UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ARGENTUM PHARMACEUTICALS LLC
`Petitioner
`v.
`CIPLA LTD.
`Patent Owner
`
`Patent No. 8,168,620
`Issue Date: May 1, 2012
`Title: COMBINATION OF AZELASTINE AND STEROIDS
`
`Inter Partes Review No.: IPR2017-00807
`
`DECLARATION OF ROBERT P. SCHLEIMER, Ph.D.
`
`Exhibit 1003
`IPR2017-00807
`ARGENTUM
`
`000001
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`Patent No. 8,168,620
`Declaration in Support of Inter Partes Review
`
`
`
`TABLE OF CONTENTS
`
`
`
`Introduction .................................................................................................... 1 
`I. 
`II.  My Background And Qualifications .............................................................. 1 
`III.  List Of Documents Considered In Formulating My Opinion ........................ 2 
`IV.  Summary of Opinions .................................................................................... 5 
`V. 
`Person Of Ordinary Skill In The Art .............................................................. 6 
`VI.  The ’620 Patent .............................................................................................. 6 
`VII.  Claim Construction ........................................................................................ 8 
`VIII.  The Claims of the ’620 Patent are Not Entitled to the Earliest Effective
`Filing Date ...................................................................................................... 9 
`IX.  Technical Background .................................................................................. 10 
`X. 
`Claims 1 and 25 are Anticipated .................................................................. 12 
`A. 
`Claim Limitation 1.1: “A pharmaceutical formulation comprising” . 12 
`B. 
`Claim Limitation 1.2: “azelastine, or a pharmaceutically acceptable
`salt thereof” ........................................................................................ 13 
`Claim Limitation 1.3: “a pharmaceutically acceptable ester of
`fluticasone” ........................................................................................ 13 
`Claim Limitation 1.4: “wherein said pharmaceutical formulation is in
`a dosage form suitable for nasal administration.” ............................. 14 
`Claim Limitation 25.1: “A nasal spray formulation comprising” ..... 14 
`Claim Limitation 25.2: “(i) azelastine, or a pharmaceutically
`acceptable salt thereof,” ..................................................................... 15 
`Claim Limitation 25.3: “(iii) a pharmaceutically acceptable ester of
`fluticasone,” ....................................................................................... 15 
`Claim Limitation 25.4: “and (iii) a pharmaceutically acceptable
`carrier or excipient therefor.” ............................................................. 15 
`Segal discloses all claim elements as arranged in Claims 1 and 25 .. 16 
`I. 
`Segal is enabling prior art .................................................................. 16 
`J. 
`XI.  Claims 1, 5-6, 24-26, and 29, were Obvious as of at least June 2002 ......... 17 
`A. 
`The cited references disclose all of the claim elements ..................... 18 
`ii
`
`E. 
`F. 
`
`C. 
`
`D. 
`
`G. 
`
`H. 
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`Patent No. 8,168,620
`Declaration in Support of Inter Partes Review
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`B. 
`
`C. 
`
`It was well known that steroids and antihistamines were effective at
`treating allergic rhinitis together ........................................................ 21 
`Fluticasone propionate was the most potent glucocorticoid for
`treating the late phase response of allergic rhinitis ............................ 25 
`D.  Azelastine was the most effective antihistamine on the market ........ 26 
`E. 
`Oral antihistamines were combined with intranasal steroids ............ 29 
`F. 
`Administration of nasal antihistamine and nasal steroid to treat
`allergic rhinitis was recommended .................................................... 30 
`G.  A co-formulation of fluticasone and azelastine has been disclosed .. 34 
`H. 
`Combining fluticasone and azelastine into a single product would
`have improved patient compliance .................................................... 36 
`Fluticasone was previously co-formulated with other drugs ............. 36 
`Clinical studies disclosed benefits to combining antihistamines and
`corticosteroids .................................................................................... 38 
`XII.  Absence of Secondary Considerations of Nonobviousness ......................... 41 
`A.  No teaching away ............................................................................... 41 
`B. 
`There was no long-felt but unmet need satisfied by the ’620 Patent . 44 
`C. 
`No evidence of unexpected results compared to the closest prior art
` ............................................................................................................ 49 
`D.  A POSA would appreciate the teachings of Cramer ......................... 54 
`XIII.  Conclusion .................................................................................................... 57 
`
`I. 
`J. 
`
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`Patent No. 8,168,620
`Declaration in Support of Inter Partes Review
`
`
`
`
`I.
`
`I, Robert Schleimer, do declare as follows:
`Introduction
`
`1.
`
`I am over the age of eighteen (18) and otherwise competent to make
`
`this declaration.
`
`2.
`
`I have been retained as an expert witness on behalf of Argentum
`
`Pharmaceuticals LLC for a inter partes review of U.S. Patent No. 8,168,620 (Ex.
`
`1001). I am being compensated for my time in connection with this IPR at my
`
`standard consulting rate, which is $400 per hour for any consulting and $600 per
`
`hour for any deposition appearances. I understand that my declaration
`
`accompanies a petition for inter partes review involving the above-mentioned U.S.
`
`Patent.
`
`II. My Background And Qualifications
`
`3. My area of expertise is in the field of allergy and immunology. At
`
`Northwestern University’s Feinberg School of Medicine, I am presently the Chief
`
`of the Division of Allergy-Immunology in the Department of Medicine, the Roy
`
`and Elaine Patterson Professor of Medicine, and a Professor of Medicine in the
`
`Division of Allergy-Immunology. I am also a Professor in the Departments of
`
`Microbiology-Immunology and Otolaryngology - Head and Neck Surgery. My
`
`research areas include the mechanisms of pathogenesis and treatment of a variety
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`Patent No. 8,168,620
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`of allergic and inflammatory diseases associated with allergy, including chronic
`
`rhinosinusitis, asthma, hay fever, rhinitis, food allergy and others. I also study the
`
`mechanisms of action of anti-inflammatory glucocorticoids, with a focus on the
`
`molecular and cellular mechanisms underlying disease and steroid action as well as
`
`developing strategies for new treatments.
`
`4.
`
`I obtained a Bachelor of Arts in Biology from the University of
`
`California, San Diego in 1974 and a Ph.D. from the University of California, Davis
`
`in Pharmacology, Toxicology, and Immunology in 1979.
`
`5.
`
`Additionally, I have been a named author on over 300 scientific
`
`papers, served as an editor or on the editorial board of ten different journals, and I
`
`have trained a large number of graduate and undergraduate students as well as
`
`postdoctoral fellows. I am currently on the Editorial Boards of the American
`
`Journal of Respiratory Cell and Molecular Biology, the Journal of Allergy, and
`
`Allergology International.
`
`6. My curriculum vitae is attached as Ex. 1051 to this document.
`
`7.
`
`In view of my experiences and expertise outlined above and provided
`
`in my curriculum vitae, I am an expert in the field of allergy and immunology.
`
`III. List Of Documents Considered In Formulating My Opinion
`
`8.
`
`In formulating my opinion, I considered the following documents:
`
`2
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`Patent No. 8,168,620
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`
`1017
`
`Exhibit
`Ex #
`1001 U.S. Patent No. 8,168,620 (“’620 patent)
`1002
`Prosecution History of U.S. Patent No. 8,168,620
`1006 UK Patent Application GB 0213739.6
`1007 U.S. Patent No. 5,164,194 (“Hettche”)
`Physician’s Desk Reference, Astelin® Label, rev.1/99, 3147-3148 (54th
`1008
`ed. 2000) (“Astelin® Label”)
`1009 U.S. Patent No. 4,335,121 (“Phillipps”)
`1010
`Flonase® Label (1998)
`1011
`European Patent Application No. 0780127 (“Cramer”)
`1012
`PCT Publication No. WO 98/48839 to Segal (“Segal”)
`Falser, N., et al., “Comparative efficacy and safety of azelastine and
`1015
`levocabastine nasal sprays in patients with seasonal allergic rhinitis.”
`ARZNEIMITTELFORSCHUNG, 51(5):387-93 (2001)
`1016 Kusters, S., et al., “Effects of Antihistamines on Leukotriene and
`Cytokine Release from Dispersed Nasal Polyp Cells.” ARZNEIM-
`FORSCH/DRUG RES., 52(2): 97-102 (Feb. 2002)
`Stellato, C., et al., An in vitro Comparison of Commonly Used Topical
`Glucocorticoid Preparations, J. ALLERGY CLIN. IMMUNOL., Vol. 104, No.
`3, Part 1, 623-629 (Sept. 1999)
`Johnson, M., Development of fluticasone propionate and comparison
`with other inhaled corticosteroids, J. Allergy Clin. Immunol., Vol. 101,
`No. 4, Part 2, S434-S439 (1998)
`1019 Dykewicz, Mark S., et al., “Diagnosis and management of rhinitis:
`complete guidelines of the joint task force on practice parameters in
`allergy, asthma and immunology,” ANNALS OF ALLERGY, ASTHMA &
`IMMUNOLOGY, Vol. 81, 478-518 (1998)
`Stoloff, R., et al., “Combination Therapy with Inhaled Long-Acting ß2-
`Agonists and Inhaled Corticosteroids: A Paradigm Shift in Asthma
`Management,” PHARMACOTHERAPY, Vol. 22, No. 2, 212-226 (Feb.
`2002)
`1021 Berger, W. E. et al., “Double-blind trials of azelastine nasal spray
`3
`
`1018
`
`1020
`
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`Patent No. 8,168,620
`Declaration in Support of Inter Partes Review
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`
`1023
`
`monotherapy versus combination therapy with loratadine tablets and
`beclomethasone nasal spray in patients with seasonal allergic rhinitis,”
`ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY, Vol. 82, 535-541
`(1999)
`1022 Cauwenberge, P. et al., “Consensus statement on the treatment of
`allergic rhinitis,” ALLERGY, Vol. 55: 116-134 (2000)
`Spector, S., “Ideal Pharmacology for Allergic Rhinitis,” J. ALLERGY
`CLIN. IMMUNOL., Vol. 103, No. 3, Part 2, S386-87 (1999)
`1024 Bousquet et al., Management of Allergic Rhinitis and Its Impact on
`Asthma, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol. 108,
`No. 5 (2001)
`1025 Markham, A., et al., “Inhaled Salmeterol-Fluticasone Propionate
`Combination, A Review of its Use in Persistent Asthma,” DRUGS 60(5)
`1207-1233 (Nov. 2000)
`1030 Advair Diskus Prescribing Information (2000)
`1031
`Juniper, E., "First-line Treatment of Seasonal (Ragweed)
`Rhinoconjunctivitis)," Canadian Medical Association Journal, Vol. 156,
`No. 8, April 1997, 1123-31.
`1034 Ratner, P., et al., “A Comparison of the Efficacy of Fluticasone
`Propionate Aqueous Nasal Spray and Loratadine, Alone and in
`Combination, for the Treatment of Seasonal Allergic Rhinitis,” JOURNAL
`OF FAMILY PRACTICE, Vol. 47, No. 2, 118-125 (Aug. 1998)
`1035 Drouin, M., et al. “Adding Loratadine to Topical Nasal Steroid Therapy
`Improves Moderately Severe Seasonal Allergic Rhinoconjunctivitis.”
`ADVANCES IN THERAPY, 12(6): 340-349; 1995.
`Simpson, R., Budesonide and terfenadine, separately and in
`combination, in the treatment of hay fever, ANNALS OF ALLERGY, Vol.
`73 497-502 (Dec. 1994)
`1038 Brooks, C. et al. “Spectrum of Seasonal Allergic Rhinitis Symptom
`Relief with Topical Corticoid and Oral Antihistamine Given Singly or in
`Combination.” AM. J. RHINOL., Vol. 10, 193-196 (1996)
`Juniper, E F., et al., “Comparison of beclomethasone dipropionate
`aqueous nasal spray, astemizole, and the combination in the prophylactic
`treatment of ragweed pollen-induced rhinoconjunctivitis,” JOURNAL OF
`4
`
`1036
`
`1039
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`Patent No. 8,168,620
`Declaration in Support of Inter Partes Review
`
`1042
`
`ALLERGY AND CLINICAL IMMUNOLOGY, Vol. 83, No. 3, Cover page,
`Publications page, 627-633 (Mar. 1989)
`1040 Benincasa, C. & Lloyd, R.S., “Evaluation of Fluticasone Propionate
`Aqueous Nasal Spray Taken Alone and in Combination with Cetirizine
`in the Prophylactic Treatment of Seasonal Allergic Rhinitis,” DRUG
`INVEST., Vol. 8, Issue 4, 225-233 (1994)
`1041 Galant, S. and Wilkinson, R., “Clinical Prescribing of Allergic Rhinitis
`Medication in the Preschool and Young School-Age Child.” BIODRUGS,
`15(7): 453-463; 2001
`Schleimer, R., “Glucocorticosteroids: Their Mechanisms of Action and
`Use in Allergic Diseases,” ALLERGY PRINCIPLES & PRACTICE, 638-660
`(1998)
`1045 Ratner, Paul H., et al., “Combination therapy with azelastine
`hydrochloride nasal spray and fluticasone propionate nasal spray in the
`treatment of patients with seasonal allergic rhinitis,” ANNALS OF
`ALLERGY, ASTHMA & IMMUNOLOGY, VOL. 100, 74-81 (2008)
`1047 NASACORT AQ Prescribing Information (2013)
`1050 Ratner, Paul H., et al., “A double-blind, controlled trial to assess the
`safety and efficacy of azelastine nasal spray in seasonal allergic
`rhinitis,” Journal of Allergy and Clinical Immunology, Vol. 94, No. 5,
`818-825 (1994)
`
`IV.
`
`Summary of Opinions
`
`9.
`
`Based on my investigation and analysis and for the reasons set forth
`
`below, it is my opinion that claims 1 and 25 of the ’620 patent are anticipated by
`
`PCT Publication No. WO 98/48839 to Segal (“Segal”).
`
`10.
`
`In addition, claims 1, 5-6, 24-26, and 29 of the ’620 patent would
`
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`have been obvious to one of ordinary skill in the art at the time of the alleged
`
`invention in view of the combined teachings of U.S. Patent No. 5,164,194
`
`(“Hettche”), U.S. Patent No. 4,335,121 (“Phillipps”), and Segal.
`
`V.
`
`Person Of Ordinary Skill In The Art
`
`11.
`
`I understand that as of June 14, 2002, a person of ordinary skill in the
`
`art (“POSA”) would “be aware of all the pertinent prior art” at that time.
`
`12. A hypothetical POSA would be part of a multidisciplinary team
`
`including a clinician/scientist and formulator. As a clinician/scientist in this field, a
`
`POSA typically would have had an M.D., Pharm. D. or Ph.D. in the field of
`
`allergy/immunology and/or pharmacology (or the equivalent), and have at least
`
`three years of experience in the treatment of, or research for treatments, of allergic
`
`rhinitis, including with nasally administered steroids and antihistamines.
`
`VI. The ’620 Patent
`
`13.
`
`I understand that U.S. Patent No. 8,168,620 (“the ’620 patent”) issued
`
`from U.S. Patent Application No. 10/518,016 (“the ’016 application”), as the 35
`
`U.S.C. § 371 national stage application of International Application No.
`
`PCT/GB03/02557 (“PCT/GB03/02557”) filed on June 13, 2003.
`
`PCT/GB03/02557 purports on its face to claim priority to UK Patent Application
`
`No. 0213739.6 (“GB 0213739.6”), titled “Pharmaceutical Compositions,” filed on
`
`June 14, 2002 (the earliest possible effective date).
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`14.
`
`I understand that the priority date to which the ’620 patent is entitled
`
`may be in dispute. I have been instructed to base my opinion from the perspective
`
`of a POSA as of June 14, 2002. However, if I were to use June 13, 2003 as the
`
`relevant date, my opinion would be the same.
`
`15.
`
`Independent claim 1 of the ‘620 patent recites:
`
`“A pharmaceutical formulation comprising: azelastine, or a
`pharmaceutically acceptable salt thereof, and a pharmaceutically
`acceptable ester of fluticasone, wherein said pharmaceutical
`formulation is in a dosage form suitable for nasal administration.”
`
`16. The specification of the ’620 patent states:
`
`It is known to use antihistamines in nasal sprays and eye
`drops to treat allergy-related conditions. Thus, for example, it is
`known to use the antihistamine azelastine (usually as the
`hydrochloride salt) as a nasal spray against seasonal or
`perennial allergic rhinitis, or as eye drops against seasonal and
`perennial allergic conjunctivitis.
`It is also known to treat these conditions using a
`corticosteroid, which will
`suppress nasal and ocular
`inflammatory conditions. Among the corticosteroids known for
`nasal use are, for example, beclomethasone, mometasone,
`fluticasone, budesonide and cyclesonide.
`
`Ex. 1001, 1:20-30.
`
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`VII. Claim Construction
`
`17.
`
`I understand from counsel that the claim terms of an unexpired patent
`
`subject to inter partes review are given the broadest reasonable construction in
`
`light of the specification of the patent.
`
`18. The ’620 patent discloses the term “conditions” in the context of the
`
`phrase “treatment of conditions for which administration of one or more anti-
`
`histamine and/or one or more steroid is indicated.” Ex. 1001, cl. 24. I understand
`
`that Petitioner contends in this proceeding that the broadest reasonable
`
`construction of the term “conditions” is “disease(s) or illness(es).” I agree with
`
`this construction given that the specification of the ’620 patent itself refers to
`
`“conditions” in the context of nasal spray treatments of “allergy-related
`
`conditions” using antihistamines and corticosteroids like azelastine and fluticasone
`
`respectively. Ex. 1001, 1:20-30. The specification mentions the treatment of
`
`“seasonal or perennial allergic rhinitis,” “seasonal and perennial allergic
`
`conjunctivitis,” as well as “nasal and ocular inflammatory conditions.” Id., 1:21-
`
`28.
`
`19.
`
`I also note that nothing in the specification or the prosecution history
`
`of the ’620 patent specifically limits “conditions” to only the specific diseases or
`
`illnesses listed in those documents.
`
`20. Accordingly, for purposes of this proceeding, I understand
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`“conditions” to mean “disease(s) or illness(es).”
`
`VIII. The Claims of the ’620 Patent are Not Entitled to the Earliest Effective
`Filing Date
`
`21.
`
`I understand from counsel that a patent claim is not entitled to rely on
`
`the filing date of an earlier-filed patent application unless the earlier-filed patent
`
`application contains an adequate written description of the claimed invention. I
`
`understand from counsel that an adequate written description of a claimed genus
`
`requires more than a generic statement of an invention’s boundaries and instead
`
`requires the disclosure of either a representative number of species falling within
`
`the scope of the genus or structural features common to the members of the genus
`
`so that one of skill in the art can ‘visualize or recognize’ the members of the genus.
`
`I am told that an adequate written description requires a precise definition, such as
`
`by structure, formula, chemical name, physical properties, or other properties, of
`
`species falling within the genus sufficient to distinguish the genus from other
`
`materials.
`
`22.
`
`It is my opinion that at least Claims 1, 4-6, 25, 42, 44 of the ’620
`
`Patent are not adequately described in GB 0213739.6 because GB 0213739.6 lacks
`
`written description support for the genus term “pharmaceutically acceptable ester
`
`of fluticasone.”
`
`23. GB 0213739.6 discloses, generally, “an ester” of fluticasone in claim
`
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`5, and provides only one specific example—“fluticasone propionate”—in claim 6.
`
`Ex. 1006, cl.5, cl.6. Moreover, GB 0213739.6 provides no additional examples, no
`
`qualitative guidance, no definition, no test, and no structure-function relationship
`
`for what it considered “pharmaceutically acceptable” esters of fluticasone. The
`
`broad genus of “an ester” of fluticasone in claim 5 of GB 0213739.6, and one
`
`specific example of “fluticasone propionate” in claim 6 of GB 0213739.6, are
`
`insufficient for a POSA to ‘visualize or recognize’ all the members of the genus
`
`“pharmaceutically acceptable ester of fluticasone” (other than fluticasone
`
`propionate).
`
`24. Therefore, it is my opinion that all claims of the ’620 patent that are
`
`not specifically limited to fluticasone propionate are not entitled to the filing date
`
`of GB 0213739.6.
`
`IX. Technical Background
`
`25. Rhinitis is a disorder characterized by the inflammation of the mucous
`
`membrane inside the nose. Nasal symptoms often include sneezing, itching,
`
`rhinorrhea (runny nose), and nasal congestion. Frequently, symptoms may spread
`
`to the eyes, ears, and throat, and post-nasal drainage may occur as well. Allergic
`
`rhinitis (“AR”), or hay fever, is one of the more common causes of rhinitis.
`
`26. Allergic rhinitis is an inflammation in the nose that results from the
`
`immune system responding to specific allergens or antigenic environmental
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`factors, such as pollen, pet dander, dust, or mold. Allergic rhinitis is widely
`
`considered to be the most common of all allergic disorders, affecting over 40
`
`million Americans.
`
`27.
`
`It is well known that allergic rhinitis responses occur in two separate
`
`phases: an early phase response (“EPR”) and a late phase response (“LPR”). The
`
`EPR occurs immediately after the patient is exposed to the allergen. Once
`
`exposed, mast cells in the nose release mediators, including histamine, tryptase,
`
`prostaglandin D2 and the cysteinyl leukotrienes. Ex. 1041, 455. These
`
`inflammatory mediators cause early phase symptoms.
`
`28. The LPR occurs roughly 4-8 hours after allergen exposure. Id. This
`
`phase is characterized by mast cells releasing mediators into the tissue at the site,
`
`which will cause a more prolonged response. The LPR is characterized by
`
`profound infiltration and activation of migrating and resident cells. The LPR is
`
`often described as a chronic inflammatory-type response, which is thought to be
`
`responsible for the persistent symptoms of allergic rhinitis. Id. The symptoms
`
`usually associated with LPR include EPR symptoms as well as nasal obstruction
`
`and enhanced sensitivity to allergens in the nasal mucosa. Id.
`
`29. Many different drugs have been used to prevent or minimize the
`
`symptoms of AR. Antihistamines, both oral and intranasal, intranasal steroids,
`
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`decongestants, cromolyn, and leukotriene receptor antagonists are the most
`
`commonly used.
`
`X. Claims 1 and 25 are Anticipated
`
`30.
`
`I understand from counsel that a patent claim is “anticipated” if all
`
`elements of the claim are disclosed in a single prior art reference in the same way
`
`the elements are arranged in the claim. I further understand that where a reference
`
`provides broad disclosure of a larger group of, e.g., combinations, as well as
`
`specific preferences for the combinations, the reference still anticipates so long as
`
`all claim elements are disclosed as arranged in the claim. I am also told that the
`
`prior art reference must be enabling (i.e., allowing a POSA to make and use the
`
`claimed invention without undue experimentation) in order to anticipate the claim.
`
`31. Segal is an international patent application filed by Warner Lambert
`
`Company and was published on November 5, 1998. Ex. 1012. It is my expert
`
`opinion that Segal anticipates Claims 1 and 25.
`
`A. Claim Limitation 1.1: “A pharmaceutical formulation comprising”
`
`32. Segal discloses “topically applicable nasal compositions comprising a
`
`therapeutically effective amount of a topical antiinflammatory agent and a
`
`therapeutically effective amount of at least one agent suitable for topical nasal
`
`administration and selected from the group consisting of a vasoconstrictor, a
`
`neuramidinase [sic] inhibitor, an anticholinergic agent, a leukotriene inhibitor, an
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`antihistamine, an antiallergic agent, an anesthetic, and a mucolytic agent.” Ex.
`
`1012, 2:10-15; see also id. cl.1. The term “therapeutically effective amount” and
`
`the listed active ingredients are pharmaceuticals. Therefore, Segal discloses a
`
`“pharmaceutical formulation” as claimed in the ’620 patent.
`
`B. Claim Limitation 1.2: “azelastine, or a pharmaceutically acceptable salt
`thereof”
`
`33. Segal states that “suitable antihistamines” can include “azelastine.”
`
`Id., 3:19-20. Likewise, Segal’s claim 4, which depends from Segal’s claim 1,
`
`discloses the combination of an antihistamine, like azelastine, with a topical anti-
`
`inflammatory agent. Therefore, Segal discloses azelastine as part of the
`
`combination nasal composition.
`
`C. Claim Limitation 1.3: “a pharmaceutically acceptable ester of
`fluticasone”
`
`34. Segal discloses fluticasone as part of the combination nasal
`
`composition. Segal identifies “fluticasone proprionate” as one of the “preferred”
`
`antiinflammatory agents of the invention. Id., 2:22-26. Likewise, Segal’s claim 2
`
`recites fluticasone proprionate as one of the topical anti-inflammatory agents in the
`
`combination nasal composition. Id., cl. 2. Therefore, Segal discloses fluticasone
`
`propionate as part of the combined nasal composition.
`
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`D. Claim Limitation 1.4: “wherein said pharmaceutical formulation is in a
`dosage form suitable for nasal administration.”
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`35. Segal states: “The compositions of the present invention are
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`formulated as aqueous solutions comprising an antiinflammatory agent and at least
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`one additional therapeutic agent and further comprising a pharmaceutically
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`acceptable nasal carrier. . . . Preferred nasal formulations are nose drops or nasal
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`sprays containing a water buffered aqueous solution as a carrier.” Ex. 1012, 3:29-
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`4:5; see also id. cl.15 (depending from Segal claim 1 or 11). Thus, Segal’s
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`pharmaceutical formulation is a nasal spray, which thus is suitable for nasal
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`administration.
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`E. Claim Limitation 25.1: “A nasal spray formulation comprising”
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`36. Segal states: “The compositions of the present invention are
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`formulated as aqueous solutions comprising an antiinflammatory agent and at least
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`one additional therapeutic agent and further comprising a pharmaceutically
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`acceptable nasal carrier. . . . Preferred nasal formulations are nose drops or nasal
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`sprays containing a water buffered aqueous solution as a carrier.” Ex. 1012, 3:29-
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`4:5; see also id. cl.15 (depending from Segal claim 1 or 11). Thus, Segal’s
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`pharmaceutical formulation is a nasal spray, which thus is suitable for nasal
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`administration.
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`F. Claim Limitation 25.2: “(i) azelastine, or a pharmaceutically acceptable
`salt thereof,”
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`37. Segal states that “suitable antihistamines” can include “azelastine.”
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`Id., 3:19-20. Likewise, Segal’s claim 4, which depends from Segal’s claim 1,
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`discloses the combination of an antihistamine, like azelastine, with a topical anti-
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`inflammatory agent. Therefore, Segal discloses azelastine as part of the
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`combination nasal composition.
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`G. Claim Limitation 25.3: “(iii) a pharmaceutically acceptable ester of
`fluticasone,”
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`38. Segal discloses fluticasone as part of the combination nasal
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`composition. Segal identifies “fluticasone proprionate” as one of the “preferred”
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`antiinflammatory agents of the invention. Id., 2:22-26. (As would be recognized
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`by one of skill in the art, “proprionate” is merely an alternative spelling of
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`“propionate” and has the same meaning.) Likewise, Segal’s claim 2 recites
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`fluticasone proprionate as one of the topical anti-inflammatory agents in the
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`combination nasal composition. Id., cl. 2. Therefore, Segal discloses fluticasone
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`propionate as part of the combined nasal composition.
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`H. Claim Limitation 25.4: “and (iii) a pharmaceutically acceptable carrier
`or excipient therefor.”
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`39. Segal discloses that the preferred “nasal formulations are nose drops
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`or nasal sprays containing a water buffered aqueous solution as a carrier.” Id., 4:4-
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`5.
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`I. Segal discloses all claim elements as arranged in Claims 1 and 25
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`40. Segal’s disclosure of “azelastine” (Ex. 1012, 3:19-20) is identified as
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`a suitable “antihistamine,” which is listed as one of the components of the
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`“topically applicable nasal compositions” of the “present invention” under the
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`“SUMMARY OF INVENTION.” This same “SUMMARY OF INVENTION”
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`lists “topical antiinflammatory agent” as another component of the same nasal
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`compositions of the present invention, a “preferred embodiment” of which Segal
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`says is “fluticasone proprionate.” Ex. 1012, 2:22-26. Segal also refers to the
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`“compositions of the present invention” as being preferably formulated as a “nasal
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`spray[] containing a water buffered aqueous solution as a carrier.” Ex. 1012, 3:29-
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`4:5. Therefore, Segal teaches to formulate a nasal spray containing azelastine,
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`fluticasone propionate, and water in the same solution.
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`J. Segal is enabling prior art
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`41. Segal was enabling at least as of June 2002. The ’620 patent
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`expressly states that “where only the ingredients of formulations according to the
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`present invention are listed, these formulations are prepared by techniques well
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`known in the art.” Ex. 1001, 7:67-8:2. The only ingredients in claims 1 and 25 are
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`azelastine, fluticasone ester, and a carrier—all of which were disclosed by Segal,
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`and therefore the combination of these ingredients could be “prepared by
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`techniques well known in the art.” Examples of such prior art include Hettche (Ex.
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`1007), the Astelin® Label (Ex. 1008), Phillipps (Ex. 1009), and the Flonase®
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`Label (Ex. 1010).
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`XI. Claims 1, 5-6, 24-26, and 29, were Obvious as of at least June 2002
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`42.
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`I understand that an obviousness analysis involves comparing a claim
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`to the prior art to determine whether the claimed invention would have been
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`obvious to a POSA in view of the prior art, and in light of the general knowledge
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`in the art. I also understand when a POSA would have reached the claimed
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`invention through routine experimentation, the invention may be deemed obvious.
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`I understand that a finding of obviousness for a specific range or ratio in a patent
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`can be overcome if the claimed range or ratio is proven to be critical to the
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`performance or use of the claimed invention.
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`43.
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`I understand that when considering the obviousness of an invention,
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`one should also consider whether there are any secondary considerations that
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`support the nonobviousness of the invention. I understand that secondary
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`considerations of nonobviousness include failure of others, copying, unexpectedly
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`superior results, perception in the industry, commercial success, and long-felt but
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`unmet need.
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`44.
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`I also understand that obviousness can be established by combining or
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`modifying the teachings of the prior art to achieve the claimed invention. It is also
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`my understanding that where this is a reason to modify or combine the prior art to
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`achieve the claimed invention, there must also be a reasonable expectation of
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`success in so doing. I understand that the reason to combine prior art references
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`can come from a variety of sources, not just the prior art itself or the specific
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`problem the patentee was trying to solve. And I understand that the references
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`themselves need not provide a specific hint or suggestion of the alteration needed
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`to arrive at the claimed invention; the analysis may include recourse to logic,
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`judgment, and common sense available to a person of ordinary skill that does not
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`necessarily require explication in any reference.
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`A. The cited references disclose all of the claim elements
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`45. Hettche, Phillipps, and Segal describe pharmaceutical formulations
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`and nasal compositions. See Ex. 1007, 2:10-11; Ex. 1009, Abstract; Ex. 1012,
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`2:10-15. Like Segal (see Section X above), Hettche discloses “azelastine or a
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`physiologically acceptable salt” and Phillipps discloses fluticasone propionate,
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`which is a pharmaceutically acceptable ester of fluticasone. Ex. 1007, Abstract;
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`Ex. 1009, cl.13. All three references disclose the use of a nasal spray. See Ex.
`