`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________
`
`
`GLAXOSMITHKLINE CONSUMER HEALTHCARE HOLDINGS (US) LLC,
`Petitioner
`
`v.
`
`CIPLA LTD.,
`Patent Owner
`
`____________________
`
`Case No. 2020-00368
`U.S. Patent No. 8,163,723
`____________________
`
`DECLARATION OF MAUREEN D. DONOVAN, PH.D.
`
`
`
`

`

`IPR2020-00368 (U.S. Patent No. 8,163,723)
`Declaration of Maureen D. Donovan, Ph.D.
`
`
`B.
`
`TABLE OF CONTENTS
`
`I.
`Qualifications and Experience ..................................................................... 1
`II. Materials Considered ................................................................................... 3
`III. Relevant Legal Standards ............................................................................. 6
`IV. Priority Date of the ’723 Patent and Level of Ordinary Skill ....................... 8
`V.
`Technical Background ................................................................................10
`A. Astelin® (Azelastine Hydrochloride) Nasal Spray Formulation .........10
`Astelin® Nasal Spray in PDR 1999 (Ex. 1010) ........................10
`1.
`2.
`Hettche (Ex. 1013) ..................................................................11
`Flonase® (Fluticasone Propionate) Nasal Spray Formulation ............16
`Flonase® Nasal Spray in PDR 1999 (Ex. 1010) .......................16
`1.
`Co-Formulations Comprising Azelastine and Fluticasone .................17
`1.
`Cramer (Ex. 1011) ..................................................................17
`2.
`Segal (Ex. 1012) .....................................................................23
`D. Handbook (Ex. 1032) ........................................................................26
`VI. The Challenged Claims ...............................................................................31
`VII. The Challenged Claims Would Have Been Obvious Over PDR 1999 in view
`of Segal .......................................................................................................32
`A.
`Insufflation Powder (Dependent Claim 6) .........................................33
`B.
`Particle Size (Dependent Claim 11) ..................................................34
`C.
`Aqueous Suspension (Dependent Claims 12-14) ...............................36
`D.
`pH (Dependent Claims 22, 23) ..........................................................37
`E.
`Surfactant (Dependent Claims 15, 24) ..............................................38
`F.
`Concentration of Surfactant (Dependent Claim 16) ...........................39
`G. Glycerin (Dependent Claims 17, 25) .................................................40
`H.
`Preservative (Dependent Claims 20, 26) ...........................................41
`I.
`Thickening Agent (Dependent Claims 21, 27) ..................................43
`J.
`Buffer (Dependent Claim 19) ............................................................44
`K.
`Buffer, Preservative, Suspending Agent, Thickening Agent
`(Dependent Claim 18) .......................................................................45
`i
`
`C.
`
`
`
`

`

`L.
`
`L.
`
`IPR2020-00368 (U.S. Patent No. 8,163,723)
`Declaration of Maureen D. Donovan, Ph.D.
`
`
`Edetate Disodium, Glycerin, Thickening Agent Comprising
`Microcrystalline Cellulose and Sodium Carboxymethyl Cellulose,
`Polysorbate 80, Benzalkonium Chloride, Phenyl Ethyl Alcohol, and
`Purified Water (Dependent Claim 28) ...............................................45
`M. Reasonable Expectation of Success in Preparing the Claimed
`Formulations .....................................................................................48
`VIII. The Challenged Claims Would Have Been Obvious Over Cramer In View
`of PDR 1999 ...............................................................................................50
`A.
`Insufflation Powder (Dependent Claim 6) .........................................51
`B.
`Particle Size (Dependent Claim 11) ..................................................52
`C.
`Aqueous Suspension (Dependent Claims 12-14) ...............................53
`D.
`pH (Dependent Claims 22, 23) ..........................................................54
`E.
`Surfactant (Dependent Claims 15, 24) ..............................................55
`F.
`Concentration of Surfactant (Dependent Claim 16) ...........................57
`G. Glycerin (Dependent Claims 17, 25) .................................................58
`H.
`Preservative (Dependent Claims 20, 26) ...........................................60
`I.
`Thickening Agent (Dependent Claims 21, 27) ..................................62
`J.
`Buffer (Dependent Claim 19) ............................................................64
`K.
`Buffer, Preservative, Suspending Agent, Thickening Agent
`(Dependent Claim 18) .......................................................................66
`Edetate Disodium, Glycerin, a Thickening Agent Comprising
`Microcrystalline Cellulose and Sodium Carboxymethyl Cellulose,
`Polysorbate 80, Benzalkonium Chloride, Phenyl Ethyl Alcohol, and
`Purified Water (Dependent Claim 28) ...............................................66
`M. Reasonable Expectation of Success in Preparing the Claimed
`Formulation ......................................................................................70
`IX. Operability of Example 3 of Cramer ...........................................................72
`X.
`Conclusion ..................................................................................................75
`
`
`
`
`ii
`
`

`

`IPR2020-00368 (U.S. Patent No. 8,163,723)
`Declaration of Maureen D. Donovan, Ph.D.
`
`
`I, Maureen D. Donovan, Ph.D., do hereby declare:
`
`1.
`
`I am making this Declaration at the request of GlaxoSmithKline
`
`Consumer Healthcare Holdings (US) LLC Consumer Healthcare Holdings (US)
`
`LLC (“GSK”) in the matter of Inter Partes Review (“IPR”) of U.S. Patent
`
`No. 8,163,723 (“’723 Patent”). I understand that the ’723 Patent is owned by
`
`Cipla Ltd. (“Patent Owner”) and licensed to Mylan Pharmaceuticals, which
`
`acquired Meda Pharmaceuticals.
`
`2.
`
`I am being compensated for my work on this matter at my standard
`
`consulting rate, which is $600 per hour for time spent providing testimony, with an
`
`eight-hour minimum per day of testimony, and $400 per hour for time spent on
`
`other tasks, such as analyzing documents and drafting declarations. My
`
`compensation in no way depends on the outcome of this proceeding or the content
`
`of my testimony, and my opinions are based on my own views of the patented
`
`technology and the prior art.
`
`I.
`
`QUALIFICATIONS AND EXPERIENCE
`3. My area of expertise is in the field of pharmaceuticals and nasal
`
`formulations. At University of Iowa’s College of Pharmacy, I am presently a
`
`Professor in the Department of Pharmaceutical Sciences and Experimental
`
`Therapeutics within the Division of Pharmaceutics and Translational Therapeutics.
`
`- 1 -
`
`

`

`IPR2020-00368 (U.S. Patent No. 8,163,723)
`Declaration of Maureen D. Donovan, Ph.D.
`
`
`4. My research areas include the development and evaluation of novel
`
`drug delivery systems for mucosal drug delivery especially via the nasal,
`
`gastrointestinal and vaginal epithelia. I also study the mechanisms of drug
`
`absorption and disposition.
`
`5.
`
`I obtained a Bachelor of Science in Pharmacy from the University of
`
`Minnesota in 1983 and a Ph.D. in Pharmaceutics from the University of Michigan
`
`in 1989.
`
`6.
`
`I have previously provided expert opinions about the ’723 Patent and
`
`related U.S. Patent Nos. 8,168,620 (“’620 Patent”) and 9,259,428 (“’428 Patent”)
`
`in a patent infringement litigation. I have also previously provided expert opinions
`
`about the ’620 Patent in a prior IPR proceeding at the U.S. Patent and Trademark
`
`Office (“USPTO”). I understand that these matters are captioned and were
`
`resolved as follows: (1) Meda Pharmaceuticals, Inc. v. Apotex Inc., No. 14-cv-
`
`01453 (D. Del.) (dismissed by stipulation on May 18, 2017) (“the Apotex
`
`litigation”); and (2) Argentum Pharmaceuticals LLC v. Cipla Ltd., IPR2017-00807
`
`(PTAB) (terminated by joint motion on May 21, 2018) (“the Argentum IPR”).
`
`7. My curriculum vitae is provided as Appendix A to this Declaration.
`
`8.
`
`In view of my experiences and expertise outlined above and provided
`
`in my curriculum vitae, I am an expert in the field of pharmaceuticals and nasal
`
`formulations.
`
`- 2 -
`
`

`

`IPR2020-00368 (U.S. Patent No. 8,163,723)
`Declaration of Maureen D. Donovan, Ph.D.
`
`
`II. MATERIALS CONSIDERED
`I have considered the following documents in preparing this
`9.
`
`Declaration:
`
`Exhibit
`No.
`Ex. 1001
`Ex. 1002
`Ex. 1003
`Ex. 1004
`
`Ex. 1005
`
`Exhibit
`Exhibit
`Name
`’620 Patent U.S. Patent No. 8,168,620 (issued May 1, 2012)
`’723 Patent U.S. Patent No. 8,163,723 (issued April 24, 2012)
`’428 Patent U.S. Patent No. 9,259,428 (issued Feb. 16, 2016)
`’585 Patent U.S. Patent No. 9,901,585 (issued Feb. 27, 2018)
`Excerpts from the prosecution file wrapper of the
`’620 Patent:
`(A) Amendments and Response to Office Action
`Dated January 23, 2009 (July 23, 2009)
`(“July 2009 ’620 Amendment”) (pages 1-20);
`(B) Declaration under 37 C.F.R. § 1.132 by Geena
`Malhotra (July 3, 2009) (“July 2009 Malhotra
`Declaration”), with Exhibits A-C (pages 21-44);
`(C) Final Office Action (April 28, 2010) (“April 2010
`’620 Final Office Action”) (pages 45-65);
`(D) Amendments and Response to Final Office Action
`Dated April 28, 2010 (Sept. 24, 2010)
`(“September 2010 ’620 Amendment”) (pages 66-
`87);
`(E) Declaration under 37 C.F.R. § 1.132 by Geena
`Malhotra (Sept. 23, 2010) (“September 2010
`Malhotra Declaration”), with Exhibits A-D
`(pages 88-117);
`(F) Office Action (Feb. 16, 2011) (“February 2011
`’620 Office Action”) (pages 118-134);
`(G) Amendments and Response to Office Action
`Dated February 16, 2011 (Aug. 16, 2011)
`(“August 2011 ’620 Amendment”) (pages 135-
`164);
`(H) Declaration under 37 C.F.R. § 1.132 by Nikhil
`Chopra (Dec. 8, 2011) (“December 2011 Chopra
`Declaration”), with Exhibit A (pages 165-173);
`
`’620 File
`History
`
`- 3 -
`
`

`

`Exhibit
`No.
`
`Exhibit
`Name
`
`Ex. 1006
`
`’723 File
`History
`
`Ex. 1007
`
`’428 File
`History
`
`IPR2020-00368 (U.S. Patent No. 8,163,723)
`Declaration of Maureen D. Donovan, Ph.D.
`
`
`Exhibit
`(I) Declaration under 37 C.F.R. § 1.132 by Geena
`Malhotra (Aug. 12, 2011) (“August 2011 Malhotra
`Declaration”), with Exhibits A-C (pages 174-
`196);
`(J) Declaration under 37 C.F.R. § 1.132 by Joachim
`Maus (Aug. 16, 2011) (“August 2011 Maus
`Declaration”), with Exhibits A-H (pages 197-
`297);
`(K) Declaration under 37 C.F.R. § 1.132 by Sujeet
`Rajan (Aug. 16, 2011) (“August 2011 Rajan
`Declaration”), with Exhibit A (pages 298-318);
`(L) Notice of Allowance and Fees Due (Oct. 3, 2011)
`with Notice of Allowability (“’620 Notice of
`Allowance”) (pages 319-327)
`(M) Notice of Allowance and Fees Due (Jan. 30,
`2012) with Supplemental Notice of Allowability
`(“’620 Supplemental Notice of Allowance”)
`(pages 328-342)
`Excerpts from the prosecution file wrapper of the
`’723 Patent:
`(A) Interview Summary (Nov. 23, 2011)
`(“November 2011 ’723 Interview Summary”)
`(pages 1-3);
`(B) Preliminary Amendment (Dec. 12, 2011)
`(“December 2011 ’723 Preliminary Amendment”)
`(pages 4-14);
`(C) Notice of Allowance and Fees Due (Jan. 26, 2012)
`(“’723 Notice of Allowance”) (pages 15-23)
`Excerpts from the prosecution file wrapper of the
`’428 Patent:
`(A) Office Action (May 7, 2015) (“May 2015
`’428 Office Action”) (pages 1-8);
`(B) Interview Summary (May 7, 2015) (“May 2015
`’428 Interview Summary”) (pages 9-10);
`(C) Amendments and Response to Office Action
`Dated May 7, 2015 (Aug. 7, 2015) (“August 2015
`’428 Amendment”) (pages 11-22);
`
`- 4 -
`
`

`

`IPR2020-00368 (U.S. Patent No. 8,163,723)
`Declaration of Maureen D. Donovan, Ph.D.
`
`
`Exhibit
`No.
`
`Exhibit
`Name
`
`Ex. 1008
`
`’585 File
`History
`
`Ex. 1011
`
`Cramer
`
`Exhibit
`(D) Supplemental Response to Office Action Dated
`May 7, 2015 (Oct. 14, 2015) (“October 2015 ’428
`Supplemental Response”) (pages 23-32);
`(E) Notice of Allowance and Fees Due (Nov. 18,
`2015) (“’428 Notice of Allowance”) (pages 33-41)
`Excerpts from the prosecution file wrapper of the
`’585 Patent:
`(A) Office Action (Feb. 1, 2017) (“February 2017
`’585 Office Action”) (pages 1-9);
`(B) Response to Office Action Dated February 1, 2017
`(Aug. 1, 2017) (“August 2017 ’585 Response”)
`(pages 10-29);
`(C) Notice of Allowance and Fees Due (Oct. 31, 2017)
`(“’585 Notice of Allowance”) (pages 30-42)
`Phillipps U.S. Patent No. 4,335,121 (issued June 15, 1982)
`Ex. 1009
`“Flonase” and “Astelin,” in the Physicians’ Desk
`Ex. 1010 PDR 1999
`Reference (1999) at 1122-1124 and 3191-3192
`European Patent Application Publication No.
`EP 0,780,127 A1 (published June 25, 1997)
`International Patent Application Publication No.
`WO 98/48839 (published November 5, 1998)
`U.S. Patent No. 5,164,194 (issued Nov. 17, 1992)
`“Flonase” and “Astelin,” in the Physicians’ Desk
`Reference (2000) at 1184-1186 and 3147-3148
`Excerpts from Perrin & Dempsey, Buffers for pH and
`Ex. 1015
`Perrin
`Metal Ion Control, (1973)
`Ex. 1032 Handbook Excerpts from Kibbe, Handbook of Pharmaceutical
`Excipients (3rd ed. 2000)
`Ex. 1033 Remington Excerpts from Remington’s Pharmaceutical Sciences
`(17th ed. 1985)
`Excerpts from Ansel, et al., Pharmaceutical Dosage
`Forms and Drug Delivery Systems, ch. 7 (6th ed. 1995)
`Excerpts from British Pharmaceutical Codex (1973)
`
`Segal
`Ex. 1012
`Hettche
`Ex. 1013
`Ex. 1014 PDR 2000
`
`Ex. 1065
`Ex. 1066
`
`Ansel
`BPC
`
`
`
`
`- 5 -
`
`

`

`IPR2020-00368 (U.S. Patent No. 8,163,723)
`Declaration of Maureen D. Donovan, Ph.D.
`
`
`III. RELEVANT LEGAL STANDARDS
`10. The opinions I express in this Declaration involve the application of
`
`my technical knowledge and experience to the evaluation of certain prior art with
`
`respect to the ’723 Patent. In addition, I understand that the following legal
`
`principles apply.
`
`11.
`
`I understand that patent claims may be independent or dependent; that
`
`an independent claim includes only the limitations it recites; and that a dependent
`
`claim includes the limitations it recites, as well as the limitations recited in the
`
`claim or claims from which it depends.
`
`12.
`
`I understand that claims are given their ordinary meaning to a person
`
`having ordinary skill in the art (“POSA”) at the relevant timeframe in light of the
`
`claim language, patent specification, and prosecution history.
`
`13.
`
`I understand that a patent claim is unpatentable for obviousness if the
`
`invention described in the claim would have been obvious to a POSA at the time
`
`the invention was made, taking into account (1) the scope and content of the prior
`
`art, (2) the differences between the prior art and the claimed invention, (3) the level
`
`of ordinary skill in the art, and (4) any objective indicia of nonobviousness,
`
`including unexpected results over the closest prior art, satisfaction by the claimed
`
`invention of a long-felt but previously unmet need, industry praise, and prior art
`
`teaching away from the claimed invention.
`
`- 6 -
`
`

`

`IPR2020-00368 (U.S. Patent No. 8,163,723)
`Declaration of Maureen D. Donovan, Ph.D.
`
`
`I understand that there are multiple rationales that can be used to
`
`14.
`
`support a conclusion of obviousness. I understand, for example, that a patent claim
`
`is unpatentable for obviousness if (1) all the claim limitations are taught in the
`
`prior art, (2) a POSA would have been motivated to combine or modify the prior
`
`art to arrive at the claimed invention, and (3) a POSA would have had a reasonable
`
`expectation of success in combining or modifying the prior art to arrive at the
`
`claimed invention. I understand that the motivation to combine or modify the prior
`
`art may be found in the prior art or in the knowledge generally available to a POSA
`
`as of the priority date.
`
`15.
`
`I understand that nonobviousness of a claimed invention may be
`
`supported by certain objective indicia of nonobviousness. I understand that the
`
`Patent Owner has the burden to (1) present any alleged objective indicia of
`
`nonobviousness, such as unexpected results over the closest prior art, satisfaction
`
`by the claimed invention of a long-felt but previously unmet need, industry praise,
`
`and prior art teaching away from the claimed invention; and (2) demonstrate that
`
`such evidence supports nonobviousness of the claimed invention.
`
`- 7 -
`
`

`

`IPR2020-00368 (U.S. Patent No. 8,163,723)
`Declaration of Maureen D. Donovan, Ph.D.
`
`
`IV. PRIORITY DATE OF THE ’723 PATENT AND LEVEL OF
`ORDINARY SKILL
`I understand that I must consider the claims of the ’723 Patent and the
`16.
`
`prior art from the perspective of a POSA as of the priority date. I understand that a
`
`POSA would be aware of all the pertinent art at that time.
`
`17. According to the face of the ’723 Patent, it is related to U.S. Patent
`
`Application No. 10/518,016 (“the ’620 Patent application”), which is the national
`
`stage application of International Patent Application No. PCT/GB03/02557, filed
`
`on June 13, 2003. (’723 Patent, (60).) According to the ’723 Patent, the
`
`International Patent Application claims priority to Great Britain Patent Application
`
`No. GB 0213739.6, filed on June 14, 2002. (Id., (30); see also id., 1:4-15.)
`
`18.
`
`I understand that the prior art discussed in this Declaration is prior art
`
`regardless of whether or not the ’723 Patent is entitled to claim priority to the
`
`June 14, 2002, date. I take no position in this Declaration on whether the
`
`’723 Patent is entitled to claim priority to that date. I nonetheless refer to June 14,
`
`2002, as “the priority date.”
`
`19. Even though I am an expert, I am qualified to render opinions as to
`
`the level of ordinary skill in the art at the relevant times.
`
`20.
`
`I understand that several factors are considered in determining the
`
`level of ordinary skill in the art. These factors include (1) the types of problems
`
`- 8 -
`
`

`

`encountered in the art, (2) the prior art solutions to those problems, (3) the rapidity
`
`IPR2020-00368 (U.S. Patent No. 8,163,723)
`Declaration of Maureen D. Donovan, Ph.D.
`
`
`with which innovations are made, (4) the sophistication of the technology, and
`
`(5) the educational level of active workers in the field.
`
`21. Based on these factors as well as my experience and expertise, a
`
`POSA in the field of pharmaceutical formulations for allergy/immunology as of the
`
`priority date would have been part of a multidisciplinary team including a
`
`clinician/scientist and formulator.
`
`22.
`
`I understand that another consultant for GSK will opine on the level of
`
`skill for the clinician/scientist.
`
`23. The formulator would have had a bachelor’s degree in chemistry,
`
`biology, chemical engineering, or pharmaceutics, or in a related field in the
`
`biological or chemical sciences; at least three to five years of experience in
`
`developing nasal dosage forms; and the ability to operate independently on
`
`formulation activities. The formulator would have also had familiarity with
`
`pharmaceutical excipients and their uses. A higher level of education or specific
`
`skill might make up for less experience, and vice-versa.
`
`24. This level of skill applies to all of my obviousness analyses and
`
`opinions in this Declaration. I reserve the right to supplement this Declaration if
`
`the Patent Owner proposes, or the USPTO adopts, a different definition for a
`
`POSA.
`
`- 9 -
`
`

`

`IPR2020-00368 (U.S. Patent No. 8,163,723)
`Declaration of Maureen D. Donovan, Ph.D.
`
`
`V. TECHNICAL BACKGROUND
`25. Before the priority date of the ’723 Patent, the prior art disclosed
`
`pharmaceutical nasal formulations comprising azelastine hydrochloride and/or
`
`fluticasone propionate.
`
`26.
`
`“Propionate” is alternatively spelled with an additional “r” as
`
`“proprionate”; the two terms are merely alternative spellings and have the same
`
`meaning. Likewise, “dipropionate” is alternatively spelled as “diproprionate,” and
`
`both terms have the same meaning.
`
`A. Astelin® (Azelastine Hydrochloride) Nasal Spray Formulation
`27. Astelin® (azelastine hydrochloride) Nasal Spray was approved for
`
`allergic rhinitis well before the priority date. (PDR 1999, 3191-3192 (further
`
`information about approval may be found on the FDA website); see also
`
`’723 Patent, 1:30-34 (acknowledging that azelastine hydrochloride nasal spray was
`
`a known treatment for allergic rhinitis).) Information about Astelin® was disclosed
`
`in various publications, including the 1999 version of the Physicians’ Desk
`
`Reference (“PDR 1999”; Ex. 1010) and U.S. Patent No. 5,164,194 (“Hettche”;
`
`Ex. 1013).
`
`Astelin® Nasal Spray in PDR 1999 (Ex. 1010)
`1.
`28. Prescribing information for Astelin® Nasal Spray was published in
`
`PDR 1999, which I understand is prior art to the ’723 Patent.
`
`- 10 -
`
`

`

`IPR2020-00368 (U.S. Patent No. 8,163,723)
`Declaration of Maureen D. Donovan, Ph.D.
`
`
`29. PDR 1999 discloses that Astelin® Nasal Spray comprises azelastine
`
`hydrochloride as its active ingredient and “is indicated for the treatment of the
`
`symptoms of seasonal allergic rhinitis such as rhinorrhea, sneezing, and nasal
`
`pruritus in adults and children 12 years and older.” (PDR 1999, 3191.)
`
`30.
`
`“Astelin® Nasal Spray contains 0.1% azelastine hydrochloride in an
`
`aqueous solution at pH 6.8 ± 0.3.” (PDR 1999, 3191.) “It also contains
`
`benzalkonium chloride (125 μg/mL), edetate disodium, hydroxypropyl methyl
`
`cellulose, citric acid, dibasic sodium phosphate, sodium chloride, and purified
`
`water.” (Id.) A POSA would have known that these ingredients may be referred to
`
`as “excipients.”
`
`2. Hettche (Ex. 1013)
`31. The Astelin® Nasal Spray formulation and other pharmaceutical
`
`formulations comprising azelastine hydrochloride were disclosed in Hettche.
`
`Hettche issued as a U.S. patent on November 17, 1992 (Hettche, [45]), and I
`
`understand it is prior art to the ’723 Patent.
`
`32. Hettche discloses “[a] medicament for nasal use or for use in the eye
`
`which contains as active ingredient azelastine or a physiologically acceptable salt.”
`
`(Hettche, [57].)
`
`33. Hettche discloses that “[t]he preferred embodiment of the invention is
`
`a sterile and stable aqueous solution of azelastine or one or more of its salts which
`
`- 11 -
`
`

`

`IPR2020-00368 (U.S. Patent No. 8,163,723)
`Declaration of Maureen D. Donovan, Ph.D.
`
`can be used in the form of drops, ointments, creams, gels, insufflatable powders or,
`
`in a particularly preferred embodiment, in the form of a spray (preferably a nasal
`
`spray).” (Hettche, 2:12-17.)
`
`34. Hettche discloses that “[w]hen suspensions are used, the maximum
`
`particle size of the solid substances (azelastine + auxiliary substances) should not
`
`exceed 30 μm.” (Hettche, 5:48-50.) For insufflatable powder, “the maximum
`
`particle size of the substances should not be greater than 20 μm.” (Id., 5:51-53.)
`
`35. Hettche discloses that “[s]olvents which may preferably be used for
`
`the formulations of the invention” include “water.” (Hettche, 2:35-40.) “The
`
`solvent used is preferably water or mixtures of water with other physiologically
`
`acceptable solvents….” (Id., 2:41-43.)
`
`36. Hettche discloses that its compositions “preferably contain
`
`preservatives and stabilizers,” such as “ethylene diamine tetra-acetic acid (edetic
`
`acid) and their alkali salts (for example dialkali salts such as disodium salt, calcium
`
`salt, calcium-sodium salt), lower alkyl p-hydroxybenzoates, chlorohexidine…,
`
`phenyl mercury borate.” (Hettche, 2:46-53.) Ethylene diamine tetra-acetic acid
`
`may also be referred to as edetic acid or EDTA; these terms are synonymous.
`
`“Each of these compounds may be used in a concentration of 0.002 to 0.05, for
`
`example 0.02% (weight/volume in liquid formulations, otherwise weight/weight).”
`
`(Id., 2:65-68.) “The total amounts of preservatives in the formulations…is
`
`- 12 -
`
`

`

`between 0.001 to 0.10, preferably 0.01 g per 100 ml of solution/suspension or
`
`IPR2020-00368 (U.S. Patent No. 8,163,723)
`Declaration of Maureen D. Donovan, Ph.D.
`
`
`100 g of formulation.” (Id., 3:56-60.)
`
`37. Hettche discloses that “[p]referred preservatives among the quaternary
`
`ammonium compounds are…alkylbenzyl dimethyl ammonium chloride and
`
`mixtures thereof, for example the compounds generally known as ‘benzalkonium
`
`chloride.’” (Hettche, 2:68-3:4.) “‘Benzalkonium chloride’…can be used in
`
`concentrations of 0.005 to 0.10, preferably 0.005 to 0.05, for example 0.01%
`
`(weight/volume in liquid formulations, otherwise weight/weight) and they may
`
`optionally be used in combination with 0.2 to 2.0, for example 0.4%
`
`(weight/volume) of 2-phenylethanol.” (Id., 3:19-25.)
`
`38. Hettche discloses that “[t]he preservative is preferably a combination
`
`of edetic acid (for example as the disodium salt) and benzalkonium chloride.”
`
`(Hettche, 4:4-6.) “In this combination, the edetic acid is used in a concentration of
`
`0.05 to 0.1%, benzalkonium chloride being used in a concentration of 0.005 to
`
`0.05%, preferably 0.01%.” (Id., 4:6-9; see also id., 4:10-13 (indicating that percent
`
`values are weight/volume for solutions/suspensions and weight/weight for solid or
`
`semi-solid formulations).)
`
`39. Hettche discloses that “[f]urther auxiliary substances which may, for
`
`example, be used for the formulations of the invention are: polyvinyl pyrrolidone,
`
`sorbitan fatty acid esters such as sorbitan trioleate, polyethoxylated sorbitan fatty
`
`- 13 -
`
`

`

`acid esters (for example polyethoxylated sorbitan trioleate), sorbimacrogol oleate,
`
`IPR2020-00368 (U.S. Patent No. 8,163,723)
`Declaration of Maureen D. Donovan, Ph.D.
`
`
`synthetic amphotensides (tritons), ethylene oxide ethers of
`
`octylphenolformaldehyde condensation products, phosphatides such as lecithin,
`
`polyethoxylated fats, polyethoxylated oleotriglycerides, polyethoxylated fatty
`
`alcohols.” (Hettche, 4:14-24; see also id., 4:24-28 (“In this context,
`
`polyethoxylated means that the relevant substances contain polyoxyethylene
`
`chains, the degree of polymerization of which is generally between 2 to 40, in
`
`particular between 10 to 20.”).) “These substances are preferably used to improve
`
`the solubility of the azelastine components.” (Id., 4:28-30.)
`
`40. Hettche discloses that “[i]n the case of dosage forms containing water,
`
`it is optionally possible to use additional isotonization agents,” such as
`
`“saccharose, glucose, glycerine, sorbitol, 1,2-propylene glycol, NaCl.” (Hettche,
`
`4:31-35.) “Isotonization agents” may be referred to as “tonicity-adjusting agents.”
`
`These agents “adjust the osmotic pressure of the formulations to the same osmotic
`
`pressure as nasal secretion.” (Id., 4:36-38.) “For this purpose these substances are
`
`in each case to be used in an amount that, for example, in the case of a solution, a
`
`reduction in the freezing point of 0.50º to 0.56ºC. is attained in comparison to pure
`
`water.” (Id., 4:38-42.) “In Example 1, for instance, such substances would be
`
`used in such an amount which is iso-osmotic with 68 g of sodium chloride
`
`(0.68%).” (Id., 4:42-44.) “In Example 1, it is possible to use instead of NaCl per
`
`- 14 -
`
`

`

`100 ml of solution, for example…glycerine 2.2 g.” (Id., 4:45-50.) “Glycerine”
`
`IPR2020-00368 (U.S. Patent No. 8,163,723)
`Declaration of Maureen D. Donovan, Ph.D.
`
`
`may also be written as “glycerin”; the two are synonymous.
`
`41. Hettche discloses that “it is possible to add thickening agents to the
`
`solutions to prevent the solution from flowing out of the nose too quickly and to
`
`give the solution a viscosity of about 1.5 to 3, preferably 2 mPa.s.” (Hettche, 4:51-
`
`54.) “Such thickening agents may, for example, be: cellulose derivatives (for
`
`example cellulose ether) in which the cellulose-hydroxy groups are partially
`
`etherified with lower unsaturated aliphatic alcohols and/or lower unsaturated
`
`aliphatic oxyalcohols (for example methyl cellulose, carboxymethyl cellulose,
`
`hydroxypropylmethylcellulose), gelatin, polyvinylpyrrolidone, tragacanth,
`
`ethoxose (water soluble binding and thickening agents on the basis of ethyl
`
`cellulose), alginic acid, polyvinyl alcohol, polyacrylic acid, pectin and equivalent
`
`agents.” (Id., 4:54-64.) “Should these substances contain acid groups, the
`
`corresponding physiologically acceptable salts may also be used.” (Id., 4:64-66.)
`
`“In the event of the use of hydroxypropyl cellulose, 0.1 % by weight are, for
`
`example, used for this purpose.” (Id., 4:67-68.)
`
`42. Hettche discloses that “[i]t is also possible to add to the formulations
`
`buffer substances such as citric acid / sodium hydrogensulphate borate buffer,
`
`phosphates (sodium hydrogenorthophosphate, disodium hydrogenphosphate),
`
`- 15 -
`
`

`

`tromethamol or equivalent conventional buffers in order, for example, to adjust the
`
`IPR2020-00368 (U.S. Patent No. 8,163,723)
`Declaration of Maureen D. Donovan, Ph.D.
`
`
`formulation to a pH value of 6 to 7.5, preferably 6.5 to 7.1.” (Id., 5:1-7.)
`
`43. Hettche’s Example 1 discloses “[n]asal spray or nasal drops or eye
`
`drops with 0.1% azelastine hydrochloride as [the] active ingredient.” (Hettche,
`
`6:6-9.) The formulation comprises water, edetic acid disodium salt, sodium
`
`chloride, benzalkonium chloride, citric acid, sodium monohydrogen-phosphate,
`
`and hydroxypropyl methyl cellulose. (Id., 6:10-18.)
`
`Flonase® (Fluticasone Propionate) Nasal Spray Formulation
`B.
`44. Flonase® (fluticasone propionate) Nasal Spray was approved for
`
`allergic rhinitis well before the priority date. (PDR 1999, 1122-1124 (further
`
`information about approval may be found on the FDA website); see also
`
`’723 Patent, 1:26-30 (acknowledging that fluticasone for nasal use was a known
`
`treatment for allergic rhinitis). Information about Flonase® was disclosed in
`
`various publications, including PDR 1999.
`
`Flonase® Nasal Spray in PDR 1999 (Ex. 1010)
`1.
`45. Prescribing information for Flonase® Nasal Spray was published in
`
`PDR 1999, which I understand is prior art to the ’723 Patent.
`
`46. PDR 1999 discloses that Flonase® Nasal Spray comprises 0.05%
`
`(w/w) fluticasone propionate as its active ingredient and “is indicated for the
`
`- 16 -
`
`

`

`management of the nasal symptoms of seasonal and perennial allergic rhinitis in
`
`IPR2020-00368 (U.S. Patent No. 8,163,723)
`Declaration of Maureen D. Donovan, Ph.D.
`
`
`adults and pediatric patients 4 years of age and older.” (PDR 1999, 1122.)
`
`47.
`
`“Flonase® Nasal Spray 50 mcg is an aqueous suspension of microfine
`
`fluticasone propionate,” and “also contains microcrystalline cellulose and
`
`carboxymethylcellulose sodium, dextrose, 0.02% w/w benzalkonium chloride,
`
`polysorbate 80, and 0.25% w/w phenylethyl alcohol.” (PDR 1999, 1122.) It “has
`
`a pH between 5 and 7.” (Id.) A POSA would have known that these ingredients
`
`may be referred to as “excipients.”
`
`C. Co-Formulations Comprising Azelastine and Fluticasone
`48. Pharmaceutical nasal formulations comprising both azelastine and
`
`fluticasone were disclosed in the prior art, including in European Patent
`
`Application Publication No. 0,780,127 A1 (“Cramer”; Ex. 1011) and International
`
`Patent Application Publication No. WO 98/48839 (“Segal”; Ex. 1012).
`
`Cramer (Ex. 1011)
`1.
`49. Pharmaceutical formulations for nasal administration comprising
`
`azelastine hydrochloride and fluticasone propionate were disclosed in Cramer.
`
`Cramer was published on June 25, 1997 (Cramer, (43)), and I understand it is prior
`
`art to the ’723 Patent.
`
`50. Cramer discloses “pharmaceutical compositions for nasal
`
`administration comprising: a) a safe and effective amount of a glucocorticoid
`
`- 17 -
`
`

`

`selected from the group consisting of beclomethasone, flunisolide, triamcinolone,
`
`IPR2020-00368 (U.S. Patent No. 8,163,723)
`Declaration of Maureen D. Donovan, Ph.D.
`
`
`fluticasone, mometasone, budesonide, pharmaceutically acceptable salts thereof
`
`and mixtures thereof; b) a safe and effective amount of a leukotriene inhibiting
`
`antihistamine selected from the group consisting of cetirizine, loratadine,
`
`azelastine, pharmaceutically acceptable salts thereof, optically active racemates
`
`thereof and mixtures thereof; and c) an intranasal carrier.” (Cramer, 2:36-44; see
`
`also id., 1:5-6 (“The present invention relates to novel nasal spray compositions
`
`comprising a safe and effective amount of a glucocorticosteroid and an
`
`antihistamine.”).)
`
`51. Cramer discloses that its compositions may be “prepared by
`
`combining the…component