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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
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`U.S. Patent No. 8,168,620
`_____________________
`
`SECOND DECLARATION OF WARNER CARR, M.D.
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`
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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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`
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Dr. Warner Carr (Exhibit 2147)
`TABLE OF CONTENTS
`
`
`I.
`
`II.
`
`Introduction ...................................................................................................... 1
`
`Professional and Educational Background ...................................................... 1
`
`III. Basis for my opinions ...................................................................................... 4
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`IV. Summary of Opinions ...................................................................................... 6
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`V.
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`Person of Ordinary Skill in the Art .................................................................. 8
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`VI. The ’620 Patent ..............................................................................................10
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`VII. Claim Construction ........................................................................................11
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`VIII. State of the Art ...............................................................................................13
`
`A. Many of the treatment options available in 2002 had
`overlapping effects in treating AR. .....................................................14
`
`B.
`
`C.
`
`A POSA would have known that co-administration of
`antihistamines and steroids provided no meaningful benefit as
`compared to steroids alone. .................................................................18
`
`The treatment recommendations and general practices prior to
`the date of invention were consistent with the co-administration
`studies’ findings, and would not have encouraged a POSA to
`pursue a fixed-dose combination. .......................................................28
`
`IX. The art did not motivate a POSA to combine azelastine and
`fluticasone into a fixed-dose combination as recited in claims 1, 4-6,
`24-26, 29, and 42-44. .....................................................................................39
`
`A.
`
`B.
`
`The art as a whole did not motivate a POSA to develop an
`inflexible fixed-dose combination. ......................................................41
`
`The art as a whole did not motivate a POSA to develop a fixed-
`dose combination that would be expected to yield no clinical
`benefit but exhibit increased side effects. ...........................................41
`
`i
`
`
`
`C.
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2147)
`The art as a whole did not motivate a POSA to select azelastine
`for use in a fixed-dose combination with a steroid in order to
`improve compliance. ...........................................................................42
`
`D. A POSA would not have been motivated to select azelastine
`based on any anti-inflammatory activity. ............................................44
`
`E.
`
`A POSA would not have been motivated to pursue a fixed-dose
`combination of an antihistamine and a steroid. ...................................45
`
`X. Objective indicia of non-obviousness suggests that the challenged
`claims are not obvious. ..................................................................................46
`
`A. Dr. Schleimer was present at the trial in district court. .......................46
`
`B.
`
`The patents-in-suit exhibit several significant, unexpected
`clinical results. .....................................................................................47
`
`1.
`
`2.
`
`C.
`
`From a clinical perspective, the closest prior art
`comprises the studies and review articles finding no
`additional benefit from adding an antihistamine to a
`steroid. .......................................................................................48
`Dymista® shows an unexpected improvement in efficacy
`when compared to the closest prior art. ....................................50
`Dymista® exhibits an unexpectedly fast onset of action
`compared to the closest prior art. ..............................................53
`Dymista® has unexpectedly reduced side effects as
`compared to either azelastine or fluticasone
`monotherapies. ..........................................................................56
`Dymista® satisfies a long-felt but unmet need in the treatment
`of AR. ..................................................................................................59
`Dymista® satisfies the long-felt need for more effective
`AR treatment. ............................................................................60
`Dymista® satisfies the long-felt need for an AR treatment
`with a faster onset. ....................................................................60
`
`3.
`
`4.
`
`1.
`
`2.
`
`
`
` ii
`
`
`
`3.
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2147)
`Dymista® satisfies the long-felt need for an AR treatment
`with fewer side effects. .............................................................62
`FDA was skeptical of Dymista®. .........................................................64
`Dymista® has been widely praised in the industry as the new
`gold standard for the treatment of AR. ................................................66
`Dymista®, Duonase, and several Indian copycat products are
`covered by the challenged claims........................................................67
`
`D.
`
`E.
`
`F.
`
`
`
` iii
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`
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2147)
`I, Warner Carr, do declare as follows:
`
`I.
`
`Introduction
`
`1.
`
`I am over the age of eighteen (18) and otherwise competent to make
`
`this declaration.
`
`2.
`
`Patent Owner Cipla Ltd. (“Cipla”) has retained me as an expert
`
`witness in the inter partes review matter referenced above concerning U.S. Patent
`
`No. 8,168,620 (“the ’620 patent”) (EX1001). I understand that this petition for
`
`inter partes review was filed by Argentum Pharmaceuticals LLC (“Argentum”).
`
`3.
`
`I am being compensated for my time in connection with this matter at
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`my customary rate of $800 per hour, and my compensation does not depend upon
`
`the ultimate outcome of this case. I will also be compensated for any reasonable
`
`expenses that arise in connection with this matter, including travel costs incurred
`
`while conducting activities associated with this inter partes review.
`
`4.
`
`I have been asked by Cipla to review and respond to Argentum’s
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`petition and the supporting declaration submitted by Dr. Robert Schleimer.
`
`II.
`
`Professional and Educational Background
`
`5.
`
`I am currently a Partner and Vice-President of Allergy and Asthma
`
`Associates of Southern California and I am the Co-Medical Director of Southern
`
`California Research. I have served in both positions since 2009 after joining the
`
`practice in 2007.
`
`
`
`1
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`
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2147)
`Prior to joining Allergy and Asthma Associates of Southern
`
`6.
`
`California, I was an Investigator for the Division of Experimental Therapeutics at
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`Walter Reed Army Institute of Research from 2004 until 2007. My responsibilities
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`at Walter Reed included clinical work treating patients, bench top research,
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`reviewing clinical programs for investigational drug products, and conducting
`
`clinical trials for new drugs.
`
`7. While at Walter Reed, I served for a year as a Medical Officer in the
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`FDA Center for Drug Evaluation and Research (CDER) in the Division of
`
`Pulmonary and Allergy Drug Products. While assigned to the FDA, I worked
`
`directly under Badrul Chowdhury, the Director of the Division of Pulmonary and
`
`Allergy Products (DPAP). My responsibilities at DPAP included reviewing
`
`submissions to the FDA under the Prescription Drug User Fee Act (PDUFA). I
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`reviewed all aspects of clinical development from phase 1 to phase 4, including
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`Investigational New Drug Applications (INDs) and New Drug Applications
`
`(NDAs). These responsibilities required me to interact directly with sponsors for
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`new drug products.
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`8.
`
`I left the FDA to serve as the Chief of Medicine for the 21st Combat
`
`Support Hospital in Iraq from March to October of 2006, after which I returned to
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`Walter Reed Army Institute of Research.
`
`
`
`2
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`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2147)
`I received my medical degree from the University of Washington
`
`9.
`
`School of Medicine in 1996 and my bachelor’s degree in Biology from Boise State
`
`University in 1991. After receiving my medical degree, I completed an internship
`
`and residency at Brooke Army Medical Center for Internal Medicine in 1999.
`
`From 1999 to 2002, I was a core member of the teaching faculty in the internal
`
`medicine residency program at William Beaumont Army Medical Center. I then
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`completed a fellowship in Allergy & Immunology at Walter Reed Army Medical
`
`Center in Washington, DC from 2002 to 2004.
`
`10.
`
`I am licensed to practice medicine in two states. I have been licensed
`
`in Maryland since 2004 and in California since 2007. I am certified in Allergy and
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`Immunology by the American Board of Allergy and Immunology and in Internal
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`Medicine by the American Board of Internal Medicine.
`
`11.
`
`I am a Fellow at the American Academy of Allergy, Asthma, and
`
`Immunology, the American College of Allergy, Asthma and Immunology
`
`(“ACAAI”), and the American College of Physicians. I was an ACAAI National
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`Fellow-in-Training Representative from November 2002 to November 2004. From
`
`November 2011 to November 2014, I was a member of the ACAAI Board of
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`Regents. I served as the president of the California Society of Allergy, Asthma and
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`Immunology. I am also currently on the Board of Directors for the Western Society
`
`of Allergy, Asthma, and Immunology.
`
`
`
`3
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`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2147)
`I have published and lectured extensively on the topic of treating
`
`12.
`
`allergic rhinitis (“AR”), which is the subject of this inter partes review. My
`
`publications can be found in my CV, which is attached as CIP2002.
`
`13.
`
`I was previously a witness for Cipla and Meda Pharmaceuticals, Inc.
`
`(“Meda”), the exclusive licensee of the ’620 patent, during the patent infringement
`
`trial against Apotex Inc. and Apotex Corp. (“Apotex”).
`
`III. Basis for my opinions
`I have considered the following documents in arriving at the opinions
`14.
`
`I express below. The product labels and journal articles are generally derived from
`
`reliable authorities in the AR field, and book excerpts are from compilations
`
`generally relied on by physicians.
`
`Cipla’s
`Description
`Exhibit #1
`2002 Warner Carr, M.D. Curriculum Vitae
`Bench Trial Transcript, Volume B, December 14, 2016, Meda
`2019
`Pharmaceuticals Inc. and Cipla Ltd., v. Apotex Inc. and Apotex
`Corp., Case No. 1:14-cv-01453-LPS (D. Del.)
`Bench Trial Transcript, Volume D, December 16, 2016, Meda
`Pharmaceuticals Inc. and Cipla Ltd., v. Apotex Inc. and Apotex
`Corp., Case No. 1:14-cv-01453-LPS (D. Del.)
`Plaintiffs' Proposed Findings of Fact, January 10, 2017, Meda
`Pharmaceuticals Inc. and Cipla Ltd., v. Apotex Inc. and Apotex
`
`1 I refer to each exhibit as EX____ or CIP____, followed by the appropriate
`
`2021
`
`2022
`
`page, paragraph, or column and line.
`
`
`
`4
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`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2147)
`
`Cipla’s
`Exhibit #1
`
`Description
`Corp., Case No. 1:14-cv-01453-LPS (D. Del.) (D.I. 155)
`Duonase Imitator Product Labels (PTX0026)
`Physicians' Desk Reference, 54th ed., pp. 1343-1344, 2404-2406,
`2781-2783 (2000)
`Howarth, P. H. "A comparison of the anti-inflammatory
`properties of intranasal corticosteroids and antihistamines in
`allergic rhinitis," Allergy, 62: 6-11; 2000 (PTX0337)
`Nielsen, Lars P. "Review Article, Intranasal Corticosteroids for
`Allergic Rhinitis - Superior Relief?" Am. J. Respir Med., 2(1):
`55-65; 2001 (PTX0338)
`Shenfield, G. M. "Fixed drug combinations: which ones can be
`recommended?" Current Therapeutics, 27(11): 15-29; 1986
`(DTX-048)
`Hampel, F., et al. "Double-blind, Placebo-Controlled Study of
`Azelastine and Fluticasone in a Single Nasal Spray Delivery
`Device," Annals of Allergy, Asthma, & Immunology, 105: 168-
`173; 2010 (PTX0230)
`2046 Weiler, J. M., et al. "Azelastine nasal spray as adjunctive
`therapy to azelastine tablets in the management of seasonal
`allergic rhinitis," Ann. Allergy Asthma Immunol, 79: 327-332;
`1997 (PTX0329)
`Blaiss, M. "Efficacy, Safety, and Patient Preference of Inhaled
`Corticosteroids: A Review of Pertinent Published Data," Allergy
`and Asthma Proc., 22(6): S5-S10; 2001 (PTX0058)
`Leung, D., et al. "The Editors' Choice: MP29-02: A Major
`Achievement in the treatment of allergic rhinitis," J. Allergy
`Clin. Immunol., 129(5): 1216; 2012 (PTX0029)
`Dymista® Prescribing Information 2015 (PTX0024)
`Duonase Nasal Spray – Prescribing Information (PTX0134)
`FDA, Center for Drug Evaluation and Research, "Allergic
`Rhinitis: Clinical Development Programs for Drug Products,"
`Guidance for Industry, 2000 (PTX0025)
`
`2031
`2034
`
`2041
`
`2042
`
`2043
`
`2045
`
`2047
`
`2052
`
`2066
`2070
`2129
`
`
`
`5
`
`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2147)
`
`Description
`Bousquet, J. et al., “Management of Allergic Rhinitis and Its
`Impact on Asthma,” Journal of Allergy and Clinical
`Immunology, 108(5); excerpt; 2001. (ARIA Contributors)
`(PTX0326)
`DataMonitor – "Commercial and Stakeholder Perspectives:
`Allergic Rhinitis," September 2004 (PTX0098)
`U.S. Patent 6,599,914
`Hayashi, H. and Hashimoto, S., “Anti-infammatory actions of
`new antihistamines,” Clinical and Experimental Allergy 29:
`1593-1596 (1999)
`Barnes, P.J., “Clinical outcome of adding long-acting β-agonists
`to inhaled corticosteroids” Respiratory Medicine 95: S12-S16
`(2001)
`Andy, C. and Thering, A., “ How effective are nasal steroids
`combined with nonsedating antihistimines for seasonal
`allergies?” J. Fam. Pract. 7: 616 (2002)
`PTX0110 – Meeting Q & A from September 7, 2007
`PTX0114 – Meeting Minutes dated April 15, 2008 (IND 77,363)
`Clarinex Product Label (2001)
`Storms, W. et al., “Allergic rhinitis: The patient’s perspective”
`Journal of Allergy and Clinical Immunology (1997)
`
`Cipla’s
`Exhibit #1
`2133
`
`2138
`
`2145
`2157
`
`2161
`
`2162
`
`2164
`2165
`2169
`2170
`
`IV. Summary of Opinions
` In my opinion, the art at the time of invention would not have
`15.
`
`motivated a POSA to develop a fixed-dose combination of an antihistamine and a
`
`steroid. Many studies had considered pairings of these drugs delivered in separate
`
`dosage forms, but in a manner as consistent as possible with a fixed-dose
`
`combination. The studies consistently showed no benefit to using an antihistamine
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`
`
`6
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2147)
`and a steroid together in a fixed-dosing regimen. The results of those studies would
`
`have deterred a POSA from developing a fixed-dose combination of an
`
`antihistamine and a steroid.
`
`16.
`
`In my opinion, rather than motivating a POSA, the prior art would
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`have taught away from a fixed-dose combination of an antihistamine and a steroid.
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`The studies I just mentioned attempted to capture the very concept of
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`complementary mechanisms of action that Dr. Schleimer points to in his
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`declaration. EX1003, ¶¶70, 84. But as I explain below, scientists in the field—in
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`articles Dr. Schleimer relied upon in the related Apotex litigation—concluded from
`
`these studies that antihistamines and steroids had redundant mechanisms of action
`
`in vivo. Considered alongside other teachings in the art, these studies would have
`
`taught away from a fixed-dose combination because such a combination was
`
`expected to (1) yield no meaningful clinical benefit beyond that provided by a
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`steroid alone; (2) induce additional side effects; and (3) remove the flexibility
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`mandated by both the prevailing treatment guidelines of the time and prevailing
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`clinical practice.
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`17. Finally, it is my opinion that the commercial embodiment of the
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`challenged claims exhibits several objective indicia of non-obviousness, including
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`(1) the unexpected results of greater efficacy, accelerated onset, and dramatically
`
`reduced side effects; (2) satisfaction of a long-felt need for more effective and
`
`
`
`7
`
`
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2147)
`faster-acting Allergic Rhinitis (AR) treatment with reduced side effects; (3) receipt
`
`of substantial praise within the AR community; and (4) copying. Moreover, even
`
`years after the invention date, Dymista® was subject to FDA skepticism related to
`
`the known drawbacks. As Dr. Schleimer states in his declaration, “one should also
`
`consider whether there are any secondary considerations that support the
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`nonobviousness of the invention.” EX1003, ¶43. Dr. Schleimer heard testimony
`
`and saw evidence in the Apotex trial regarding each of these objective indicia of
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`nonobviousness.
`
`V.
`
`Person of Ordinary Skill in the Art
`
`18. Counsel informed me that a person of ordinary skill in the art
`
`(“POSA”) is a hypothetical person presumed to be aware of all pertinent art, who
`
`thinks in accordance with conventional wisdom in the art, and has ordinary
`
`creativity, as adjudged to the time of invention. I have also been informed that the
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`priority date, or time of invention, for the ’620 patent is June 14, 2002. A POSA at
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`that time would have had the knowledge and experience of both a clinician and a
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`formulation scientist, or would draw upon the knowledge of a multi-disciplinary
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`team. The clinical aspect of this POSA requires a medical degree and 2-4 years of
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`experience as a general practitioner. I defer to Dr. Hugh Smyth for the formulation
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`scientist aspect of this POSA.
`
`
`
`8
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`
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2147)
`I disagree with Dr. Schleimer’s proposal that experience treating
`
`19.
`
`patients is optional for a POSA. EX1003, ¶12. His proposed definition places an
`
`emphasis on laboratory work. However, as I explain below, at the time of
`
`invention, the activities of steroids and antihistamines were known to differ
`
`between laboratory studies, where the two classes exhibited different activity, and
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`in patients where they were effectively redundant. See, e.g., EX1016, 4 (explaining
`
`that mechanisms of action suggested by lab testing were not shown in vivo). Each
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`claim contains the term “pharmaceutical,” and therefore it is clear to me that these
`
`claims are directed to formulations used in patients. Accordingly, knowledge of
`
`and experience in treatment is more relevant in the context of the ’620 patent than
`
`laboratory experiments that a Ph.D. or Pharm.D. might undertake. Indeed, as I
`
`explain below, several laboratory-based concepts upon which Dr. Schleimer relies
`
`were tested in vivo and were found not to affect patients. A POSA would have
`
`been aware of this art. Nevertheless, my opinion would not change under either
`
`definition.
`
`20.
`
`I have been informed that Argentum also argues that the ’620 patent
`
`should not be accorded a priority date of June 14, 2002, but should instead be
`
`afforded a priority date of June 13, 2003. My opinion is unchanged under either
`
`priority date.
`
`
`
`9
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`
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2147)
`
`VI. The ’620 Patent
`21. The ’620 patent is directed to pharmaceutical formulations containing
`
`azelastine hydrochloride (“azelastine”) and fluticasone propionate (“fluticasone”)
`
`with various excipients and in various dosage forms “suitable for nasal
`
`administration.” I have been informed that the ’620 patent issued from U.S. Patent
`
`Application No. 10/518,016 (“the ’016 application”), and that the ’016 application
`
`is the U.S. national stage application of International Application No.
`
`PCT/GB03/02557 (“GB 02557”), filed on June 13, 2003. I further understand that
`
`GB 02557 claims priority to a UK Patent Application No. 0213739.6, filed on June
`
`14, 2002.
`
`22. Counsel has informed me that the Board has instituted review on the
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`patentability of claims 1, 4-6, 24-26, 29, and 42-44 (collectively, “the challenged
`
`claims”). Counsel has informed me that independent claims are to be read on their
`
`own, while “dependent claims” incorporate the limitations of each claim from
`
`which they depend. I also understand that each of the challenged claims was
`
`involved, either directly or dependently, in the Meda Pharmaceuticals v. Apotex
`
`litigation, in which I testified at trial in December of 2016. See CIP2021, 49.
`
`23.
`
`In the Apotex case, Dr. Michael Kaliner and I offered testimony, on
`
`behalf of plaintiffs Cipla and Meda, regarding the prima facie and objective indicia
`
`that I discuss below. Dr. Schleimer testified on Apotex’s behalf in response to my
`
`
`
`10
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2147)
`testimony and in response to Dr. Kaliner’s testimony. Dr. Schleimer’s declaration
`
`fails to address the testimony Dr. Kaliner and I presented at trial.
`
`VII. Claim Construction
`24. Counsel has informed me that claim terms in an unexpired patent
`
`subject to inter partes review are given the broadest reasonable construction in
`
`light of the patent’s intrinsic record, i.e., the specification and prosecution history.
`
`25.
`
`I agree with Dr. Schleimer’s construction of the claim term
`
`“condition(s).” It is also my opinion that “condition(s)” means “disease(s) or
`
`illness(es)” in the context of the challenged claims.
`
`26.
`
`In my opinion, the claim terms “suitable for nasal administration” and
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`“nasal spray,” which appear in claims 1 and 25, respectively, mean
`
`“pharmaceutical formulations that are tolerable to patients, that are homogeneous,
`
`and that can be suitably deposited onto the nasal mucosa.”
`
`27. My interpretation of these claim terms is rooted in the prosecution
`
`history of the ’620 patent. During prosecution, claims 1 and 25 (then listed as
`
`claims 1 and 56) were rejected as anticipated under 35 U.S.C. § 102 and/or obvious
`
`under 35 U.S.C. §103 in view of EP 0780127 (“Cramer Example III”). EX1002,
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`507-522. The Examiner concluded that Cramer Example III was the closest prior
`
`art. See, e.g., EX1002, 519-520. Testing of Cramer Example III conducted by
`
`Cipla confirmed that the disclosed formulation had several defects that rendered
`
`
`
`11
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`
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2147)
`the formulation unstable and intolerable to patients, and thus the formulation was
`
`not appropriate for deposition onto the nasal mucosa. EX1002, 286-287.
`
`28. Specifically, Cipla’s testing showed three specific problems with
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`Cramer Example III: (1) an unacceptably high osmolality for a product to be used
`
`in the treatment of AR, i.e., a product to be used consistently for an extended
`
`period of time, because this high osmolality would cause significant burning and
`
`other discomfort to the patient; (2) unacceptable spray qualities (i.e., jet spray
`
`rather than mist), which could both negatively affect deposition upon the nasal
`
`mucosa and risk perforation of the mucosa, another serious tolerability concern;
`
`and (3) unacceptable settling of the active ingredients, which again would
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`negatively affect the homogeneity of the drug distribution within the spray which
`
`can change the way in which the active ingredients are deposited on the mucosa.
`
`Id.
`
`29. As a result of this testing, Cipla told the Examiner that “Example 3 of
`
`Cramer (identified by the April 28, 2010 Office Action, page 16, as the closest
`
`example) is inoperable and unacceptable as a pharmaceutical formulation in a
`
`dosage form suitable for nasal administration.” EX1002, 220-221 (emphasis
`
`added). The italicized language appears in as-issued claim 1. EX1001, 11:46-51.
`
`30.
`
`In addition, Cipla explained that a “nasal spray,” as recited in claim
`
`25, is also a particular species of a “pharmaceutical formulation in a dosage form
`
`
`
`12
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2147)
`suitable for nasal administration.” EX1002, 220. Thus, Cramer Example III could
`
`not teach the “nasal spray” limitation of claim 25, either.
`
`31. Subsequently, the Examiner allowed the as-amended claims, finding
`
`that the claims were “unexpectedly and surprisingly unobvious over, different
`
`from, and superior to the prior art of record.” EX1002, 146.
`
`32. Counsel has informed me that Cipla’s statements and amendments,
`
`and the Examiner’s reliance thereupon, should be considered in determining the
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`meaning of the claims. In my opinion, a POSA reviewing the prosecution history
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`would understand that the claim terms “suitable for nasal administration” and
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`“nasal spray” incorporate the Applicants’ arguments regarding the deficiencies of
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`Cramer Example III, and those deficiencies speak to tolerability, homogeneity, and
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`operability for use on the nasal mucosa.
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`VIII. State of the Art
`33. AR is defined as the inflammation of the membranes lining the nose.
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`AR is a common health condition that affects millions of people in the U.S. It is
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`characterized by four primary symptoms: itching, sneezing, runny nose
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`(rhinorrhea), and congestion. EX1019, 3. These symptoms can cause other indirect
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`symptoms, like sleep loss, headaches, concentration issues, and other negative
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`factors in a sufferer’s life. Id., 13.
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`13
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2147)
`34. AR is characterized as one of two classes: seasonal, which lasts two to
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`four weeks; and perennial, which lasts year-round. Id., 6. The key difference
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`between the two categories is the allergen that gives rise to the symptoms. Id.
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`Mold, pollen, and the like are short-term allergens, while pet dander or insect
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`allergies may induce symptoms all year long.
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`35.
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`In the laboratory setting, AR reactions can be artificially broken down
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`into two phases: the early- and late-phase reactions by exposing cells to a single
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`allergen with no further exposure. EX1024, 49-52. These phases are extremely
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`difficult to isolate in clinical practice because continuous daily exposure to
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`allergens leads to ongoing and simultaneous early- and late-phase reactions.
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`Accordingly, both treatment and FDA approval are based on symptom relief. All
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`four symptoms are present in both phases, and congestion can frequently be the
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`predominant symptom in the early phase. EX1019, 5 (explaining that in the early
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`phase, “some subjects have sensations of nasal congestion as their predominant
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`symptom”.). Accordingly, clinical AR treatment decisions are made without
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`consideration of theoretical phases.
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`A. Many of the treatment options available in 2002 had overlapping
`effects in treating AR.
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`36. Numerous AR treatment options were known in 2002. These options
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`generally fell into one of six classes: antihistamines, anticholinergics,
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`decongestants, leukotriene receptor antagonists, mast cell stabilizers, and steroids.
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`14
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2147)
`Each of these classes had its uses, benefits, and drawbacks, and there was very
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`little clinical distinction between most drugs within each class. For example, the art
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`at the date of invention did not distinguish between intranasal steroids—they were
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`all viewed as equally effective. See, e.g., EX1040, 2 (explaining that fluticasone,
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`beclomethasone, and flunisolide are “equivalent in efficacy”). The vast majority of
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`these drugs were administered through one of two modes: oral or topical.
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`37. Drugs selected from among the six known drug classes frequently had
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`redundant clinical effects. Specifically, as I explain below, each of the drug classes
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`available at the time of invention was known to work on at least one of the four
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`main symptoms of AR.
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`38. There were at least 24 antihistamines known in 2002 that worked
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`primarily on itching, sneezing, and runny nose, and the early, “first-generation”
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`antihistamines were also known to cause sedation in patients. These issues were
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`remedied by “second-generation” drugs like fexofenadine (Allegra®), loratadine
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`(Claritin®), and desloratadine (Clarinex®) which caused virtually no sedation.
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`CIP2034, 4, 9; CIP2169, 2. From among the known antihistamines, at least three
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`were known for topical use, including azelastine, levocabastine, and ketotifen.
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`EX1024, 89. The other antihistamines, including the blockbuster drugs Claritin®,
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`cetirizine (Zyrtec®), Allegra®, and Clarinex® were available in oral dosage forms
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`(pills). CIP2034, 3, 5, 8.
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`15
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2147)
`In addition, there were numerous first-generation antihistamines
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`39.
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`available over-the-counter. In my experience, patients often took these pills first,
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`before consulting a physician. Such OTC antihistamines included
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`chlorpheniramine and diphenhydramine. See, e.g., EX1019, 38. On some
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`occasions, it made the most sense for a prescribing physician like myself to
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`“recommend” one of these OTC options to patients rather than one of the other
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`oral or intranasal antihistamines. For example, if a patient is having trouble
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`sleeping due to his allergies, a sedating antihistamine may be the best treatment
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`option. Because these were standard considerations in the art, a POSA who treats
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`patients would have been aware of this and other issues, and thus would have
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`known that these first-generation antihistamines were used quite frequently.
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`40. Anticholingerics decrease secretions from the tissues that line the
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`nasal passage, and thus work very well on a runny nose. EX1024, 98. At least four
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`of these agents were known at the time of invention. EX1019, 31. These drugs had
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`to be administered intranasally as they showed little to no effect when administered
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`orally.
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`41. Antileukotrienes (or leukotriene receptor antagonists) were orally
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`administered drugs known primarily for their effects on congestion, but they had
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`some effect on the other symptoms of AR. EX1024, 98. At least three
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`antileukotrienes were known prior to the date of invention. Id. Studies of these
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`16
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2147)
`drugs used in fixed-dosing combinations with antihistamines showed an
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`improvement greater than that offered by either drug alone. Id.
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`42. Decongestants work to reduce congestion in the nasal passage by
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`inducing vasoconstriction, which decreases swelling in the affected organ. See, e.g.
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`EX1024, 96. At least nine decongestants were known at the time of invention,
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`including the popular drug pseudoephedrine (Sudafed®). Id., 96-97. Notably,
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`decongestants actually had effects complementary to antihistamines because
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`decongestants work on congestion, but not the other symptoms of AR, while
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`antihistamines tend to work best on itching, sneezing, and runny nose. Thus,
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`antihistamines and decongestants were often combined with great effect in
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`products like Allegra-D®, Claritin-D®, and Zyrtec-D®. Id., 97.
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`43. Two mast cell stabilizers, or chromones, were known prior to the date
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`of invention. Id., 95-96. Mast cell stabilizers required multiple doses per day. Id.
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`Nevertheless, these drugs worked on all four symptoms associated with AR when
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`taken correctly. Id.
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`44. Corticosteroids, available in oral and intranasal dosage forms, were
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`known to work extremely well on all four symptoms of AR. EX1024, 91. Their
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`efficacy in intranasal form led experts to declare them the most effective treatment
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`option for AR available at the time of invention. EX1019, 29. These dru