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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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`ARGENTUM PHARMACEUTICALS LLC
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`Petitioner
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`v.
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`CIPLA LIMITED
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`Patent Owner
`
`_____________________
`
`Case No. IPR2017-00807
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`U.S. Patent No. 8,168,620
`_____________________
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`DECLARATION OF ALEXANDER DOMINIC D’ADDIO, Ph.D.
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`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`
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`CIP2003
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
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`1
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Alexander Dominic D’Addio, Ph.D.(Exhibit 2003)
`TABLE OF CONTENTS
`
`I.
`Introduction .................................................................................................... 1
`Background – Education, Expertise and Responsibility ........................... 2
`II.
`III. Product Journey ............................................................................................. 3
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`i
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`2
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Alexander Dominic D’Addio, Ph.D.(Exhibit 2003)
`I, Alexander Dominic D’Addio, declare that:
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`1.
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`I am over the age of eighteen (18) and otherwise competent to make this
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`declaration.
`
`I.
`
`Introduction
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`2.
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`In connection with this inter partes review proceeding, I have been asked by
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`Cipla Ltd. (“Cipla”) to explain the pharmaceutical development of Dymista®, Meda
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`Pharmaceutical Inc.’s (“Meda”) azelastine-fluticasone combination nasal spray. During the
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`course
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`of Dymista®’s
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`development, Meda
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`and
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`its
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`predecessor MedPointe
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`Pharmaceuticals1 failed to formulate and develop a nasal spray containing a single formulation
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`of azelastine and fluticasone, and subsequently licensed the application that became U.S. Patent
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`No. 8,168,620 (“the ’620 patent”) from Cipla Ltd.
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`3.
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`I am being compensated for my time in connection with this inter partes review
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`matter at a rate of $400 per hour, and my compensation does not depend upon the ultimate
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`outcome of this case. I will also be compensated for any reasonable expenses, including travel
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`costs.
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`4.
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`This declaration is based on my own personal knowledge of Meda’s research and
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`development of the allergy treatment Dymista®.
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`5.
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`For this declaration, I rely on the following documents:
`
`Cipla's
`Exhibit #2
`2004
`
`Description
`
`Alexander Dominic D’Addio, Ph.D. Curriculum Vitae
`
`
`1In 2007, Meda acquired MedPointe Pharmaceuticals. I will refer to both companies as “Meda.”
`2 Throughout this declaration, I will refer to these exhibits as “[Exhibit Number],
`[paragraph/page number(s)].”
`
`1
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`3
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Alexander Dominic D’Addio, Ph.D.(Exhibit 2003)
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`2006 Cipla-Meda License Agreement with Quality Agreement (PTX1016)
`
`MedPointe Making Medicine Better: Astelin® Day Life CyclePlan, November
`1, 2002 (PTX1005)
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`MedPointe Product & Process Development Program Priorities and Issues -
`September 9, 2002 (PTX0143)
`
`Astelin Nasal Spray Life Cycle Management Projects (Preliminary Plan)
`(PTX1006)
`
`2006.02.06 Email from Paul Edick to Dennis Fuge re: Pfeiffer Bi Dose Nasal
`Spray System (PTX0149)
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`2006.03.21 Email and attachment from Kalidas Kale to Alex D’Addio re:
`Astelin – Flonase Combination Product Feasibility Assessment Plan
`(PTX0151)
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`Dang, Phuong Grace, et al. U.S. Patent No. 8,071,073 (Filed November 22,
`2005; Issued December 6, 2011)
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`Dang, Phuong Grace, et al. U.S. Patent No. 8,518,919 (Filed November 10,
`2011; Issued August 27, 2013)
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`MedPointe Laboratory Notebook No. 1044 - Excerpts (PTX0142)
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`MedPointe Product & Process Development, Program Priorities and Issues -
`November 18, 2002, “Commercial Product Technical Support” (PTX0144)
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`2006.02.06 Email from Richard Spivey to Alex D’Addio re: Pfeiffer Bi Dose
`Nasal Spray System (PTX0150)
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`2003.11.11 Email and attachment from Mary Lehr to Gul Balwani (PTX0255)
`
`2049
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`2054
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`2055
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`2056
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`2057
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`2058
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`2059
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`2060
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`2061
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`2120
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`2121
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`2122
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`II.
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`Background – Education, Expertise and Responsibility
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`6.
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`I obtained my bachelor’s degree in chemistry from Kean University in 1975. In
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`1983, I received my Ph.D. in analytical chemistry from Seton Hall University.
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`7.
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`For 26 years, I was involved in the research and development of allergy-related
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`products for Meda and its predecessors, MedPointe Pharmaceuticals and Carter-Wallace. Until
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`February 2017, I was the Vice President of Scientific Affairs and Medical Communications at
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`2
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`4
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Alexander Dominic D’Addio, Ph.D.(Exhibit 2003)
`Meda. I first joined Carter-Wallace as a laboratory supervisor in 1990. At Carter-Wallace, I was
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`promoted to department head in 1993 and eventually became a director in 1997. After
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`MedPointe Pharmaceuticals acquired the Wallace Laboratories division of Carter-Wallace in
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`2001, I was appointed Vice President of Product and Process Development, a position that I held
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`until 2010. In that position, I supervised the research and development of new drug products for
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`MedPointe and for Meda after its 2007 acquisition of MedPointe.
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`8.
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`I was involved in the research and development of Meda’s azelastine
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`hydrochloride nasal sprays, Astelin® and Astepro®. In October 2002, Meda began to investigate
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`an azelastine and steroid nasal spray combination project under my direction. I was involved in
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`all aspects of research, clinical development, Food and Drug Administration (“FDA”) approval,
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`launch, and post-approval support of the product that eventually became Dymista®. My duties
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`included overseeing the scientific effort to determine the feasibility of developing a combination
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`nasal spray.
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`9.
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`As Vice President of Product and Process Development, I oversaw Meda’s
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`Product & Process Development (PPD) group. From within the PPD group, the Formulation
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`Development (FD) group was responsible for the research and development of potential new
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`drugs, as well as the support of current drug products in Meda’s portfolio. The FD group
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`included Dr. Kalidas Kale, Mr. Gul Balwani, and Mr. John D’Aconti, among others. In 2002,
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`Mr. Gul Balwani was appointed lead formulator of the group. My CV appears at CIP2004.
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`III.
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`Product Journey
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`10.
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`Throughout the 1990s, Meda was working to develop an azelastine hydrochloride
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`(“azelastine”) nasal spray formulation for the treatment of symptoms of allergic rhinitis. During
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`that time, Meda had significant experience with formulating azelastine. In fact, by 2002 Meda
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Alexander Dominic D’Addio, Ph.D.(Exhibit 2003)
`had over a decade of experience formulating azelastine into nasal spray formulations. By 1997,
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`Meda received FDA-approval for an intranasal azelastine HCl product marketed as Astelin®.
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`11.
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`The PPD group maintained a weekly “Program Priorities & Issues” chart that
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`catalogued the status of all the drugs currently under development in Meda’s portfolio in order to
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`keep track of each drug’s development timeline. In 2002, Meda was considering the product
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`lifecycle strategies it would undertake for its Astelin® product. The three options being
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`considered were: (1) making an Astelin®/steroid combination, (2) making a new Astelin®
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`formulation that masked the bitter taste issues associated with azelastine, and (3) developing a
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`new azelastine formulation with improved taste and dosing profiles. CIP2054, 10. By September
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`2002, the PPD group had started analyzing the first option: an Astelin®/steroid combination
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`product. CIP2055, 1. The PPD group added the task “New Nasal Solution Product, Combination
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`of Azelastine HCl and an Approved Steroid” to its weekly “Program Priorities & Issues” chart.
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`CIP2055, 1. At that point, Meda had not selected any particular steroid allergy treatment to use
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`in the proposed combination formulation.
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`12.
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`By October/November of 2002, the PPD group had assessed the feasibility of an
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`azelastine/steroid combination product. The PPD group viewed the technical aspects of
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`developing an azelastine/steroid combination as “difficult” and considered the project to have a
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`“high degree of technical difficulty.” CIP2054, 11; CIP2056, 11. This assessment was based on
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`at least two factors.
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`13.
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`First, we recognized that Astelin® is a solution formulation, where the azelastine
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`is fully dissolved in the nasal spray vehicle, but that steroids are suspension formulations, where
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`the steroid particles are not dissolved in the nasal spray vehicle but are instead suspended in it.
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`CIP2054, 11; CIP2056, 11. The PPD group also conducted literature searches to see whether we
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Alexander Dominic D’Addio, Ph.D.(Exhibit 2003)
`could find any guidance on how to formulate a solution formulation with a suspension
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`formulation, but we were unable to find any. See CIP2055, 1.
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`14.
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`Second, we recognized that azelastine is dosed two sprays/nostril twice daily,
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`while the nasal steroids are dosed two sprays/nostril once daily or one spray/nostril twice daily.
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`This meant that the dosing of azelastine and whichever steroid selected would have to be
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`reconciled. For example, administering a combination formulation to deliver two sprays/nostril
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`twice daily would result in over-administering the steroid by twice the recommended dose. And
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`administering a combination formulation on the same frequency as a steroid (two sprays/nostril
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`once daily or one spray/nostril twice daily) would result in administering half as much azelastine
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`as is FDA-approved. In light of these factors, I, and the PPD group, drafted two documents
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`(CIP2054; CIP2056) to report our findings to Meda management. We reported that the technical
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`“feasibility” of developing an azelastine/steroid combination product was “low.”
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`15.
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`Additionally, the PPD group recognized that because the ultimate goal was to
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`develop a new commercial product, any combination product would need to satisfy the FDA’s
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`“combination rule” in order to be approved. It was our understanding that the FDA’s
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`combination rule required that both agents in a combination contribute to the overall efficacy of
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`the combination product. CIP2056, 11. Again, we reported to Meda management that the
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`“likelihood of success” of the azelastine/steroid combination satisfying the combination rule was
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`“low” because we did not anticipate that Meda could show that the combination was actually
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`better than the individual components. CIP2056, 11.
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`16.
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`Based on the low probability of success and the anticipated technical obstacles to
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`developing a combination nasal spray, the project became a low priority for Meda. CIP2120, 3.
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`Instead, the PPD group began to look into alternative ways to deliver the steroid/azelastine
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`5
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Alexander Dominic D’Addio, Ph.D.(Exhibit 2003)
`combination. From late-2003 through 2006, Meda began work to identify possible dual-chamber
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`devices that would allow azelastine and fluticasone to be stored in separate bottle chambers but
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`could also co-administer the two actives in one spray. CIP2122, 3. By January 2006, the PPD
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`group rejected the dual-chamber approach because we were unable to find any suitable devices.
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`CIP2057, 1-2.
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`17. With the dual-chamber device no longer an option, management requested that
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`the PPD group consider developing an azelastine/fluticasone combination formulation. Although
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`we understood that this combination product would be technically challenging, we still greatly
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`underestimated the difficulty associated with developing the azelastine and fluticasone
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`combination, because we believed that it was possible to create a combination formulation
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`through either a simple solution or suspension formulation. CIP2057, 1.
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`18.
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`The FD group began a small-scale formulation effort to confirm conceptually if
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`an existing formulation could work as the starting point for the combination development.
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`CIP2121, 2. I asked Dr. Kalidas Kale, a Senior Scientist in Liquid Formulations for Meda with
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`experience in nasal spray development, to draft a feasibility assessment plan for an Astelin® and
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`Flonase® combination. Dr. Kale circulated the feasibility draft in March 2006. CIP2058, 1-3. At
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`this time, Dr. Kale had a Ph.D. in Chemistry and 15-20 years of formulation experience, and he
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`devised three different “Combination Product Feasibility Assessment” plans. CIP2058, 2-3.
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`These plans explored various mixtures of existing solution and suspension formulations that
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`could potentially lead to a suitable azelastine/fluticasone combination.
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`19.
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`Plan A outlined an experiment to test whether azelastine could be soluble in the
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`Flonase® suspension. CIP2058, 2. Plan B proposed to identify a water soluble steroid compatible
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Alexander Dominic D’Addio, Ph.D.(Exhibit 2003)
`with an azelastine hydrochloride solution. CIP2058, 3. Plan C proposed testing various solubility
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`enhancement technologies to increase the solubility of fluticasone propionate. CIP2058, 3.
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`20. We moved forward with Plan A first, which we believed had the greatest chance
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`of success. Under Plan A, the first step was to determine whether azelastine could dissolve in the
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`Flonase® nasal spray formulation after the fluticasone particles had been removed. CIP2058, 2. If
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`azelastine was soluble in the Flonase® nasal spray formulation, we would have next tried to
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`dissolve azelastine directly into commercial Flonase®. CIP2058, 2.
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`21. Mr. Gul Balwani, who reported to me as the Director of New Product
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`Formulations in the PPD group, was assigned the task of attempting to formulate the
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`combination product. Mr. Balwani had a Master’s degree in Pharmacy and was an experienced
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`formulator, having 15-20 years of formulation experience at this point. Mr. Balwani was also a
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`named inventor on two patents relating to azelastine formulations. See CIP2059, 1; CIP2060, 1.
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`22.
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`Beginning on April 24, 2006, Mr. John D’Aconti, an Assistant Formulation
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`Scientist, began experiments under the direction of Mr. Balwani to create a combination nasal
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`spray. At this time, Mr. D’Aconti had a bachelor’s degree in pharmaceutical sciences and 3-4
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`years of formulation experience. He first conducted a screening experiment by combining
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`Flonase®, a commercial fluticasone propionate nasal spray, with Astelin®, a commercial
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`azelastine hydrochloride nasal spray. This experiment was designed to understand whether any
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`gross formulation changes occurred with the combination of Flonase® and Astelin®. CIP2061,
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`17. The sample was sonicated for 15 minutes and then assessed by visual observation only.
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`CIP2061, 17. No precipitation was observed. CIP2061, 17. As this was only a screening
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`experiment, no further assessment of this sample was done. CIP2061, 17.
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Alexander Dominic D’Addio, Ph.D.(Exhibit 2003)
`On April 25, 2006, Mr. D’Aconti attempted the first step under Plan A: dissolve
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`23.
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`azelastine into the Flonase® nasal spray vehicle. After removing the solid fluticasone particles
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`via centrifugation, the sample of Flonase® nasal spray vehicle remained cloudy. CIP2061, 18.
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`Viewed under a microscope, the sample appeared to be free of any solids. CIP2061, 18. The
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`sample was filtered, and because the force required to filter this sample was more than the filter
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`could withstand, the sample spilled and was lost. CIP2061, 18.
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`24.
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`The next day, April 26, 2006, the team prepared another sample in a similar
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`fashion. This time, the Flonase® supernatant sample was filtered. CIP2061, 18. The sample was
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`transferred into a pre-weighted scintillation vial containing a magnetic stir rod. CIP2061, 18. An
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`aliquot of azelastine hydrochloride equivalent to a 0.1 % concentration in the final formulation
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`was added. CIP2061, 18. The sample was stirred overnight. CIP2061, 18. The following morning
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`the sample was observed for clarity/solubility, and the team found that a major portion of the
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`azelastine hydrochloride had not dissolved. CIP2061, 18.
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`25.
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`The following day, April 27, 2006, the sample was put through alternating cycles
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`of stirring and heating. CIP2061, 19. The sample became an opaque white. CIP2061, 19. The
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`sample did not change after another 15 minutes of heating. CIP2061, 19. The sample was then
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`left overnight to cool, and the following morning the team observed that a solid had in fact
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`precipitated out of the sample. CIP2061, 19. The team determined that the sample needed further
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`investigation through an analytical azelastine hydrochloride assay after it had been filtered.
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`CIP2061, 19. The following day, the team filtered the samples and submitted the samples for an
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`azelastine hydrochloride analytical assay for further investigation. CIP2061, 19.
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`26.
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`Shortly thereafter, in May 2006, Meda discovered Cipla’s published patent
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`application directed to azelastine/steroid formulations, US 2006/0025391, and that Cipla was
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Alexander Dominic D’Addio, Ph.D.(Exhibit 2003)
`selling a nasal spray product Duonase—a combination formulation of azelastine hydrochloride
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`and fluticasone propionate. I asked Mr. Balwani to procure samples of Duonase from India.
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`Given the concerns we anticipated in 2002 followed by the difficulties we encountered in 2006, I
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`was surprised that someone had been able to successfully develop a combination nasal spray
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`containing azelastine and fluticasone.
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`27. With this new information, Meda had to decide either to continue pursuing its
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`internal development of the azelastine and fluticasone formulation or to pursue a license from
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`Cipla to market the combination product. Meda considered a number of factors in deciding
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`whether to enter into a license with Cipla: the most important considerations being that Cipla had
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`already filed a patent application on the combination nasal spray and had successfully developed
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`a formulation that it marketed in India. It was also PPD’s view that our attempts to develop an
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`azelastine/fluticasone combination formulation had failed because none of our attempts resulted
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`in a viable product. And given the difficulties we encountered at only the initial stages of the
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`azelastine/fluticasone combination formulation process, the PPD group believed that further
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`formulation efforts were futile, especially in light of Cipla’s available intellectual property.
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`28.
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`In November 2006, Meda and Cipla signed the agreement to license Cipla’s
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`patents. CIP2049, 25. Together, Meda and Cipla went on to successfully develop the azelastine
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`and fluticasone combination nasal spray that would become Dymista®. The license was very
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`important to Meda because without it, Meda would not have been able to develop and obtain
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`FDA approval for Dymista®.
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`9
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`11
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`---- -----------------------------------
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`Inter Partes Review of us. Patent No. 8,168,620
`Declaration of Alexander Dominic D'Addio. Ph.D. (Exhibit 2003)
`I declare under penalty of perjury that the foregoing is true and correct,
`to the best of my
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`knowledge,
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`information, and belief.
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`Dated: May 26, 2017
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`12
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