`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`ARGENTUM PHARMACEUTICALS LLC
`
`Petitioner
`
`v.
`
`CIPLA LIMITED
`
`Patent Owner
`
`_____________________
`
`Case No. IPR2017-00807
`
`U.S. Patent No. 8,168,620
`_____________________
`
`
`
`
`SECOND DECLARATION OF HUGH DAVID CHARLES SMYTH, PH.D.
`
`
`
`
`
`
`
`Mail Stop "PATENT BOARD"
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`CIP2176
`Argentum Pharmaceuticals v. Cipla Ltd.
`IPR2017-00807
`
`

`

`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2176)
`TABLE OF CONTENTS
`
`B.
`
`I.
`Introduction ...................................................................................................... 1
`Professional and educational background ....................................................... 2
`II.
`III. Basis for my opinions ...................................................................................... 4
`IV. Summary of my opinions ................................................................................ 7
`V.
`Person of ordinary skill in the art .................................................................... 8
`VI. The '620 patent ................................................................................................. 9
`VII. Claim construction ........................................................................................... 9
`VIII. Given the expected technical difficulties in 2002, a POSA would not have
`been motivated to combine azelastine and fluticasone with a reasonable
`expectation of success. ..................................................................................12
`A.
`The lack of meaningful guidance in the art would have dissuaded a
`POSA from combining azelastine and fluticasone into a combination
`formulation. .........................................................................................12
`The prior art taught that fluticasone would aggregate when co-
`formulated in liquid formulations with another active ingredient,
`which would have undercut any motivation a POSA may have had to
`combine azelastine and fluticasone into a fixed-dose combination
`formulation with any reasonable expectation of success. ...................17
`Cramer's Example III would have undercut any reasonable
`expectation of successfully combining azelastine and fluticasone into
`a fixed-dose combination. ...................................................................20
`i. Dr. Govindarajan's and Dr. Herpin's testing confirms Ms.
`Malhotra's findings that Example III is not “suitable for nasal
`administration.” ...................................................................................21
`ii. Routine experimentation would not remedy the shortcomings of
`Example III. .........................................................................................26
`IX. As of June 2002, a POSA would not have had a motivation to use the
`excipients recited in claims 42-44 in an azelastine/fluticasone combination
`formulation, and would not have had a reasonable expectation of success. .28
`A.
`The prior art would have led a POSA away from using the thickening
`agents "microcrystalline cellulose and sodium carboxymethyl
`cellulose" as recited in claims 42-44. ..................................................29
`
`C.
`
`i
`
`

`

`B.
`
`C.
`
`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2176)
`The prior art provided no motivation to use a three-preservative
`combination of "edetate disodium" / "benzalkonium chloride" /
`"phenyl ethyl alcohol" as recited in claims 42-44. ..............................32
`The prior art would not have motivated a POSA to use "glycerin" as
`the isotonicity agent as recited in claims 42-44. .................................35
`X. Objective indicia of non-obviousness ...........................................................37
`A. Dymista® and Duonase embody the challenged claims .....................38
`B.
`The Duonase Imitator Products embody the challenged claims .........47
`C. Meda was skeptical that an azelastine/steroid combination formulation
`could be formulated and developed. ...................................................60
`D. Meda's failure to develop an azelastine/fluticasone combination
`formulation. .........................................................................................62
`XI. Conclusion .....................................................................................................64
`
`
`
`ii
`
`

`

`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2176)
`I, Hugh Charles David Smyth, do declare as follows:
`
`1.
`
`I am over the age of eighteen (18) and otherwise competent to make
`
`this declaration.
`
`I.
`
`Introduction
`
`2.
`
`I have been retained as an expert witness by Cipla Ltd. ("Cipla") in
`
`the above inter partes review matter concerning U.S. Patent No. 8,168,620 ("the
`
`'620 patent") (EX1001) that was filed by Petitioner Argentum Pharmaceuticals
`
`LLC ("Argentum"). 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").
`
`3.
`
`I have been asked by Cipla to review Argentum's Petition and the
`
`declaration submitted on behalf of Argentum by Dr. Maureen Donovan, and to
`
`respond to those documents to the extent that their contents fall within my
`
`expertise.
`
`4.
`
`I am being compensated for my time in connection with this inter
`
`partes review matter at a rate of $600 per hour, and my compensation does not
`
`depend upon the ultimate outcome of this case. I will also be compensated for any
`
`reasonable expenses, including travel costs incurred in conducting activities at
`
`counsel's request.
`
`1
`
`

`

`
`
`II.
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2176)
`Professional and educational background
`
`5.
`
`I am presently an Associate Professor with Tenure (Hamm Endowed
`
`Faculty Fellow) in the College of Pharmacy at the University of Texas, Austin. I
`
`have held this position since 2011. I am also an Adjunct Associate Scientist at the
`
`Lovelace Respiratory Research Institute in Albuquerque, New Mexico, a position I
`
`have held since 2009. From 2009 to 2011, I served as an Assistant Professor in the
`
`College of Pharmacy at the University of Texas, Austin. From 2005 to 2009, I was
`
`an Assistant Professor in the College of Pharmacy at the University of New
`
`Mexico. And from 2004 to 2005, I was a Research Assistant Professor in the
`
`College of Pharmacy at the University of North Carolina, Chapel Hill.
`
`6.
`
`I received a Bachelor of Pharmacy in 1995 from the University of
`
`Otago, in Dunedin, New Zealand. In 1997, I earned a Post Graduate Diploma in
`
`Pharmacy, with Distinction, from the University of Otago. In 2000, I received my
`
`Ph.D. in Pharmaceutical Sciences from the University of Otago. My thesis topic
`
`was the "Investigation of Electrically Assisted Drug Delivery in the Percutaneous
`
`Delivery of Peptides." From 2001 to 2003, I was a Post-Doctoral Fellow at the
`
`School of Pharmacy at the University of North Carolina, Chapel Hill.
`
`7. My current research focuses on the development of novel methods for
`
`drug delivery including nasal, inhalation, transdermal, ophthalmic, and oral
`
`delivery systems for a variety of diseases.
`
`
`
`2
`
`

`

`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2176)
`8. My responsibilities at the University of Texas include teaching
`
`graduate courses and mentoring graduate students. I have taught courses on
`
`Advanced Manufacturing Pharmacy, Recent Advances in Pharmaceutics, and
`
`Molecular and Cellular Pharmacology, to name a few. I have supervised 18 post-
`
`doctoral fellows and visiting scientists; served on over 38 graduate student
`
`committees and the primary advisor for 12 graduate students.
`
`9.
`
`I have published over 100 papers in peer-reviewed journals, 20 books
`
`or book chapters, and have presented over a hundred times at conferences.
`
`10.
`
` I am currently the Editor-in-Chief of Drug Development and
`
`Industrial Pharmacy and serve on the Editorial Boards of the Journal of
`
`Bioequivalence & Bioavailability and Drug Delivery Letters. In the past, I served
`
`as Guest Editor on the Journal of Nanomaterials. I also served on the Editorial
`
`Advisory Board of Books for the Controlled Release Society and on the Editorial
`
`Advisory Committee for Books for the American Association of Pharmaceutical
`
`Scientists. My curriculum vitae, which includes a list of my publications, is listed
`
`as CIP2008.
`
`11.
`
`In addition, I was previously an expert and trial witness for Cipla in
`
`the related district court litigation concerning the '620 patent against Apotex Inc.
`
`and Apotex Corp. (collectively, "Apotex").
`
`
`
`3
`
`

`

`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2176)
`III. Basis for my opinions
`I have considered the following documents in coming to the opinions
`12.
`
`I express below:
`
`Cipla's
`Exhibit #1
`2008
`
`Description
`
`Hugh David Charles Smyth, Ph.D. Curriculum Vitae
`
`2014
`
`2019
`
`2021
`
`Dr. Maureen Donovan Deposition transcript, October 7,
`2016, Meda Pharmaceuticals Inc. and Cipla Ltd., v.
`Apotex Inc. and Apotex Corp., Case No. 1:14-cv-01453-
`LPS (D. Del.)
`Bench Trial Transcript, Volume B, December 14, 2016,
`Meda 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.)
`Gennaro, A. R. Remington's Pharmaceutical Sciences
`(17th ed., 1985), Ch. 80: 1455-1477; Ch. 82: 1478-1491;
`Ch. 84:1492-1517
`Avomeen Analytical Services Report, June 30, 2016
`(PTX0129)
`Expert Report of Dr. Matthew J. Herpin and
`Corresponding Documents (PTX1663)
`Expert Report of Dr. Govindarajan and Corresponding
`Documents (PTX1664)
`
`1 Throughout this declaration, I will refer to these exhibits as "[Exhibit Number],
`
`2026
`
`2028
`
`2029
`
`2030
`
`[paragraph/page number(s)]."
`
`
`
`4
`
`

`

`
`
`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2176)
`
`Cipla's
`Exhibit #1
`2031
`
`2038
`
`2040
`
`2044
`
`2051
`
`2054
`
`2056
`
`2058
`
`2061
`
`2070
`
`2103
`
`2104
`
`2105
`
`2111
`
`Description
`
`Duonase Imitator Product Labels (PTX0026)
`
`Khan, M., et al. Pharmaceutical and Clinical
`Calculations (2nd ed., 2000), pp. 149-167 (PTX0194)
`British Pharmaceutical Codex (1973), "Hypromellose,"
`pp. 232, 307-308 (PTX0193)
`Michael, Y., et al. "Characterisation of the aggregation
`behavior in a salmeterol and fluticasone propionate
`inhalation aerosol system," International Journal of
`Pharmaceutics, 221: 165-174; 2001 (PTX0179)
`Claritin® Approval Letter, Application Numbers 19-
`658/S-018, 19-670/S-018, 20-470/S-016, 20-641/S-009,
`and 20-704/S-008
`MedPointe Making Medicine Better: Astelin® Day Life
`CyclePlan, November 1, 2002 (PTX1005)
`Astelin® Nasal Spray Life Cycle Management Projects
`(Preliminary Plan) (PTX1006)
`2006.03.21 Email and attachment from Kalidas Kale to
`Alex D'Addio re: Astelin – Flonase Combination
`Product Feasibility Assessment Plan (PTX0151)
`MedPointe Laboratory Notebook No. 1044 - Excerpts
`(PTX0142)
`Duonase Nasal Spray – Prescribing Information
`(PTX0134)
`The United States Pharmacopeia: 24 National Formulary
`19 (1999), pp. 2107-2130 (PTX0188)
`Lieberman, H. A., et al. Pharmaceutical Dosage Forms
`(2nd ed., 1996), Ch. 4: 149-181 (PTX0177)
`Shin Etsu Pharmacoat USP Hypromellose Brochure
`(2005) (PTX0186)
`Michael, Y., et al. "The physico-chemical properties of
`salmeterol and fluticasone propionate in different solvent
`
`5
`
`

`

`
`
`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2176)
`
`Cipla's
`Exhibit #1
`
`Description
`
`2112
`
`2113
`
`2114
`
`2135
`
`2136
`
`2141
`
`2144
`
`2148
`
`2151
`
`2152
`
`2153
`
`2154
`
`2155
`
`2156
`
`environments," International Journal of Pharmaceutics,
`200: 279-288; 2000 (PTX0180)
`Allen, Jr., L.V. The Art, Science, and Technology of
`Pharmaceutical Compounding (1998), Ch. 20: 219-238
`(PTX0167)
`Lieberman, H. A., et al. Pharmaceutical Dosage Forms
`(2nd ed., 1996), vol. 2, Ch. 5: 183-241 (PTX0192)
`Meda Highlights of Prescribing Information 2015
`(PTX0154)
`Wade, A., and Weller, P. Handbook of Pharmaceutical
`Excipients (2nd ed., 1994), p. 154
`Talbot, Andrew, et al. "Mucociliary Clearance and
`Buffered Hyperonic Saline Solution," Laryngoscope,
`107(4): 500-503; 1997
`Physicians’ Desk Reference, Accolate® and Allegra-D®
`Prescribing Information (2002)
`Physicians’ Desk Reference, Zyrtec-D® Prescribing
`Information (2002)
`Alexander Dominic D'Addio, Ph.D. Declaration
`
`Cipla Duonase Manufacturing Guide (PTX0153)
`
`Cipla Duonase Manufacturing Guide (PTX0135)
`
`Meda Investigation report: Dymista 6.4 g Nasal Spray
`Stability results (PTX0141)
`Meda NDA excerpt 3.2.P.3 Manufacture [Dymista
`(azelastine hydrochloride and fluticasone propionate)
`Nasal Spray, 137mcg/50 mcg] (PTX0138)
`Cipla Duonase Stability Testing Form
`
`Kibbe, A. H., Antimicrobial preservative Index, in
`Handbook of Pharmaceutical Excipients (3rd ed., 2000),
`
`6
`
`

`

`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2176)
`
`Cipla's
`Exhibit #1
`
`pp. 646-647
`
`Description
`
`
`IV. Summary of my opinions
`13. As I explain below, a POSA would understand the claim phrases
`
`"dosage form suitable for nasal administration" and "nasal spray" to mean
`
`"pharmaceutical formulations that are tolerable to patients, that are homogeneous,
`
`and that can be suitably deposited onto the nasal mucosa."
`
`14. As I explain below, a POSA would not have been motivated to
`
`combine azelastine and fluticasone into the claimed combination formulation with
`
`a reasonable expectation of doing so because (1) the prior art did not provide a
`
`POSA any meaningful information in order to make such a formulation, (2)
`
`fluticasone was known to aggregate and flocculate when co-formulated with
`
`another active ingredient which would have discouraged a POSA from attempting
`
`to combine azelastine and fluticasone, and (3) following the closest prior art
`
`formulation disclosed in Example III of Cramer—an azelastine/triamcinolone
`
`formulation—did not allow a POSA to arrive at a fixed-dose combination of the
`
`challenged claims.
`
`15. As I explain below, a POSA would not have had a motivation to select
`
`the explicitly recited excipients of claims 42-44 because the prior art would have
`
`
`
`7
`
`

`

`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2176)
`discouraged their use either with azelastine, fluticasone, or the other claimed
`
`excipients. And additionally, a POSA would not have had a reasonable expectation
`
`of success for these same reasons.
`
`16. As I explain below, Meda's commercial azelastine/fluticasone
`
`product, Dymista®, Cipla's commercial azelastine/fluticasone product, Duonase,
`
`and the Duonase Imitator Products are embodiments of certain challenged claims.
`
`As I explain further below, objective indicia of non-obviousness, including
`
`skepticism of others, failure of others, copying, and unexpected results exist with
`
`respect to the challenged claims.
`
`V.
`
`Person of ordinary skill in the art
`
`17. Counsel has informed me that the critical date for assessing
`
`patentability of the '620 patent is June 2002. I note that Dr. Donovan uses the same
`
`date for her analysis. EX1004, ¶¶14-15.
`
`18. Counsel also 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 along conventional wisdom in the art, and is a person of ordinary creativity.
`
`A POSA at that time would have the knowledge and experience of both a clinician
`
`and a formulation scientist. I believe this is the appropriate standard because the
`
`'620 patent relates to both the treatment of patients and the formulation of a
`
`therapeutically-effective nasal spray. In my opinion, the formulation aspect of this
`
`
`
`8
`
`

`

`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2176)
`POSA would require a B.S. in Pharmaceutical Sciences and 4-5 years of
`
`experience as a formulator, although the POSA could also be a person with a
`
`higher level of formal education and fewer years of experience. The formulator
`
`would have educational, practical training, and expertise to formulate a nasal
`
`spray. I understand from counsel that another expert will address the clinical aspect
`
`of this POSA.
`
`VI. The '620 patent
`In general, the '620 patent is directed to pharmaceutical formulations
`19.
`
`containing azelastine hydrochloride ("azelastine") and fluticasone propionate
`
`("fluticasone") with various excipients in a dosage form that is "suitable for nasal
`
`administration" or that is a "nasal spray." See claims 1, 24, and 25.
`
`VII. Claim construction
`I understand from counsel that the claim terms of the '620 patent are
`20.
`
`to be given their broadest reasonable interpretation. I also understand from counsel
`
`that the patent applicant—here Cipla—can explicitly or implicitly define terms
`
`used in the claims by amending the language in those claims and/or by the patent
`
`applicant's statements to the patent examiner.
`
`21. The challenged claims include the claim phrases "dosage form
`
`suitable for nasal administration" or "nasal spray." I have reviewed the '620 patent
`
`and the prosecution history of that patent. It is my opinion, based on my review of
`
`
`
`9
`
`

`

`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2176)
`the patent and the prosecution history, that the claim phrases "dosage form suitable
`
`for nasal administration" and "nasal spray" require "pharmaceutical formulations
`
`that are tolerable to patients, that are homogeneous, and that can be suitably
`
`deposited onto the nasal mucosa."
`
`22. During prosecution, the '620 patent had been rejected as anticipated
`
`under 35 U.S.C. § 102 and/or obvious under 35 U.S.C. § 103 in view of EP
`
`0780127 ("Cramer"), particularly the formulation of Example III. EX1002, 219-
`
`221, 507-522. In response, Cipla amended the pending claims to include the
`
`language "said pharmaceutical formulation is in a dosage form suitable for nasal
`
`administration," and likewise noted that other claims recited a "nasal spray."
`
`EX1002, 206-216, 220. A POSA would understand Cipla's statement to the patent
`
`examiner as specifying that a "nasal spray" and a dosage form "suitable for nasal
`
`administration" require these characteristics.
`
`23. Cipla also submitted a declaration from co-inventor Geena Malhotra
`
`recreating the prior art Cramer Example III formulation and reporting that Cramer's
`
`Example III formulation exhibited (1) unacceptably high osmolality which was
`
`expected to cause irritation to patients, (2) unacceptable spray quality which
`
`adversely effects whether the intended amount of the drug is suitably deposited on
`
`
`
`10
`
`

`

`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2176)
`the nasal mucosa, and (3) unacceptable settling, which reduces drug homogeneity2
`
`in the formulation. EX1002, 284-287. Cipla used the declaration to tell the patent
`
`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, 223-224 (emphasis added). Cipla also told the patent examiner
`
`that the term “suitable for nasal administration” was synonymous with the term
`
`“nasal spray,” as used in the ’620 patent. EX1002, 220 (“Likewise, independent
`
`claims 55 and 56 each recite a ‘nasal spray’…”). Cipla additionally told the patent
`
`examiner that "the inoperability of Cramer's closest example as cited by the Office
`
`Action is a further basis for the novelty of independent claims 1 [and] 56…"
`
`EX1002, 221 (emphasis added). The patent examiner subsequently allowed the
`
`pending claims over Cramer. EX1002, 139-146. Because the "dosage form suitable
`
`for nasal administration" and "nasal spray" language of the pending claims were
`
`used to distinguish the prior art from Cipla's claimed invention, a POSA would
`
`understand that the formulations of the pending claims did not suffer from the
`
`
`2 Drug homogeneity, also known as drug uniformity, relates to the uniformity of
`
`the drug dispersion within the formulation, and is necessary to ensure safe and
`
`effective dosing for patients.
`
`
`
`11
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`

`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2176)
`same shortcomings as Example III—i.e., they were not expected to cause irritation,
`
`suitably deposited the intended amount of the drug on the nasal mucosa, and were
`
`homogeneous. A POSA therefore would have understood the claim phrases
`
`"dosage form suitable for nasal administration" and "nasal spray" to require
`
`"pharmaceutical formulations that are tolerable to patients, that are homogeneous,
`
`and that can be suitably deposited onto the nasal mucosa."
`
`VIII. Given the expected technical difficulties in 2002, a POSA would not
`have been motivated to combine azelastine and fluticasone with a
`reasonable expectation of success.
`
`24. Argentum and Dr. Donovan opine that claims 1, 4-6, 24-26, and 29
`
`would have been obvious to a POSA in 2002 in view of the combined teachings of
`
`U.S. Patent No. 5,164,194 ("Hettche") (EX1007), U.S. Patent No. 4,335,121
`
`("Phillipps") (EX1009), and Segal (EX1012). EX1004, ¶ 12. I disagree for the
`
`reasons below.
`
`A. The lack of meaningful guidance in the art would have dissuaded
`a POSA from combining azelastine and fluticasone into a
`combination formulation.
`
`25. Dr. Donovan was "asked by counsel to assume it was obvious to
`
`combine azelastine hydrochloride and fluticasone propionate into a single nasal
`
`spray." EX1004, ¶40. Therefore, Dr. Donovan does not provide any opinion on
`
`whether a formulator would have been motivated to combine azelastine and
`
`fluticasone into a single, fixed-dose combination formulation. But a POSA would
`
`
`
`12
`
`

`

`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2176)
`not have been motivated to combine Segal, Hettche, and Phillipps to arrive at a
`
`fixed-dose combination of azelastine and fluticasone because (1) there was no
`
`guidance in the prior art (e.g., working examples, textbooks, articles, or industry
`
`knowledge/experience) of how to combine a solution formulation with a
`
`suspension formulation, as encompassed by the challenged claims, and (2) the
`
`inordinate technical difficulties involved with combining two different
`
`formulations were known, as explained in more detail below.
`
`26. First, a POSA would not have been motivated to combine azelastine
`
`and fluticasone into a combined formulation because there was no teaching,
`
`understanding, or guidance in the prior art of how a POSA would formulate such a
`
`product. Dr. Donovan's declaration is devoid of any explanation of how a POSA
`
`would have combined azelastine and fluticasone. EX1004, ¶40 ("I have been asked
`
`by counsel to assume it was obvious to combine azelastine hydrochloride and
`
`fluticasone propionate…") (emphasis added). She cites to no prior art teachings or
`
`prior art guidance, nor any prior art exemplary products. EX1004, ¶¶21-39. In fact,
`
`the product labels for the only FDA-approved combination allergic rhinitis drugs
`
`
`
`13
`
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`

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`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2176)
`by 2002—Allegra D, Claritin D, and Zyrtec D—all state that those products are
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`solid oral dosage forms. CIP2141, 4; CIP2144, 3; CIP2051, 2.3
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`27. Dr. Donovan identifies two prior art references—Segal (EX1012) and
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`Cramer (EX1011)—as disclosing antihistamine/steroid combination formulations.
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`EX1004, ¶51. But the disclosures of Segal and Cramer would not have provided
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`any motivation for a POSA to combine azelastine and fluticasone with any
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`reasonable expectation of success.
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`28. Among Segal's disclosure of a laundry list of drugs, Segal disclosed
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`"anti-inflammatory agents," such as corticosteroids. EX1012, 4. A POSA would
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`understand that anti-inflammatory agents are suspension formulations, where the
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`drug particles are dispersed in a medium. Indeed, the Flonase® label states that
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`fluticasone "is practically insoluble in water" and that Flonase® is formulated as
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`"an aqueous suspension." EX1010, 1. By contrast, many of Segal's other identified
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`drug classes are solution formulations, where the active ingredient is dissolved and
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`molecularly dispersed in a solvent. EX1012, 5. For example, Astelin®'s label states
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`3 The Physicians’ Desk Reference is a reliable and authoritative sources of
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`information for formulators and the public to understand what active ingredients
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`and excipients are contained in a commercially available FDA-approved drug.
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`14
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2176)
`that azelastine is "sparingly soluble in water" and that Astelin® is formulated as
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`"an aqueous solution." EX1008, 2.
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`29. Segal, however, contains no formulation examples from which a
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`POSA would understand that Segal had successfully combined any of the disclosed
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`anti-inflammatory agents like fluticasone (typically formulated as suspensions)
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`with any of the other disclosed drugs like azelastine (typically formulated as
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`solutions). EX1012, 3-6. Absent any explicit formulation details, such as
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`formulation ingredients and concentrations, Segal's only mention of any guidance
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`in the art as to how to formulate a combination product is a passing reference to the
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`general industry text Remington's Pharmaceutical Sciences, 1985, 17th ed.
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`EX1012, 6:14. A POSA would not find this disclosure meaningful because Segal
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`does not cite to any specific passages of Remington's, but instead cites generally to
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`the entire text. Id. Moreover, Remington's fails to disclose combination
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`solution/suspension nasal formulations, instead it discusses solution formulations
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`separately from suspension formulations. CIP2026, 13-14. If solution/suspension
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`combination formulations were known in 2002, a POSA would have expected a
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`general text like Remington's to address it—it does not.
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`30. Next, the lack of meaningful guidance in the art is confirmed by
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`Cramer. Cramer contains a much more explicit disclosure of formulation
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`information than Segal, including a lengthy discussion regarding possible
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`15
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2176)
`excipients and explicit formulation examples. EX1011, 4:6-6:51. Indeed, I
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`observed Argentum's clinical expert, Dr. Robert Schleimer, testify in the related
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`Apotex trial that Segal's disclosure is "less specific" than Cramer's. CIP2019,
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`66:17-20. But a POSA following the more explicit guidance in Cramer would not
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`arrive at a “nasal spray” or a formulation that was “suitable for nasal
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`administration.”
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`31. But even with Cramer's additional information, a POSA would not
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`have been able to arrive at a "nasal spray" or a formulation that was " suitable for
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`nasal administration" within the scope of challenged claims. Co-inventor Geena
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`Malhotra determined that Cramer's Example III formulation exhibits unacceptably
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`high osmolality, poor spray quality, and unacceptable settling and caking. EX1002,
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`286-87. And as discussed more below, Cipla's and Apotex's experts in the related
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`Apotex case confirmed that the Example III formulation was (i) unacceptably
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`acidic; (ii) unstable, leading to significant caking of drug; and (iii) unacceptably
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`high osmolality. See § VIII.C below.
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`32. Argentum also asserts that the '620 patent "admits" that the art teaches
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`a POSA to formulate Segal's combination formulation because the '620 patent
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`contains the following statement preceding its formulation examples: "In Examples
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`where only the ingredients of formulations according to the present invention are
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`listed, these formulations are prepared by techniques well known in the art." Pet.
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2176)
`36; EX1001, 11, col. 7, line 67 – col. 8, line 2 (emphasis added). A POSA would
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`have viewed this sentence to be limited to the Examples listed in the '620 patent
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`which set out the specific formulation ingredients and concentrations. EX1001, 11,
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`col. 8, line 1 – col. 11, line 43. In that context, the fact that "these formulations are
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`prepared by techniques well known in the art" makes sense because the examples
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`already identify what, and how much, formulation ingredients to use. Unlike the
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`formulation examples of the '620 patent, Segal contains no formulation examples
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`and therefore would not be understood by a POSA to "list" "the ingredients of the
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`formulation according to [Segal's invention]"—indeed, no formulations are listed.
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`See EX1012, 4-6.
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`33. Argentum also cites to the fact that azelastine and fluticasone were
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`"disclosed and claimed" in Hettche and Phillipps. Pet. 39-40. But neither Hettche
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`nor Phillipps disclose any combination formulations, and therefore would not
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`provide any guidance to a POSA. EX1007, Abstract ("…contains as active
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`ingredient azelastine or a physiologically acceptable salt."); EX1009, Abstract
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`("Pharmaceutical compositions containing the compounds of formula I…"). That
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`is, Hettche and Phillipps provide even less guidance than Segal and Cramer, and
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`neither would lead a POSA to a formulation of the challenged claims.
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`B.
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`The prior art taught that fluticasone would aggregate when co-
`formulated in liquid formulations with another active ingredient,
`which would have undercut any motivation a POSA may have
`had to combine azelastine and fluticasone into a fixed-dose
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`Inter Partes Review of U.S. Patent No. 8,168,620
`Second Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2176)
`combination formulation with any reasonable expectation of
`success.
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`34. A POSA would not have been motivated to combine fluticasone with
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`a second active ingredient—like azelastine in the challenged claims—because the
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`prior art taught that fluticasone aggregated when co-formulated in a liquid
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`formulation with another active drug. By 2000, a POSA would have known that
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`researchers at GlaxoSmithKline—the developers of fluticasone—also published an
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`investigation on a co-formulation of fluticasone and salmeterol xinafoate
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`("salmeterol") in a propellant-based suspension system. CIP2111, 1.
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`GlaxoSmithKline’s publications report that the fluticasone and salmeterol undergo
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`flocculation whereby the individual particles of the two drugs aggregate together,
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`which can lead to substantial non-uniform drug suspensions, e.g., rapid settling or
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`creaming, and caking of the drugs. CIP2111, 1; CIP2044, 1.4 GlaxoSmithKline
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`further reported its investigation on whether the fluticasone-salmeterol flocs could
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`be broken apart. The publication states that "the flocs persisted even at the highest
`
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`4 CIP2111 and CIP2044 are both peer-reviewed publications in reputable journals.
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`Such journals, and the information contained in such publications, are considered
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`reliable accurate and reliable sources of information upon which experts and
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`formulators can rely. And, indeed, such journals and such publications