`
`
`
`
`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 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
`
`CIP2007
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
`
`1
`
`CIPLA LTD. EXHIBIT 2037 PAGE 1
`
`

`

`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2007)
`TABLE OF CONTENTS
`
`I. 
`Introduction ...................................................................................................... 1 
`Professional and educational background ....................................................... 2 
`II. 
`III.  Basis for my opinions ...................................................................................... 4 
`IV.  Summary of my opinions ................................................................................ 6 
`V. 
`Person of ordinary skill in the art .................................................................... 8 
`VI.  The '620 patent ................................................................................................. 9 
`VII.  Claim construction ........................................................................................... 9 
`VIII.  Segal does not enable the azelastine/fluticasone combination formulations of
`claims 1 and 25. ............................................................................................. 11 
`IX.  As of June 2002, a POSA would have been led away from combining
`azelastine and fluticasone into a fixed-dose combination formulation, and a
`POSA would not have had a reasonable expectation of success. .................. 19 
`A.  A POSA would not have been motivated to combine azelastine and
`fluticasone into a fixed-dose combination because of the difficulties in
`doing so and the lack of guidance in the prior art. .............................. 20 
`The prior art taught that fluticasone would aggregate when co-
`formulated with another active ingredient, which would have led a
`POSA away from combining azelastine and fluticasone into a fixed-
`dose combination formulation and would have undercut any
`reasonable expectation of success. ...................................................... 23 
`Cramer's Example III would have been led away from combining
`azelastine and fluticasone into a fixed-dose combination, and would
`have undercut any reasonable expectation of success. ....................... 24 
`Dr. Govindarajan's and Dr. Herpin's testing confirms Ms. Malhotra's
`i. 
`findings. ............................................................................................................. 25 
`Routine experimentation would not remedy the shortcomings of
`ii. 
`Example III. ....................................................................................................... 29 
`X.  As of June 2002, a POSA would have been led away from using the
`excipients recited in claims 42-44 in an azelastine/fluticasone combination
`formulation, and would not have had a reasonable expectation of success. . 31 
`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. .................................................. 31 
`
`B. 
`
`C. 
`
`i
`
`2
`
`CIPLA LTD. EXHIBIT 2037 PAGE 2
`
`

`

`
`
`B. 
`
`C. 
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2007)
`The prior art would have led a POSA away from employing a three-
`preservative combination of "edetate disodium" / "benzalkonium
`chloride" / "phenyl ethyl alcohol" as recited in claims 42-44. ............ 34 
`The prior art would not have led a POSA to use "glycerin" as the
`isotonicity agent as recited in claims 42-44. ....................................... 36 
`XI.  Objective indicia of non-obviousness ........................................................... 38 
`A.  Dymista® and Duonase embody the challenged claims ...................... 38 
`B. 
`The Duonase Imitator Products embody the challenged claims ......... 39 
`C.  Meda was skeptical that an azelastine/steroid combination formulation
`could be formulated and developed. ................................................... 52 
`D.  Meda's failure to develop an azelastine/fluticasone combination
`formulation. ......................................................................................... 54 
`Dymista®, Duonase, and the Imitator Products are unexpectedly
`"suitable for nasal administration." ..................................................... 56 
`XII.  Conclusion ..................................................................................................... 57 
`
`E. 
`
`
`
`ii
`
`3
`
`CIPLA LTD. EXHIBIT 2037 PAGE 3
`
`

`

`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2007)
`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
`
`4
`
`CIPLA LTD. EXHIBIT 2037 PAGE 4
`
`

`

`
`
`II.
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2007)
`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
`
`5
`
`CIPLA LTD. EXHIBIT 2037 PAGE 5
`
`

`

`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2007)
`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 approximately 85 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
`
`6
`
`CIPLA LTD. EXHIBIT 2037 PAGE 6
`
`

`

`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2007)
`III. Basis for my opinions
`12.
`I have considered the following documents in coming to the opinions
`
`I express below:
`
`Cipla's
`Exhibit #1
`
`2003
`
`2008
`
`2014
`
`2019
`
`2021
`
`2026
`
`2027
`
`2028
`
`2029
`
`2030
`
`2031
`
`Description
`
`Alexander Dominic D'Addio, Ph.D. Declaration
`
`Hugh David Charles Smyth, Ph.D. Curriculum Vitae
`
`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
`Accolate Approval Letter and Label, Application Number 20-
`547/S011, Zeneca Pharmaceuticals
`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)
`Duonase Imitator Product Labels (PTX0026)
`
`Allegra-D Approval Letter, Application Number 20786, Approved
`
`2032
`
`1 Throughout this declaration, I will refer to these exhibits as "[Exhibit Number],
`
`[paragraph/page number(s)]."
`
`
`
`4
`
`7
`
`CIPLA LTD. EXHIBIT 2037 PAGE 7
`
`

`

`
`
`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2007)
`
`Cipla's
`Exhibit #1
`
`Description
`
`2036
`
`2038
`
`2040
`
`2044
`
`2051
`
`2054
`
`2056
`
`2058
`
`2061
`
`2070
`
`2103
`
`2104
`
`2105
`
`2110
`
`2111
`
`December 24, 1997, (PTX0126)
`Zyrtec-D FDA Label, Approved August 10, 2001
`
`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)
`Kibbe, A. H. "Hydroxypropyl Methylcellulose," in Handbook of
`Pharmaceutical Excipients (3rd ed., 2000), pp. 252-255
`(PTX0198)
`Michael, Y., et al. "The physico-chemical properties of salmeterol
`and fluticasone propionate in different solvent environments,"
`International Journal of Pharmaceutics, 200: 279-288; 2000
`(PTX0180)
`
`5
`
`8
`
`CIPLA LTD. EXHIBIT 2037 PAGE 8
`
`

`

`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2007)
`
`Cipla's
`Exhibit #1
`
`2112
`
`2113
`
`2135
`
`2136
`
`Description
`
`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)
`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
`
`
`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 view Segal as anticipating the
`
`azelastine/fluticasone combination formulation of claims 1 and 25 because Segal
`
`does not enable a "pharmaceutical formulation that is tolerable to patients, that is
`
`homogenous, and that can be suitably deposited onto the nasal mucosa."
`
`15. As I explain below, a POSA would not have been motivated to
`
`combine azelastine and fluticasone into the claimed combination formulation
`
`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
`
`
`
`6
`
`9
`
`CIPLA LTD. EXHIBIT 2037 PAGE 9
`
`

`

`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2007)
`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. In addition, in view of the
`
`technical challenges required to make such an azelastine/fluticasone combination
`
`formulation, a POSA would have been dissuaded from trying.
`
`16. 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
`
`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.
`
`17. 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.
`
`
`
`7
`
`10
`
`CIPLA LTD. EXHIBIT 2037 PAGE 10
`
`

`

`
`
`V.
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2007)
`Person of ordinary skill in the art
`18. 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.
`
`19. 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
`
`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.
`
`20. My opinion of the qualifications of a POSA would not change if the
`
`critical date for the '620 patent was determined to be June 13, 2003. In addition,
`
`
`
`8
`
`11
`
`CIPLA LTD. EXHIBIT 2037 PAGE 11
`
`

`

`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2007)
`my opinions expressed below would not change under Dr. Donovan's definition of
`
`a POSA.
`
`VI. The '620 patent
`21.
`In general, the '620 patent is directed to pharmaceutical formulations
`
`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."
`
`VII. Claim construction
`22.
`I understand from counsel that the claim terms of the '620 patent are
`
`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.
`
`23. 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
`
`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."
`
`
`
`9
`
`12
`
`CIPLA LTD. EXHIBIT 2037 PAGE 12
`
`

`

`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2007)
`24. 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. In response, Cipla amended the pending claims to include the language "said
`
`pharmaceutical formulation is in a dosage for 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.
`
`25. 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
`
`the nasal mucosa, and (3) unacceptable settling, which reduces drug homogeneity2
`
`in the formulation. EX1002, 286-287. Cipla used the declaration to tell the patent
`
`
`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.
`
`
`
`10
`
`13
`
`CIPLA LTD. EXHIBIT 2037 PAGE 13
`
`

`

`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2007)
`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 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
`
`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. Segal does not enable the azelastine/fluticasone combination
`formulations of claims 1 and 25.
`26.
`
`I understand from counsel that for a prior art genus to anticipate a
`
`species, a prior art genus must sufficiently describe the species so that a POSA can
`
`
`
`11
`
`14
`
`CIPLA LTD. EXHIBIT 2037 PAGE 14
`
`

`

`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2007)
`immediately envisage the claimed species from the genus. I further understand
`
`from counsel that to be anticipatory, a prior art reference must enable a POSA to
`
`practice without undue experimentation the allegedly anticipatory disclosure.
`
`27.
`
`I have reviewed Argentum's Petition and the PCT Publication No.
`
`WO 98/48839 ("Segal") that Argentum alleges anticipates the formulations of
`
`claims 1 and 25, and the documents cited therein. It is my opinion that Segal does
`
`not enable a POSA to practice the formulations encompassed by claims 1 and 25
`
`without undue experimentation for the reasons below. I understand from counsel
`
`that another expert will address whether Segal's disclosure allows a POSA to
`
`immediately envisage the claimed azelastine/fluticasone combination formulations.
`
`28. Among Segal's disclosure of a laundry list of drugs, a POSA would
`
`understand that Segal's disclosed "anti-inflammatory agents," such as
`
`corticosteroids, are suspension formulations, where the drug particles are dispersed
`
`in a medium. Indeed, the Flonase® label states that fluticasone "is practically
`
`insoluble in water" and that Flonase® is formulated as "an aqueous suspension."
`
`EX1010, 1. Additionally, many of Segal's other identified drug classes are solution
`
`formulations, where the active ingredient is dissolved and molecularly dispersed in
`
`a solvent. For example, Astelin®'s label states that azelastine is "sparingly soluble
`
`in water" and that Astelin® is formulated as "an aqueous solution." EX1008, 2.
`
`
`
`12
`
`15
`
`CIPLA LTD. EXHIBIT 2037 PAGE 15
`
`

`

`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2007)
`29. Segal, however, contains no formulation examples from which a
`
`POSA would understand that Segal had successfully combined any of the disclosed
`
`anti-inflammatory drugs, like fluticasone, with any of the other disclosed drugs,
`
`like azelastine. EX1012, 4-6. Absent any explicit formulation details, such as
`
`formulation ingredients and concentrations, Segal's only mention of any guidance
`
`in the art as to how to formulate a combination product is a passing reference to the
`
`general industry text Remington's Pharmaceutical Sciences, 1985, 17th ed.
`
`EX1012, 6:14. A POSA would not find this disclosure meaningful because Segal
`
`does not cite to any specific passages of Remington's, but instead cites generally to
`
`the entire text. Id. Indeed, Remington's discusses solution formulations separately
`
`from suspension formulations, and further contains no discussion of combination
`
`solution/suspension formulations. CIP2026, 13-14. If solution/suspension
`
`combination formulations were known in 2002, a POSA would have expected a
`
`general text like Remington's to address it—it does not.
`
`30. Next, a POSA would also not view Segal as enabling a
`
`fluticasone/azelastine combination formulation because the prior art reference with
`
`more explicit guidance—Cramer—does not result in a "pharmaceutical
`
`formulation that is tolerable to patients, that is homogeneous, and that can be
`
`suitably deposited onto the nasal mucosa." As shown in the table below, the
`
`Cramer reference contains all of the same disclosures that Argentum relies upon
`
`
`
`13
`
`16
`
`CIPLA LTD. EXHIBIT 2037 PAGE 16
`
`

`

`
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2007)
`from the Segal reference, but in contrast to Segal's meager guidance, Cramer
`
`contains much more explicit guidance, including a lengthy discussion regarding
`
`possible excipients and explicit formulation examples. EX1011, 4:6-6:51.
`
`'620 Patent Claims
`
`Segal (Pet. 19-21)
`
`Cramer (EX1011)
`
`1. A pharmaceutical
`formulation
`comprising:
`
`azelastine, or a
`pharmaceutically
`acceptable salt
`thereof, and
`
`"The present invention
`provides 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 inhibitor, an
`anticholinergic agent, a
`leukotriene inhibitor, an
`antihistamine, an antiallergic
`agent, an anesthetic, and a
`mucolytic agent." EX1012,
`4:10-15; see also id. cl.1.
`
`"Suitable antihistamines are
`diphenhydramine,
`chlorpheniramine, cetirizine
`terfenadine, fenofexadine,
`astemizole norastemizole,
`azelastine, and azatidine."
`EX1012, 7:19-20; see also id.
`cl.4 (depending from Segal
`claim 1).
`
`
`
`14
`
`"The present invention
`relates to novel nasal spray
`compositions," EX1011,
`2:5.
`
`The present invention
`comprises an
`"antihistamine selected
`from the group consisting
`of cetirizine, loratadine,
`azelastine,
`pharmaceutically
`acceptable salts thereof,
`optically active racemates
`thereof and mixtures
`
`17
`
`CIPLA LTD. EXHIBIT 2037 PAGE 17
`
`

`

`
`
`
`
`Inter Paartes Revieww of U.S. Pattent No. 8,1668,620
`
`
`
`
`
`Declarationn of Hugh Daavid Charless Smyth, Ph..D.(Exhibit 22007)
`
`
`theereof." EX11011, 2:36
`-43.
`
`
`
`
`"In aa preferred embodimeent
`
`
`
`the toopical antiiinflammattory
`
`
`agennt is beclommethasone
`
`
`
`diprooprionate, bbudesonidde,
`
`
`
`dexaamethasonee, mometassone
`
`
`furoaate, fluticasone
`
`
`
`propionate or trriamcinoloone
`
`
`
`acetoonide." EXX1012, 6:233-26;
`
`
`
`see aalso id. cl.22 (dependinng
`
`
`fromm Segal claiim 1).
`
`nvention Thee present in
`
`
`
`
`
`commprises a ""glucocortiicoid
`
`
`
`seleected fromm the groupp
`
`connsisting of
`
`
`becclomethasoone,
`
`
`
`flunnisolide, trriamcinoloone,
`
`
`
`flutticasone, mmometasonne,
`
`buddesonide,
`
`
`phaarmaceuticcally
`
`
`
`accceptable saalts thereof f and
`011,
`
`
`mixxtures therreof." EX1
`
`2:336-40.
`
`"Thee compositions of thee
`
`theraapeutic ageent and furtrther
`
`
`
`
`
`
`preseent invention are
`
`
`formmulated as aaqueous
`
`
`soluttions compprising an
`
`
`
`antiinnflammatoory agent aand at
`
`
`leastt one additiional
`
`
`
`
`compprising a
`
`
`
`pharmmaceuticallly acceptaable
`
`
`
`nasall carrier…Preferred nnasal
`
`
`
`formmulations arre nose droops
`
`
`
`or naasal sprays containingg a
`
`
`wateer buffered aqueous
`
`
`soluttion as a caarrier."
`
`
`EX1012, 7:29-4:5; see allso
`
`id. cl
`
`
`l.15 (depennding fromm
`
`
`Segaal claim 1 oor 11).
`
`
`
`
`
`a pharmmaceuticallyy
`f
`
`acceptabble ester o
`
`fluticasoone,
`
`
`whereinn said
`ceutical
`pharma
`a formulaation is in a
`
`
`
`
`dosage form suitabble
`
`for nasaal
`
`adminisstration.
`
`closes a wwater carrierr,
`
`
`
`EXX1011, 6:300-41. This
`
`
`exaample fromm Cramer
`dis
`
`
`the
`
`e same formmulation
`
`
`
`infoformation ffrom Segall
`
`ideentified by
`
`Argentumm.
`
`
`
`Thee above exxemplary
`
`
`
`formmulation ffrom Crammer,
`
`Exaample III,
`is the close
`est
`
`
`
`prioor art as coonfirmed bby
`
`
`
`thee PTO (EXX1002, 221)),
`
`
`andd was showwn during
`
`
`proosecution aand again
`
`
`durring litigatiion to be
`
`
`unssuitable forr nasal
`
`admministratio
`
`
`n. EX10022,
`
`Segaal providedd no exampplary
`
`
`
`
`
`formmulations.
`
`
`
`15
`
`18
`
`CIPLA LTD. EXHIBIT 2037 PAGE 18
`
`

`

`
`
`25. A nasal spray
`formulation
`comprising
`
`(i) azelastine, or a
`pharmaceutically
`acceptable salt
`thereof,
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2007)
`284-287; and § IX.C.i
`below.
`
`EX1011, 6:30-41. This
`example from Cramer
`discloses a water carrier,
`the same formulation
`information from Segal
`identified by Argentum.
`
`The above exemplary
`formulation from Cramer,
`Example III, is the closest
`prior art as confirmed by
`the PTO (EX1002, 221),
`and was shown during
`prosecution and litigation
`not to be a "nasal spray"
`within the meaning of the
`claim. EX1002, 284-287; §
`IX.C.i below.
`
`See EX1011, 2:36-43.
`
`"The compositions of the
`present invention are
`formulated as aqueous
`solutions comprising an
`antiinflammatory agent and at
`least one additional
`therapeutic agent and further
`comprising a
`pharmaceutically acceptable
`nasal carrier…Preferred nasal
`formulations are nose drops
`or nasal sprays containing a
`water buffered aqueous
`solution as a carrier."
`EX1012, 5:29-4:5; see also
`id. cl.15 (depending from
`Segal claim 1 or 11).
`
`"Suitable antihistamines are
`diphenhydramine,
`chlorpheniramine, cetirizine
`terfenadine, fenofexadine,
`astemizole norastemizole,
`azelastine, and azatidine."
`EX1012, 5:19-20; see also id.
`cl.4 (depending from Segal
`claim 1).
`
`
`
`16
`
`19
`
`CIPLA LTD. EXHIBIT 2037 PAGE 19
`
`

`

`
`
`(ii) a
`pharmaceutically
`acceptable ester of
`fluticasone,
`
`Inter Partes Review of U.S. Patent No. 8,168,620
`Declaration of Hugh David Charles Smyth, Ph.D.(Exhibit 2007)
`
`EX1011, 2:36-43.
`
`"In a preferred embodiment
`the topical antiinflammatory
`agent is beclomethasone
`diproprionate, budesonide,
`dexamethasone, mometasone
`furoate, fluticasone
`propionate or triamcinolone
`acetonide." EX1012, 4:23-26;
`see also id. cl.2 (depending
`from Segal claim 1).
`
`and (iii) a
`pharmaceutically
`acceptable carrier or
`excipient therefor.
`
`"Preferred nasal formulations
`are nose drops or nasal sprays
`containing a water buffered
`aqueous solution as a carrier."
`EX1012, 6:4-5.
`
`"One other essential
`component of the present
`invention is a
`pharmaceutically-
`acceptable intranasal
`carrier. Preferred for use
`herein are aqueous saline
`solution carriers." EX1011,
`3:34-35.
`
`
`
`31.
`
`Indeed, I observed Argentum's clinical expert, Dr. Robert Schleimer,
`
`testify in the related Apotex trial that Segal's disclosure is "less specific" than
`
`Cramer's. CIP2019, 66:17-20. Further, a POSA would have also appreciated that
`
`Cramer contains exemplar formulations, including specific ingredients and
`
`concentrations, that are missing from Segal. EX1011, 6:3