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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
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`
`ARGENTUM PHARMACEUTICALS LLC
`
`Petitioner
`
`v.
`
`CIPLA LIMITED
`
`Patent Owner
`
`_____________________
`
`Case No. IPR2017-00807
`
`U.S. Patent No. 8,168,620
`_____________________
`
`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
`
`
`
`
`CIP2003
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
`
`1
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`CIPLA LTD. EXHIBIT 2038 PAGE 1
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`

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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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`CIPLA LTD. EXHIBIT 2038 PAGE 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:
`
`1.
`
`I am over the age of eighteen (18) and otherwise competent to make this
`
`declaration.
`
`I.
`
`Introduction
`
`2.
`
`In connection with this inter partes review proceeding, I have been asked by
`
`Cipla Ltd. (“Cipla”) to explain the pharmaceutical development of Dymista®, Meda
`
`Pharmaceutical Inc.’s (“Meda”) azelastine-fluticasone combination nasal spray. During the
`
`course
`
`of Dymista®’s
`
`development, Meda
`
`and
`
`its
`
`predecessor MedPointe
`
`Pharmaceuticals1 failed to formulate and develop a nasal spray containing a single formulation
`
`of azelastine and fluticasone, and subsequently licensed the application that became U.S. Patent
`
`No. 8,168,620 (“the ’620 patent”) from Cipla Ltd.
`
`3.
`
`I am being compensated for my time in connection with this inter partes review
`
`matter at a rate of $400 per hour, and my compensation does not depend upon the ultimate
`
`outcome of this case. I will also be compensated for any reasonable expenses, including travel
`
`costs.
`
`4.
`
`This declaration is based on my own personal knowledge of Meda’s research and
`
`development of the allergy treatment Dymista®.
`
`5.
`
`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
`
`3
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`CIPLA LTD. EXHIBIT 2038 PAGE 3
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`

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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)
`
`2006 Cipla-Meda License Agreement with Quality Agreement (PTX1016)
`
`MedPointe Making Medicine Better: Astelin® Day Life CyclePlan, November
`1, 2002 (PTX1005)
`
`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)
`
`2006.03.21 Email and attachment from Kalidas Kale to Alex D’Addio re:
`Astelin – Flonase Combination Product Feasibility Assessment Plan
`(PTX0151)
`
`Dang, Phuong Grace, et al. U.S. Patent No. 8,071,073 (Filed November 22,
`2005; Issued December 6, 2011)
`
`Dang, Phuong Grace, et al. U.S. Patent No. 8,518,919 (Filed November 10,
`2011; Issued August 27, 2013)
`
`MedPointe Laboratory Notebook No. 1044 - Excerpts (PTX0142)
`
`MedPointe Product & Process Development, Program Priorities and Issues -
`November 18, 2002, “Commercial Product Technical Support” (PTX0144)
`
`2006.02.06 Email from Richard Spivey to Alex D’Addio re: Pfeiffer Bi Dose
`Nasal Spray System (PTX0150)
`
`2003.11.11 Email and attachment from Mary Lehr to Gul Balwani (PTX0255)
`
`2049
`
`2054
`
`2055
`
`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
`
`2122
`
`
`II.
`
`Background – Education, Expertise and Responsibility
`
`6.
`
`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.
`
`7.
`
`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
`
`2
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`4
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`CIPLA LTD. EXHIBIT 2038 PAGE 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.
`
`8.
`
`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.
`
`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
`
`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.
`
`Product Journey
`
`10.
`
`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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`3
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`5
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`CIPLA LTD. EXHIBIT 2038 PAGE 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)
`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.
`
`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
`
`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
`
`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.
`
`By October/November of 2002, the PPD group had assessed the feasibility of an
`
`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
`
`“high degree of technical difficulty.” CIP2054, 11; CIP2056, 11. This assessment was based on
`
`at least two factors.
`
`13.
`
`First, we recognized that Astelin® is a solution formulation, where the azelastine
`
`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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`4
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`6
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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
`
`formulation, but we were unable to find any. See CIP2055, 1.
`
`14.
`
`Second, we recognized that azelastine is dosed two sprays/nostril twice daily,
`
`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
`
`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.
`
`Additionally, the PPD group recognized that because the ultimate goal was to
`
`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.
`
`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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`7
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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
`
`devices that would allow azelastine and fluticasone to be stored in separate bottle chambers but
`
`could also co-administer the two actives in one spray. CIP2122, 3. By January 2006, the PPD
`
`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
`
`the PPD group consider developing an azelastine/fluticasone combination formulation. Although
`
`we understood that this combination product would be technically challenging, we still greatly
`
`underestimated the difficulty associated with developing the azelastine and fluticasone
`
`combination, because we believed that it was possible to create a combination formulation
`
`through either a simple solution or suspension formulation. CIP2057, 1.
`
`18.
`
`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.
`
`CIP2121, 2. I asked Dr. Kalidas Kale, a Senior Scientist in Liquid Formulations for Meda with
`
`experience in nasal spray development, to draft a feasibility assessment plan for an Astelin® and
`
`Flonase® combination. Dr. Kale circulated the feasibility draft in March 2006. CIP2058, 1-3. At
`
`this time, Dr. Kale had a Ph.D. in Chemistry and 15-20 years of formulation experience, and he
`
`devised three different “Combination Product Feasibility Assessment” plans. CIP2058, 2-3.
`
`These plans explored various mixtures of existing solution and suspension formulations that
`
`could potentially lead to a suitable azelastine/fluticasone combination.
`
`19.
`
`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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`6
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`8
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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
`
`enhancement technologies to increase the solubility of fluticasone propionate. CIP2058, 3.
`
`20. We moved forward with Plan A first, which we believed had the greatest chance
`
`of success. Under Plan A, the first step was to determine whether azelastine could dissolve in the
`
`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.
`
`21. Mr. Gul Balwani, who reported to me as the Director of New Product
`
`Formulations in the PPD group, was assigned the task of attempting to formulate the
`
`combination product. Mr. Balwani had a Master’s degree in Pharmacy and was an experienced
`
`formulator, having 15-20 years of formulation experience at this point. Mr. Balwani was also a
`
`named inventor on two patents relating to azelastine formulations. See CIP2059, 1; CIP2060, 1.
`
`22.
`
`Beginning on April 24, 2006, Mr. John D’Aconti, an Assistant Formulation
`
`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
`
`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
`
`experiment, no further assessment of this sample was done. CIP2061, 17.
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`CIPLA LTD. EXHIBIT 2038 PAGE 9
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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
`
`23.
`
`azelastine into the Flonase® nasal spray vehicle. After removing the solid fluticasone particles
`
`via centrifugation, the sample of Flonase® nasal spray vehicle remained cloudy. CIP2061, 18.
`
`Viewed under a microscope, the sample appeared to be free of any solids. CIP2061, 18. The
`
`sample was filtered, and because the force required to filter this sample was more than the filter
`
`could withstand, the sample spilled and was lost. CIP2061, 18.
`
`24.
`
`The next day, April 26, 2006, the team prepared another sample in a similar
`
`fashion. This time, the Flonase® supernatant sample was filtered. CIP2061, 18. The sample was
`
`transferred into a pre-weighted scintillation vial containing a magnetic stir rod. CIP2061, 18. An
`
`aliquot of azelastine hydrochloride equivalent to a 0.1 % concentration in the final formulation
`
`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
`
`azelastine hydrochloride had not dissolved. CIP2061, 18.
`
`25.
`
`The following day, April 27, 2006, the sample was put through alternating cycles
`
`of stirring and heating. CIP2061, 19. The sample became an opaque white. CIP2061, 19. The
`
`sample did not change after another 15 minutes of heating. CIP2061, 19. The sample was then
`
`left overnight to cool, and the following morning the team observed that a solid had in fact
`
`precipitated out of the sample. CIP2061, 19. The team determined that the sample needed further
`
`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
`
`azelastine hydrochloride analytical assay for further investigation. CIP2061, 19.
`
`26.
`
`Shortly thereafter, in May 2006, Meda discovered Cipla’s published patent
`
`application directed to azelastine/steroid formulations, US 2006/0025391, and that Cipla was
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`8
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`CIPLA LTD. EXHIBIT 2038 PAGE 10
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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
`
`and fluticasone propionate. I asked Mr. Balwani to procure samples of Duonase from India.
`
`Given the concerns we anticipated in 2002 followed by the difficulties we encountered in 2006, I
`
`was surprised that someone had been able to successfully develop a combination nasal spray
`
`containing azelastine and fluticasone.
`
`27. With this new information, Meda had to decide either to continue pursuing its
`
`internal development of the azelastine and fluticasone formulation or to pursue a license from
`
`Cipla to market the combination product. Meda considered a number of factors in deciding
`
`whether to enter into a license with Cipla: the most important considerations being that Cipla had
`
`already filed a patent application on the combination nasal spray and had successfully developed
`
`a formulation that it marketed in India. It was also PPD’s view that our attempts to develop an
`
`azelastine/fluticasone combination formulation had failed because none of our attempts resulted
`
`in a viable product. And given the difficulties we encountered at only the initial stages of the
`
`azelastine/fluticasone combination formulation process, the PPD group believed that further
`
`formulation efforts were futile, especially in light of Cipla’s available intellectual property.
`
`28.
`
`In November 2006, Meda and Cipla signed the agreement to license Cipla’s
`
`patents. CIP2049, 25. Together, Meda and Cipla went on to successfully develop the azelastine
`
`and fluticasone combination nasal spray that would become Dymista®. The license was very
`
`important to Meda because without it, Meda would not have been able to develop and obtain
`
`FDA approval for Dymista®.
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`CIPLA LTD. EXHIBIT 2038 PAGE 11
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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
`
`knowledge,
`
`information, and belief.
`
`Dated: May 26, 2017
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