`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`ARGENTUM PHARMACEUTICALS LLC
`
`Petitioner
`
`v.
`
`CIPLA LIMITED
`
`Patent Owner
`
`_____________________
`
`Case No. IPR2017-00807
`
`U.S. Patent No. 8,168,620
`_____________________
`
`
`
`
`SECOND DECLARATION OF ALEXANDER DOMINIC D’ADDIO, Ph.D.
`
`
`
`
`
`
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`CIP2148
`Argentum Pharmaceuticals v. Cipla Ltd.
`IPR2017-00807
`
`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Alexander Dominic D’Addio, Ph.D.(Exhibit 2148)
`TABLE OF CONTENTS
`
`Introduction .................................................................................................... 1
`I.
`Background – Education, Expertise and Responsibility ........................... 3
`II.
`III. Product Journey ............................................................................................. 5
`
`
`i
`
`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Alexander Dominic D’Addio, Ph.D.(Exhibit 2148)
`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®.
`
`For this declaration, I rely on the following documents:
`5.
`
`1In 2007, Meda acquired MedPointe Pharmaceuticals. I will refer to both
`companies as “Meda.”
`
`1
`
`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Alexander Dominic D’Addio, Ph.D.(Exhibit 2148)
`
`Description
`
`Alexander Dominic D’Addio, Ph.D. Curriculum Vitae
`
`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)
`
`Cipla’s
`Exhibit #2
`2004
`
`2049
`
`2054
`
`2055
`
`2056
`
`2057
`
`2058
`
`2059
`
`2060
`
`2061
`
`MedPointe Laboratory Notebook No. 1044 - Excerpts (PTX0142)
`
`2120
`
`2121
`
`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)
`
`
`2 Throughout this declaration, I will refer to these exhibits as “[Exhibit Number],
`[paragraph/page number(s)].”
`
`2
`
`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Alexander Dominic D’Addio, Ph.D.(Exhibit 2148)
`
`2122
`
`2003.11.11 Email and attachment from Mary Lehr to Gul Balwani
`(PTX0255)
`
`Exhibit CIP2061 is a laboratory notebook that contains the observations of
`
`the laboratory technicians as they conducted their testing and experimentation. As
`
`the Vice President of Product and Process Development, I was ultimately
`
`responsible for ensuring Meda had policies and procedures in place with respect to
`
`recording information in our laboratory notebooks, and that our policies and
`
`procedures were complied with. It was our policy for the technicians to record
`
`information, data, or observations at or as near as possible to the time an event
`
`occurred. Also, it was the regular practice of Meda to record information, data, or
`
`observations relating to Meda’s research and development work in laboratory
`
`notebooks. Laboratory notebooks like CIP2061 were kept in the ordinary course of
`
`Meda’s regularly conducted research and development activities of drug products.
`
`II.
`
`Background – Education, Expertise and Responsibility
`
`6.
`
`I obtained my bachelor’s degree in chemistry from Kean University in
`
`1975. In 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 products for Meda and its predecessors, MedPointe Pharmaceuticals
`
`and Carter-Wallace. Until February 2017, I was the Vice President of Scientific
`
`3
`
`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Alexander Dominic D’Addio, Ph.D.(Exhibit 2148)
`Affairs and Medical Communications at Meda. I first joined Carter-Wallace as a
`
`laboratory supervisor in 1990. At Carter-Wallace, I was promoted to department
`
`head in 1993 and eventually became a director in 1997. After MedPointe
`
`Pharmaceuticals acquired the Wallace Laboratories division of Carter-Wallace in
`
`2001, I was appointed Vice President of Product and Process Development, a
`
`position that I held until 2010. In that position, I supervised the research and
`
`development of new drug products for MedPointe and for Meda after its 2007
`
`acquisition of MedPointe.
`
`8.
`
`I was involved in the research and development of Meda’s azelastine
`
`hydrochloride nasal sprays, Astelin® and Astepro®. In October 2002, Meda began
`
`to investigate an azelastine and steroid nasal spray combination project under my
`
`direction. I was involved in all aspects of research, clinical development, Food and
`
`Drug Administration (“FDA”) approval, launch, and post-approval support of the
`
`product that eventually became Dymista®. My duties included overseeing the
`
`scientific effort to determine the feasibility of developing a combination nasal
`
`spray.
`
`9.
`
`As Vice President of Product and Process Development, I oversaw
`
`Meda’s 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 drugs, as well as the support of current drug
`
`4
`
`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Alexander Dominic D’Addio, Ph.D.(Exhibit 2148)
`products in Meda’s portfolio. The FD group included Dr. Kalidas Kale, Mr. Gul
`
`Balwani, and Mr. John D’Aconti, among others. In 2002, Mr. Gul Balwani was
`
`appointed lead formulator of the group. My CV appears at CIP2004.
`
`III. Product Journey
`
`10. Throughout the 1990s, Meda was working to develop an azelastine
`
`hydrochloride (“azelastine”) nasal spray formulation for the treatment of symptoms
`
`of allergic rhinitis. During that time, Meda had significant experience with
`
`formulating azelastine. In fact, by 2002 Meda had over a decade of experience
`
`formulating azelastine into nasal spray formulations. By 1997, Meda received
`
`FDA-approval for an intranasal azelastine HCl product marketed as Astelin®.
`
`11. The PPD group maintained a weekly “Program Priorities & Issues”
`
`chart3 that catalogued the status of all the drugs currently under development in
`
`Meda’s portfolio in order to keep track of each drug’s development timeline. In
`
`2002, under my direction Meda was considering the product lifecycle strategies it
`
`would undertake for its Astelin® product. The three lifecycle options being
`
`considered were: (1) making an Astelin®/steroid combination, (2) making a new
`
`3 These “Program Priorities & Issues” charts—CIP2055 and CIP212—were
`
`created on a regular basis within the PPD group, including throughout 2002. These
`
`charts were generated in ordinary course of the PPD groups research and
`
`developments and were regularly generated to track progress on our many tasks.
`
`5
`
`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Alexander Dominic D’Addio, Ph.D.(Exhibit 2148)
`Astelin® formulation that masked the bitter taste issues associated with azelastine,
`
`and (3) developing a new azelastine formulation with improved taste and dosing
`
`profiles. CIP2054, 10. By September 2002, under my leadership 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 of Azelastine HCl and an Approved Steroid” to its weekly “Program
`
`Priorities & Issues” chart. CIP2055, 1. I was listed as the manager of this task.
`
`CIP2055, 1. At that point, Meda had not selected any particular steroid allergy
`
`treatment to use in the proposed combination formulation.
`
`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 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, the PPD group 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 the steroid particles are not
`
`dissolved in the nasal spray vehicle but are instead suspended in it. CIP2054, 11;
`
`CIP2056, 11. The PPD group also conducted literature searches to see whether we
`
`6
`
`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Alexander Dominic D’Addio, Ph.D.(Exhibit 2148)
`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. This meant that the dosing of azelastine and whichever
`
`steroid selected would have to be 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 administering
`
`a combination formulation on the same frequency as a steroid (two sprays/nostril
`
`once daily or one spray/nostril twice daily) would result in administering half as
`
`much azelastine as is FDA-approved. In light of these factors, I, and the PPD
`
`group, drafted two documents (CIP2054; CIP2056)4 to report our findings to Meda
`
`management. We reported that the technical “feasibility” of developing an
`
`azelastine/steroid combination product was “low.”
`
`
`4 These “Life Cycle Plans”—CIP2054 and CIP2056—were regularly created when
`
`Meda was considering its next steps for product development, including
`
`throughout 2002. These plans were generated in ordinary course of the PPD groups
`
`research and developments and were regularly generated to help us evaluate our
`
`research and development options.
`
`7
`
`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Alexander Dominic D’Addio, Ph.D.(Exhibit 2148)
`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 “combination rule” in order to be approved. It was our
`
`understanding that the FDA’s combination rule required that both agents in a
`
`combination contribute to the overall efficacy of the combination product.
`
`CIP2056, 11. Again, we reported to Meda management that the “likelihood of
`
`success” of the azelastine/steroid combination satisfying the combination rule was
`
`“low” because we did not anticipate that Meda could show that the combination
`
`was actually better than the individual components. CIP2056, 11.
`
`16. Based on the low probability of success and the anticipated technical
`
`obstacles to developing a combination nasal spray, the project became a low
`
`priority for Meda. CIP2120, 3. Instead, the PPD group began to look into
`
`alternative ways to deliver the steroid/azelastine 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. CIP2057, 1-2.
`
`17. With the dual-chamber device no longer an option, management
`
`requested that the PPD group consider developing an azelastine/fluticasone
`
`8
`
`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Alexander Dominic D’Addio, Ph.D.(Exhibit 2148)
`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 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 Flonase® suspension. CIP2058, 2. Plan B proposed to identify a
`
`water soluble steroid compatible with an azelastine hydrochloride solution.
`
`9
`
`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Alexander Dominic D’Addio, Ph.D.(Exhibit 2148)
`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 azelastine was soluble in
`
`the Flonase® nasal spray formulation, we would have next tried to 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 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 Flonase®, a commercial
`
`fluticasone propionate nasal spray, with Astelin®, a commercial azelastine
`
`10
`
`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Alexander Dominic D’Addio, Ph.D.(Exhibit 2148)
`hydrochloride nasal spray. This experiment was designed to understand whether
`
`any gross formulation changes occurred with the combination of Flonase® and
`
`Astelin®. CIP2061, 17. The sample was sonicated for 15 minutes and then assessed
`
`by visual observation only. 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.
`
`23. On April 25, 2006, Mr. D’Aconti attempted the first step under Plan
`
`A: dissolve 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 the sample was
`
`11
`
`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Alexander Dominic D’Addio, Ph.D.(Exhibit 2148)
`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. 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 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.
`
`12
`
`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Alexander Dominic D’Addio, Ph.D.(Exhibit 2148)
`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®.
`
`
`
`13
`
`
`
`Inter Partes Review of us. Patent No. 8,168,620
`Second Declaration of Alexander Dominic D 'Addio, Ph.D. (Exhibit 2148)
`I declare under penalty of perjury that the foregoing is true and correct,
`to
`
`the best of my knowledge,
`
`Dated: November 20,2017
`
`information, and belief.
`
`(JfJ~Z3
`
`Alexander Dominic D' Addio, Ph.D.
`
`
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