught systems comprising
`
`fentanyl, rather than estradiol. Id. Applicants also filed a terminal disclaimer to
`
`address the double patenting rejection. Id.
`
`-14-
`
`
`
`
`
`
`
`34. Following filing a second summary of the June 10, 2015 interview, on
`
`June 15, 2015 (id. at 0146-47), the Examiner mailed a Notice of Allowance on
`
`October 2, 2015. Id. at 0149-55.
`
`35. On December 18, 2015, Applicants submitted an Amendment after
`
`Allowance, attempting to change the estradiol dose per unit area limitation in the
`
`independent claims from “greater than 0.156 mg/cm2” to “from about 0.195 to
`
`about 0.260 mg/cm2” as well as to change the estradiol flux limitation from
`
`“greater than 0.01 mg/cm2/day” to “from about 0.0125 to about 0.0167 mg
`
`/cm2/day.” Id. at 0166-69. A Request for Continued Examination (RCE) on
`
`December 31, 2015 was also filed, asserting:
`
`[P]aragraph
`
`[0016] of
`
`the
`
`specification as
`
`filed…discloses
`
`embodiments having “about 1.25, 1.33, 1.5, [or] 1.67” times the
`
`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 ...
`
`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
`
`-15-
`
`
`
`
`
`
`
`achieve an estradiol flux of from about 0.0125 to about 0.0167
`mg/cm2/day.
`Id. at 0178.
`
`36. Applicants further argued that the criticality of the endpoints was
`
`taught in the Examples disclosed in the specification, as well as in Figure 1, stating
`
`“both compositions…achieved an estradiol flux greater than that of the Vivelle-
`
`Dot® product…and within the range of from about 0.0125 to about 0.0167
`
`mg/cm2/day recited in the amended claims.” Id. at 0179.
`
`37. The Examiner issued an office action January 5, 2016 disapproving
`
`the December 18, 2015 amendments, stating that they constituted new matter and
`
`changed the scope of the claims. Id. at 0186-87. The Examiner stated that “[t]here
`
`is no support for the ranges or for the criticality of the endpoints selected.” Id. at
`
`0187.
`
`38. The Examiner issued a Non-Final Office Action on May 5, 2016
`
`rejecting all claims except for claim 13, under 35 U.S.C. §112 (a) stating that the
`
`claims contained new matter. Id. at 0219-24. The Examiner stated that the
`
`disclosure in the specification is limited to describing the estradiol per unit area as
`
`“greater than the 0.156 mg/cm2 estradiol of the Vivelle-Dot® products.” Id. at
`
`0222-23. The Examiner further stated that the specification disclosed “coat weight
`
`that is about 1.25, 1.33, 1.5, 1.67, 1.75, 2, or 3 times the coat weight of the Vivelle-
`
`Dot® products,” however, this statement was not a teaching of the estradiol per
`
`-16-
`
`
`
`
`
`
`
`unit area. Id. at 0223 (internal quotations omitted). The Examiner further stated
`
`that the specification does not teach the flux range recited in the amended claims
`
`and that disclosure of “discrete points” is “not a range” since the range “includes
`
`values…that are not disclosed in the originally filed specification.” Id.
`
`Furthermore, the Examiner stated that “there is no disclosure…that the newly
`
`claimed amounts of estradiol achieve the newly claimed flux.” Id.
`
`39. An applicant-initiated interview summary was filed on July 7, 2016
`
`providing a summary of an interview that took place on June 28, 2016, stating that
`
`an amendment to the flux to “0.0125-0.05 mg/cm2/day” was suggested, but no
`
`agreement was reached on the estradiol dose. Id. at 0237-38.
`
`40. Applicants responded on August 2, 2016, reverting the estradiol dose
`
`back to “greater than 0.156 mg/cm2” and amending the estradiol flux to recite that
`
`“the system” achieves an estradiol flux from about 0.0125 to about 0.05
`
`mg/cm2/day. Id. at 0241. Applicants also cancelled pending claim 13, adding
`
`dependent claims 21-25 (now issued claims 10-14), which each respectively recite
`
`that the system achieves estradiol flux values of “about 0.0125 mg/cm2/day,”
`
`“about 0.0133 mg/cm2/day,” “about 0.015 mg/cm2/day,” “about 0.0167
`
`mg/cm2/day,” and “about 0.0175 mg/cm2/day.” Id. at 0242. I note that all of these
`
`flux values fall within the broader range of “about 0.0125 to about 0.05
`
`mg/cm2/day” recited in claim 1. I also note that Applicants erroneously introduced
`
`-17-
`
`
`
`
`
`
`
`claims 21-25 (now issued claims 10-14) to as depending from “[t]he method of
`
`claim 1,” despite the fact that claim 1 does not recite a method, but rather a
`
`“transdermal drug delivery system.”
`
`41. A Notice of Allowance was mailed on September 15, 2016. Id. at
`
`0253, 0257-60. The Examiner noted that authorization was given for an examiner’s
`
`amendment to specify that claims 21-25 (now issued claims 10-14) depend from
`
`“transdermal drug delivery system” claims rather than “method” claims. Id. at
`
`0258-59, 0261.
`
`42. Thereafter, issuance of the ’310 patent was delayed by over 9 months
`
`by a series of RCEs filed together with information disclosure statements (“IDSs”)
`
`or claim amendments. Id. at 0276-81, 0316-21, 0365-72, 0408. I note none of these
`
`IDS, or any other IDS in the file history, mentions Chien (EX1009), Kim
`
`(EX1010), or Ghosh (EX1014), discussed in this declaration.
`
`43. Following a Notice of Allowance mailed on April 26, 2017 (EX1004,
`
`0322), Applicants filed an RCE on June 6, 2017, adding a new claim to recite “the
`
`adhesive polymer matrix comprises about 1.6% by weight estradiol, based on the
`
`total dry weight of the adhesive polymer matrix.” EX1004, 0371. An applicant-
`
`initiated interview summary was filed on June 14, 2017 regarding a June 8, 2017
`
`interview. Id. at 0378-79. This summary states that “Applicant’s representative and
`
`Dr. Guy explained how the included data supported the unexpected results that
`
`-18-
`
`
`
`
`
`
`
`increasing the coat weight of the drug-containing adhesive layer resulted in an
`
`increased flux per unit area, and permitted the development of smaller transdermal
`
`drug delivery systems that achieve comparable daily dosages.” Id. at 0379. An
`
`outline for the June 8, 2017 Examiner Interview was also provided. Id. at 0381-
`
`0403.
`
`44. Applicants further filed a Supplemental Response and Declaration
`
`under 37 C.F.R. § 1.132 of Dr. Richard H. Guy (“the Guy Declaration”) on June
`
`15, 2017 along with an IDS. Id. at 0404-0523. The Guy Declaration asserts that the
`
`prior art does not teach that increasing coat weight increases flux. Id. at 0415-16.
`
`Dr. Guy also in