`
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`
`
`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
`_____________________
`
`DECLARATION OF WARNER CARR, M.D.
`
`
`
`
`
`
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`CIP2001
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
`
`1
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`CIPLA LTD. EXHIBIT 2036 PAGE 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 2001)
`TABLE OF CONTENTS
`
`
`I. 
`
`II. 
`
`Introduction ...................................................................................................... 1 
`
`Professional and Educational Background ...................................................... 1 
`
`III.  Basis for my opinions ...................................................................................... 4 
`
`IV.  Summary of Opinions ...................................................................................... 6 
`
`V. 
`
`Person of Ordinary Skill in the Art .................................................................. 7 
`
`VI.  The ’620 Patent ................................................................................................ 9 
`
`VII.  Claim Construction ........................................................................................ 10 
`
`VIII.  State of the Art ............................................................................................... 12 
`
`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. ................................................................. 17 
`
`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......................................................... 26 
`
`IX.  A POSA would not have been able to envision a combination of
`azelastine and fluticasone from among the more than 800 million
`combinations disclosed in Segal. ................................................................... 33 
`
`X. 
`
`The art taught away from claims 1, 4-6, 24-26, 29, and 42-44. .................... 37 
`
`A. 
`
`B. 
`
`The art as a whole taught away from inflexible fixed-dose
`combinations. ...................................................................................... 38 
`
`The art as a whole taught away from fixed-dose combinations
`that yielded no clinical benefit but exhibited increased side
`effects. ................................................................................................. 39 
`
`i
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`2
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`CIPLA LTD. EXHIBIT 2036 PAGE 2
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`

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`C. 
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2001)
`The art as a whole taught away from selecting azelastine for use
`in a fixed-dose combination with a steroid in order to improve
`compliance. .......................................................................................... 39 
`
`D.  A POSA would not have been motivated to pursue a fixed-dose
`combination of an antihistamine and a steroid. ................................... 41 
`
`XI.  Objective indicia of non-obviousness suggest that the challenged
`claims are not obvious. .................................................................................. 41 
`
`A.  Dr. Schleimer was present at the trial in district court. ....................... 41 
`
`B. 
`
`The patents-in-suit exhibit several significant, unexpected
`clinical results. ..................................................................................... 42 
`
`1. 
`
`2. 
`
`3. 
`
`4. 
`
`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. ....................................................................................... 43 
`Dymista® shows an unexpected improvement in efficacy
`when compared to the closest prior art. .................................... 45 
`Dymista® exhibits an unexpectedly fast onset of action
`compared to the closest prior art. .............................................. 48 
`Dymista® has unexpectedly reduced side effects as
`compared to either azelastine or fluticasone
`monotherapies. .......................................................................... 51 
`Dymista® satisfies a long-felt but unmet need in the treatment
`of AR. .................................................................................................. 54 
`Dymista® satisfies the long-felt need for more effective
`AR treatment. ............................................................................ 55 
`Dymista® satisfies the long-felt need for an AR treatment
`with a faster onset. .................................................................... 55 
`Dymista® satisfies the long-felt need for an AR treatment
`with fewer side effects. ............................................................. 57 
`
`C. 
`
`1. 
`
`2. 
`
`3. 
`
`
`
` ii
`
`3
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`CIPLA LTD. EXHIBIT 2036 PAGE 3
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2001)
`D.  Dymista® has been widely praised in the industry as the new
`gold standard for the treatment of AR. ................................................ 59 
`Dymista®, Duonase, and several Indian copycat products are
`covered by the challenged claims........................................................ 60 
`
`E. 
`
`
`
` iii
`
`4
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`CIPLA LTD. EXHIBIT 2036 PAGE 4
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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 2001)
`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
`
`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
`
`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
`
`5
`
`CIPLA LTD. EXHIBIT 2036 PAGE 5
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`

`

`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2001)
`Prior to joining Allergy and Asthma Associates of Southern
`
`6.
`
`California, I was an Investigator for the Division of Experimental Therapeutics at
`
`Walter Reed Army Institute of Research from 2004 until 2007. My responsibilities
`
`at Walter Reed included clinical work treating patients, bench top research,
`
`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
`
`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
`
`reviewed all aspects of clinical development from phase 1 to phase 4, including
`
`Investigational New Drug Applications (INDs) and New Drug Applications
`
`(NDAs). These responsibilities required me to interact directly with sponsors for
`
`new drug products.
`
`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
`
`Walter Reed Army Institute of Research.
`
`
`
`2
`
`6
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`CIPLA LTD. EXHIBIT 2036 PAGE 6
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`

`

`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2001)
`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
`
`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
`
`Immunology by the American Board of Allergy and Immunology and in Internal
`
`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
`
`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
`
`Regents. I served as the president of the California Society of Allergy, Asthma and
`
`Immunology. I am also currently on the Board of Directors for the Western Society
`
`of Allergy, Asthma, and Immunology.
`
`
`
`3
`
`7
`
`CIPLA LTD. EXHIBIT 2036 PAGE 7
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`

`

`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2001)
`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
`14.
`I have considered the following documents in arriving at the opinions
`
`I express below:
`
`2021
`
`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
`Corp., Case No. 1:14-cv-01453-LPS (D. Del.) (D.I. 155)
`Duonase Imitator Product Labels (PTX0026)
`
`2022
`
`2031
`
`
`1 I refer to each exhibit as EX____ or CIP____, followed by the appropriate
`
`page, paragraph, or column and line.
`
`
`
`4
`
`8
`
`CIPLA LTD. EXHIBIT 2036 PAGE 8
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`

`

`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2001)
`
`Cipla’s
`Exhibit #1
`2034
`
`2041
`
`2042
`
`2043
`
`2045
`
`Description
`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)
`DataMonitor – "Commercial and Stakeholder Perspectives:
`Allergic Rhinitis," September 2004 (PTX0098)
`
`2047
`
`2052
`
`2066
`2070
`2129
`
`2138
`
`
`
`5
`
`9
`
`CIPLA LTD. EXHIBIT 2036 PAGE 9
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`

`

`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2001)
`
`Cipla’s
`Exhibit #1
`2133
`
`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)
`
`IV. Summary of Opinions
`15.
` In my opinion, the art at the time of invention would not have
`
`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
`
`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.
`
`16.
`
`In my opinion, rather than motivating a POSA, the prior art would
`
`have taught away from a fixed-dose combination of an antihistamine and a steroid.
`
`The studies I just mentioned attempted to capture the very concept of
`
`complementary mechanisms of action that Dr. Schleimer points to in his
`
`declaration. EX1003, ¶¶70, 84. But as I explain below, scientists in the field—in
`
`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
`
`
`
`6
`
`10
`
`CIPLA LTD. EXHIBIT 2036 PAGE 10
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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 2001)
`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
`
`steroid alone; (2) induce additional side effects; and (3) remove the flexibility
`
`mandated by both the prevailing treatment guidelines of the time and prevailing
`
`clinical practice.
`
`17. Finally, it is my opinion that the commercial embodiment of the
`
`challenged claims exhibits several objective indicia of non-obviousness, including
`
`(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
`
`faster-acting AR treatment with reduced side effects; (3) receipt of substantial
`
`praise within the AR community; and (4) copying. As Dr. Schleimer states in his
`
`declaration, “one should also consider whether there are any secondary
`
`considerations that support the nonobviousness of the invention.” EX1003, ¶ 43.
`
`Dr. Schleimer heard testimony and saw evidence in the Apotex trial regarding each
`
`of these objective indicia of 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
`
`
`
`7
`
`11
`
`CIPLA LTD. EXHIBIT 2036 PAGE 11
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`

`

`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2001)
`priority date, or time of invention, for the ’620 patent is June 14, 2002. A POSA at
`
`that time would have had the knowledge and experience of both a clinician and a
`
`formulation scientist, or would draw upon the knowledge of a multi-disciplinary
`
`team. The clinical aspect of this POSA requires a medical degree and 2-4 years of
`
`experience as a general practitioner. I defer to Dr. Hugh Smyth for the formulation
`
`scientist aspect of this POSA.
`
`19.
`
`I disagree with Dr. Schleimer’s proposal that experience treating
`
`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
`
`in patients where they were effectively redundant. Each 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. Nevertheless, my opinion would not
`
`change under either definition.
`
`
`
`8
`
`12
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`CIPLA LTD. EXHIBIT 2036 PAGE 12
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2001)
`I have been informed that Argentum also argues that the ’620 patent
`
`20.
`
`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.
`
`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 Argentum has challenged the
`
`patentability of claims 1, 4-6, 24-26, 29, and 42-44 (collectively, “the challenged
`
`claims”). Counsel has also informed me that “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 through dependence, in the
`
`
`
`9
`
`13
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`CIPLA LTD. EXHIBIT 2036 PAGE 13
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`

`

`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2001)
`Meda Pharmaceuticals v. Apotex litigation, in which I testified at trial in December
`
`of 2016.
`
`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
`
`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 specification.
`
`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
`
`“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
`
`
`
`10
`
`14
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`CIPLA LTD. EXHIBIT 2036 PAGE 14
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2001)
`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”). EX1002, 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 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
`
`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
`
`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
`
`
`
`11
`
`15
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`CIPLA LTD. EXHIBIT 2036 PAGE 15
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`

`

`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2001)
`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
`
`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, as amended, 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
`
`meaning of the claims. In my opinion, a POSA reviewing the prosecution history
`
`would understand that the claim terms “suitable for nasal administration” and
`
`“nasal spray” incorporate the Applicants’ arguments regarding the deficiencies of
`
`Cramer Example III, and those deficiencies speak to tolerability, homogeneity, and
`
`operability for use on the nasal mucosa.
`
`VIII. State of the Art
`33. AR is defined as the inflammation of the membranes lining the nose.
`
`AR is a common health condition that affects millions of people in the U.S. It is
`
`
`
`12
`
`16
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2001)
`characterized by four primary symptoms: itching, sneezing, runny nose
`
`(rhinorrhea), and congestion. EX1019, 3. These symptoms can cause other indirect
`
`symptoms, like sleep loss, headaches, concentration issues, and other negative
`
`factors in a sufferer’s life. EX1019, 13.
`
`34. AR is characterized as one of two classes: seasonal, which lasts two to
`
`four weeks; and perennial, which lasts year-round. Id., 6. The key difference
`
`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.
`
`35.
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`In the laboratory setting, AR can be broken down into two phases: the
`
`early- and late-phase reactions. 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 phases.
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`
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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 2001)
`A. Many of the treatment options available in 2002 had overlapping
`effects in treating AR.
`36. Numerous AR treatment options were known in 2002. These options
`
`generally fell into one of six classes: antihistamines, anticholinergics,
`
`decongestants, leukotriene receptor antagonists, mast cell stabilizers, and steroids.
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`Each of these classes has its uses, benefits, and drawbacks, and there was very little
`
`clinical distinction between most drugs within each class. The vast majority of
`
`these drugs were administered through one of two modes: oral or topical.
`
`37. Drugs selected from among the six known drug classes frequently had
`
`redundant clinical effects. Specifically, each of the drug classes available at the
`
`time of invention was known to work on at least one of the four main symptoms of
`
`AR.
`
`38. There were at least 24 antihistamines known in 2002 that worked
`
`primarily on itching, sneezing, and runny nose, and the early, “first-generation”
`
`antihistamines were also known to cause sedation in patients. These issues were
`
`remedied by “second-generation” drugs like fexofenadine (Allegra) and loratadine
`
`(Claritin), which caused virtually no sedation. CIP2034, 4, 9. From among the
`
`known antihistamines, at least three were known for topical use, including
`
`azelastine, levocabastine, and ketotifen. EX1024, 89. The other antihistamines,
`
`including the blockbuster drugs loratadine (Claritin), cetirizine (Zyrtec), and
`
`
`
`14
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2001)
`fexofenadine (Allegra), were available in oral dosage forms (pills). CIP2034, 3, 5,
`
`8.
`
`39.
`
`In addition, there were numerous first-generation antihistamines
`
`available over-the-counter. Patients often took these pills first, before consulting a
`
`physician. Such OTC antihistamines included chlorpheniramine, hydroxyzine, and
`
`diphenhydramine. See, e.g., EX1019, 38. On some occasions, it made the most
`
`sense for a prescribing physician like myself to “recommend” one of these OTC
`
`options to patients rather than one of the other oral or intranasal antihistamines. A
`
`POSA who treats patients would have been aware of this practice, and thus would
`
`have known that these first-generation antihistamines were used quite frequently.
`
`40. Anticholingerics decrease secretions from the glands that line the
`
`nasal passage, and thus work very well on a runny nose. EX1024, 98. At least four
`
`of these agents were known at the time of invention. EX1019, 31. These drugs had
`
`to be administered intranasally as they showed little to no effect when administered
`
`orally.
`
`41. Antileukotrienes (or leukotriene receptor antagonists) were orally
`
`administered drugs known primarily for their effects on congestion, but they had
`
`some effect on the other symptoms of AR. EX1024, 98. At least three
`
`antileukotrienes were known prior to the date of invention. Id. Studies of these
`
`
`
`15
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2001)
`drugs used in fixed-dosing combinations with antihistamines showed an
`
`improvement greater than that offered by either drug alone. EX1024, 98.
`
`42. Decongestants work to reduce congestion in the nasal passage by
`
`inducing vasoconstriction, which decreases swelling in the affected organ. See, e.g.
`
`EX1024, 96. At least nine decongestants were known at the time of invention,
`
`including the popular drug pseudoephedrine (Sudafed). Notably, decongestants
`
`actually had effects complementary to antihistamines because decongestants work
`
`on congestion, but not the other symptoms of AR, while antihistamines tend to
`
`work best on itching, sneezing, and runny nose. Thus, antihistamines and
`
`decongestants were often combined with great effect in products like Allegra-D,
`
`Claritin-D, and Zyrtec-D. See EX1024, 97. Both antihistamines and decongestants
`
`were commonly used in both oral and nasal forms. EX1024, 89-90, 96.
`
`43. Mast cell stabilizers required multiple doses per day. EX1024, 95-96.
`
`Two mast cell stabilizers were known prior to the date of invention. Id.
`
`Nevertheless, these drugs worked on all four symptoms associated with AR when
`
`taken correctly. Id.
`
`44. Corticosteroids, available in oral and intranasal dosage forms, were
`
`known to work extremely well on all four symptoms of AR. EX1024, 91. Their
`
`efficacy in intranasal form led experts to declare them the most effective treatment
`
`option for AR available at the time of invention. EX1019, 29. These drugs were
`
`
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Dr. Warner Carr (Exhibit 2001)
`largely used intranasally because of the high incidence of serious side effects when
`
`administered orally. See EX1024, 94-95.
`
`B. A POSA would have known that co-administration of
`antihistamines and steroids provided no meaningful benefit as
`compared to steroids alone.
`45. By the date of invention, it was established in the field that the
`
`addition of an antihistamine to a steroid (via co-administration of two separate
`
`monotherapies) conferred no meaningful benefit over the steroid alone when used
`
`in vivo. Although co-administration of two drugs yielded no greater efficacy, it was
`
`shown to increase side effects. EX1035, 8; EX1036, 5; EX1039, 6.
`
`46.
`
`Intranasal steroids first become commonplace for use in the treatment
`
`of AR in the early- to mid-1990s. As these drugs were used more frequently,
`
`studies were conducted to compare their efficacy to the prevailing “first-line”
`
`treatment: oral antihistamines. It was determined that steroids were superior to oral
`
`antihistamines, such that intranasal corticosteroids became the new first-line
`
`treatment. EX1024, 94; EX1019, 29.
`
`47. At the same time, physicians recognized that steroids alone were
`
`unable to adequately address the most severe symptom