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`Patent No. 8,791,154
`Petition For Inter Partes Review
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`APOTEX INC. and APOTEX CORP.
`Petitioner
`v.
`
`ALCON RESEARCH, LTD
`Patent Owner
`
`
`Patent No. 8,791,154
`Issue Date: July 29, 2014
`Title: HIGH CONCENTRATION OLOPATADINE
`OPHTHALMIC COMPOSITION
`_______________
`
`Inter Partes Review No. IPR2016-01640
`
`
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 7,791,154
`UNDER 35 U.S.C. §§ 311-319 AND 37 C.F.R. § 42.100 ET SEQ.
`
`
`
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`Ayla Pharma LLC (IPR2020-00295) Ex. 1016 p. 001
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`

`

`Patent No. 8,791,154
`Petition For Inter Partes Review
`TABLE OF CONTENTS
`
`NOTICE OF LEAD AND BACKUP COUNSEL .......................................... 1 
`I. 
`II.  NOTICE OF SERVICE INFORMATION ...................................................... 1 
`III.  NOTICE OF EACH REAL-PARTY-IN-INTEREST ..................................... 1 
`IV.  NOTICE OF RELATED MATTERS ............................................................. 1 
`V.  GROUNDS FOR STANDING ........................................................................ 2 
`VI.  STATEMENT OF PRECISE RELIEF REQUESTED ................................... 2 
`VII.  THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW ............... 2 
`VIII.  STATEMENT OF REASONS FOR RELIEF REQUESTED ........................ 3 
`A. 
`Technical Introduction .......................................................................... 3 
`1. Background ........................................................................................... 3 
`2. Alcon’s Olopatadine Evergreening Strategy ......................................... 5 
`The ’154 Patent ................................................................................... 10 
`Level of Ordinary Skill in the Art ....................................................... 11 
`Claim Construction Under 37 C.F.R. § 42.104(b)(3) ......................... 13 
`1. Claims 1, 4, 8, and 21 -- Preamble ...................................................... 14 
`2. Claims 1, 4, 8, and 21 -- Construction of “solution comprising … at
`least 0.67 w/v % olopatadine … dissolved in the solution” ............... 15 
`3. Claims 1, 4, 8, 21, and 22 -- Construction of “w/v %” ....................... 16 
`None of the Claims Are Entitled to the Priority Date of Provisional
`Application 61/487,789 ............................................................. 16 
`Claim-By-Claim Explanation of Grounds for Unpatentability ........... 18 
`1. Ground 1: Claims 1-4, 8, 12, 13, 21, and 22 are unpatentable under
`35 U.S.C. § 103(a) over Bhowmick, Yanni, and Castillo ................... 18 
`a.  Claims 1-3 ..................................................................................... 22 
`b.  Claims 4, 8, 21, and 22 ................................................................. 28 
`c.  Claims 12 and 13 .......................................................................... 32 
`
`B. 
`C. 
`D. 
`
`E. 
`
`F. 
`
`i
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`Patent No. 8,791,154
`Petition For Inter Partes Review
`
`d.  Claim Chart ................................................................................... 33 
`2. Ground 2: Claims 1-4, 8, 12, 13, 21, and 22 are unpatentable under
`35 U.S.C. § 103(a) over Schneider in view of Hayakawa, Bhowmick,
`and Castillo .......................................................................................... 41 
`a.  Claims 1-4, 8, 21, and 22 .............................................................. 45 
`b.  Claims 12 and 13 .......................................................................... 49 
`c.  Claim chart .................................................................................... 50 
`G.  Absence of Secondary Considerations ................................................ 57 
`IX.  CONCLUSION .............................................................................................. 59 
`
`
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`
`
`ii
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`Ayla Pharma LLC (IPR2020-00295) Ex. 1016 p. 003
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`Patent No. 8,791,154
`Petition For Inter Partes Review
`
`TABLE OF EXHIBITS
`
`Exhibit
`Ex #
`1001 U.S. Patent No. 8,791,154 B2 (“’154 Patent”)
`1002 Declaration of Dr. Erning Xia
`1003 Declaration of Dr. Leonard Bielory
`1004 WO 2008/015695 A2 (“Bhowmick”)
`1005 YANNI et al., “The In Vitro and In Vivo Ocular Pharmacology of
`Olopatadine (AL-4943A), an Effective Anti-Allergic/Antihistaminic
`Agent,” Journal of Ocular Pharmacology and Therapeutics, Volume 12,
`Number 4, 1996, pp. 389-400 (“Yanni”)
`1006 U.S. Pat. No. 6,995,186 B2 (“Castillo”)
`1007 U.S. Pat. Pub. No. 2011/0082145 A1 (“Schneider”)
`1008 U.S. Pat. No. 5,641,805 B2(“Hayakawa”)
`1009
`Image File Wrapper for U.S. Patent No. 8,791,154 B2
`1010
`Image File Wrapper for U.S. Provisional Appl. No. 61/487,789
`1011
`Image File Wrapper for U.S. Provisional Appl. No. 61/548,957
`1012 WO 1999/018963 (“Lisi”)
`1013 WO 2002/024116 A1 (“Shahinian”)
`LOFTSSON et al., “Cyclodextrins in eye drop formulations: enhanced
`1014
`topical delivery of corticosteroids to the eye,” Acta Ophthamologica
`Scandinavica, 2002, pp. 144-150.
`1015 NANDI et al., “Synergistic Effect of PEG-400 and Cyclodextrin to
`Enhance Solubility of Progesterone,” AAPS PharmSciTech 2003; 4 (1),
`pp 1-5.
`1016 WO 2011/138801 A1 (“Khopade”)
`JANSOOK et al., “CDs as solubilizers: Effects of excipients and
`1017
`competing drugs,” International Journal of Pharmaceutics, 379, 2009,
`pp. 32-40.
`1018 HARADA, A., “Preparation and structures of supramolecules between
`cyclodextrins and polymers,” Coordination Chemistry Reviews, 148,
`1996, pp. 115-133.
`
`iii
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`Ayla Pharma LLC (IPR2020-00295) Ex. 1016 p. 004
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`Patent No. 8,791,154
`Petition For Inter Partes Review
`
`1019 WO 2012/159064A1 (“Gamache”)
`1020
`EP 0 799 044 B1 (“Yanni III”)
`1021 WO 2001/054687 A1 (“Yanni II”)
`1022 WO 2009/003199 A1 (“Pipkin”)
`1023 WO 2000/78396 A2 (“Graff”)
`1024 Curriculum Vitae for Dr. Erning Xia
`1025 Curriculum Vitae for Dr. Leonard Bielory
`1026 U.S. Pat. No. 7,687,646 B2 (“Bader”)
`1027 U.S. Pat. No. 4,871,865 (“Lever”)
`1028 U.S. Pat. No. 5,116,863 (“Oshima”)
`1029
`EP 0214779 B1 (“Lever”)
`1030 Alcon Research, Ltd. v. Apotex Inc., 687 F.3d 1362 (Fed. Cir. 2012)
`1031 Alcon Research, Ltd. v. Apotex Inc., 790 F. Supp. 2d 868 (S.D. Ind.
`2011)
`1032
`EP 0 235 796 B2 (“Oshima”)
`1033 ABELSON et al., “Combined Analysis of Two Studies Using the
`Conjunctival Allergen Challenge Model to Evaluate Olopatadine
`Hydrochloride, a New Ophthalmic Antiallergic Agent With Dual
`Activity,” American Journal of Ophthalmology, Volume 126, No. 6, pp.
`797-804.
`1034 WO 2004/024126 A1 (“Thompson”)
`1035 CHAUDHARI et al., “Solubility enhancement of hydrophobic drugs
`using synergistically interacting cyclodextrins and cosolvent,” Current
`Science, 1586 Vol. 92, No. 11, 10 June 2007; pp. 1586-1591.
`1036 ANSEL, Howard C., Pharmaceutical Calculations, 13th Ed., Wolters
`Kluwer, 2010, pp. 82-83
`1037
`PATANOL® Label
`1038
`PATADAY® Label
`1039
`PATANASE® Label
`1040 GENNARO, Alfonso R., Remington: The Science and Practice of
`
`iv
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`Ayla Pharma LLC (IPR2020-00295) Ex. 1016 p. 005
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`Patent No. 8,791,154
`Petition For Inter Partes Review
`
`1044
`
`1042
`
`Pharmacy, Philadelphia College of Pharmacy and Science, 1995, Vol.
`1., pp. 613-627
`1041 GENNARO, Alfonso R., Remington: The Science and Practice of
`Pharmacy, Philadelphia College of Pharmacy and Science, 1995, Vol.
`2., pp. 1563-1576
`LIDE, David R., CRC Handbook of Chemistry and Physics, CRC Press,
`2006, pp. 6-4 – 6-5.
`1043 ABELSON and ANDERSON, “Demystifying Dumulcents,” Review of
`Ophthalmology, November 2006, pp. 122-125.
`LOFTSSON, et al., “The effect of water-soluble polymers on the
`aqueous solubility and complexing abilities of β-cyclodextrin,”
`International Journal of Pharmaceutics, 1998, Vol. 163, pp. 15-21
`1045 U.S. Patent Publication US 2009/0156568 A1 (“Hughes”)
`1046 U.S. Pat. No. 5,985,310 (“Castillo III”)
`1047 U.S. Pat. No. 7,977,376 B2 (“Singh I”)
`1048 U.S. Pat. No. 8,399,508 B2 (“Singh II”)
`1049 U.S. Pat. No. 7,402,609 B2 (“Castillo II”)
`1050 WADE, et al., “Ophthalmic antihistamines and H1–H4 receptors,”
`Current Opinion in Allergy and Clinical Immunology, 2012, Vol. 12,
`No. 5, pp. 510–516
`1051 CHOI, et al., “Late-phase reaction in ocular allergy,” Current Opinion in
`Allergy and Clinical Immunology, 2008, Vol 8, pp. 438–444.
`1052 U.S. Pat. Pub. 2004/0198828 (“Abelson 2004”)
`LEONARDI, et al., “Double-masked, randomized, placebo-controlled
`1053
`clinical study of the mast cell-stabilizing effects of treatment with
`olopatadine in the conjunctival allergen challenge model in humans,”
`Clin Ther 2003; 25, pp. 2539–2552.
`PROUD, et al., “Inflammatory mediator release on conjunctival
`provocation of allergic subjects with allergent provocation of allergic
`subjects with allergen,” Mediator generation in ocular allergy, 1989,
`Vol. 85. No. 5, pp. 896-905
`SHARIF, et al., “Characterization of the Ocular Antiallergic and
`Antihistaminic Effects of Olopatadine (AL-4943A), a Novel Drug for
`
`1054
`
`1055
`
`v
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`Ayla Pharma LLC (IPR2020-00295) Ex. 1016 p. 006
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`Patent No. 8,791,154
`Petition For Inter Partes Review
`
`
`
`1056
`
`1057
`1058
`
`Treating Ocular Allergic Diseases,” The Journal OF Pharmacology and
`Experimental Therapeutics, 1996, Vol. 278, No. 3, pp. 1252-1261
`LOFTSSON, et al., “Pharmaceutical Applications of Cyclodextrins. 1.
`Drug Solubilization and Stabilization,” Journal of Pharmaceutical
`Sciences, October 1996, Vol. 85, No. 10, pp. 1017-1025
`21 C.F.R. §349.12
`Polyvinylpyrrolidone K 30,
`http://www4.mpbio.com/ecom/docs/proddata.nsf/(webtds2)/102787
`SWEI, et al., “Viscosity Correlation for Aqueous Polyvinylpyrrolidone
`(PVP) Solutions,” Journal of Applied Polymer Science, 2003, Vol. 90,
`pp. 1153-1155
`1060
`68 Fed. Reg. 106, 32981-32983
`1061 U.S. Pat. No. 6,316,483 B1 (“Haslwanter”)
`1062 U.S. Pat. Pub. No. 2010/0010082 A1 (“Chong”)
`1063 U.S. Pat. Pub. No. 2009/0136598 (“Chapin”)
`
`1059
`
`vi
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`Ayla Pharma LLC (IPR2020-00295) Ex. 1016 p. 007
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`

`Patent No. 8,791,154
`Petition For Inter Partes Review
`NOTICE OF LEAD AND BACKUP COUNSEL
`
`I.
`
`Lead Counsel
`
`Back-Up Counsel
`
`Teresa Stanek Rea (Reg. No. 30,427)
`CROWELL & MORING LLP
`Intellectual Property Group
`1001 Pennsylvania Avenue, N.W.
`Washington, DC 20004-2595
`Telephone No.: (202) 624-2620
`Facsimile No.: (202) 628-5116
`TRea@Crowell.com
`
`Deborah H. Yellin (Reg. No. 45,904)
`CROWELL & MORING LLP
`Intellectual Property Group
`1001 Pennsylvania Avenue, N.W.
`Washington, DC 20004-2595
`Telephone No.: (202) 624-2947
`Facsimile No.: (202) 628-5116
`DYellin@Crowell.com
`
`Vincent J. Galluzzo (Reg. No. 67,830)
`CROWELL & MORING LLP
`Intellectual Property Group
`1001 Pennsylvania Avenue, N.W.
`Washington, DC 20004-2595
`Telephone No.: (202) 624-2781
`Facsimile No.: (202) 628-5116
`VGalluzzo@Crowell.com
`II. NOTICE OF SERVICE INFORMATION
`Please direct all correspondence regarding this Petition to lead counsel at the
`
`above address. Petitioners consent to service by email at: TRea@Crowell.com,
`
`DYellin@Crowell.com, and VGalluzzo@Crowell.com.
`
`III. NOTICE OF EACH REAL-PARTY-IN-INTEREST
`Petitioners Apotex Inc. and Apotex Corp. are the real parties-in-interest.
`
`IV. NOTICE OF RELATED MATTERS
`U.S. Patent No. 8,791,154 (“the ’154 Patent”) is the subject of the following
`
`litigations: Alcon Research, Ltd. v. Watson Labs., 1-15-cv-01159 (D. Del.), filed
`
`
`
`1
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`December 16, 2015; and Alcon Research, Ltd. v. Lupin Ltd. et al, 1-16-cv-00195
`
`Patent No. 8,791,154
`Petition For Inter Partes Review
`
`(D. Del.), filed March 28, 2016. U.S. Patent Appl. No. 14/304,124, is currently
`
`pending and claims priority to the ’154 Patent.
`
`V. GROUNDS FOR STANDING
`Petitioners hereby certify that the patent for which review is sought is available
`
`for inter partes review, and that the Petitioners are not barred or estopped from
`
`requesting an inter partes review challenging the patent claims on the Grounds
`
`identified in the petition.
`
`VI. STATEMENT OF PRECISE RELIEF REQUESTED
`Petitioners respectfully request that claims 1-4, 8, 12, 13, 21, and 22 of U.S.
`
`Patent No. 8,791,154 (Ex. 1001) be canceled.
`
`VII. THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW
`A petition for inter partes review must demonstrate “a reasonable likelihood
`
`that the petitioners would prevail with respect to at least 1 of the claims challenged
`
`in the petition.” 35 U.S.C. § 314(a). The Petition meets this threshold. Each of
`
`the elements of claims 1-4, 8, 12, 13, 21, and 22 of the ’154 patent are taught in the
`
`prior art as explained below in the proposed Grounds of unpatentability under 35
`
`U.S.C. § 103(a). Also provided are motivations to combine those elements and an
`
`explanation of why a POSA would have had a reasonable expectation of success in
`
`achieving the benefits of the claimed compositions.
`
`
`
`2
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`Patent No. 8,791,154
`Petition For Inter Partes Review
`
`
`VIII. STATEMENT OF REASONS FOR RELIEF REQUESTED
`A. Technical Introduction
`The following technical introduction is supported by the Declaration of Dr.
`
`Erning Xia (“Xia Decl.”), Ex. 1002 ¶¶ 22-51, and the Declaration of Dr. Leonard
`
`Bielory (“Bielory Decl.”), Ex. 1003 ¶¶ 24-45, and as indicated.
`
`1.
`Well before the filing date of the ’154 patent, topical ophthalmic compositions
`
`Background
`
`comprising aqueous solutions of the drug olopatadine were known to be useful for
`
`treating allergic eye diseases such as allergic conjunctivitis. Ex. 1002 ¶¶ 22-24.
`
`Olopatadine was understood to have antihistamine activity, as well as human
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`conjunctival mast cell stabilizer activity. Ex. 1003 ¶ 29. Depending on
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`olopatadine concentration, administration can be as infrequently as once or twice
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`daily. Id.
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`It was also understood that, unlike some other antihistamine or mast cell
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`stabilizer anti-allergy drugs, olopatadine did not exhibit a “biphasic effect,” in
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`which a drug can actually provoke histamine release at higher concentrations as
`
`compared to lower concentration where antihistaminic activity is observed. Ex.
`
`1003 ¶57. The duration of olopatadine’s anti-allergic activity was known to be
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`dose dependent, with higher concentrations providing more prolonged effects. Id.
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`
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`3
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`To provide long-term, shelf-stable solutions of olopatadine, especially those
`
`Patent No. 8,791,154
`Petition For Inter Partes Review
`
`
`
`having olopatadine concentrations above 0.18 w/v% or so, solubilizing excipients
`
`have been widely used for years in olopatadine formulations, including in
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`ophthalmic applications. See Ex. 1002, ¶¶ 25-50. Polyvinylpyrrolidone (PVP) has
`
`long been known to increase olopatadine solubility in aqueous solutions as well as
`
`increase the physical stability of such solutions. Id. ¶ 32. Complexes of
`
`olopatadine with cyclodextrins, such as hydroxypropyl-β-cyclodextrin,
`
`hydroxypropyl--cyclodextrin, and sulfobutyl ether-β-cyclodextrin, have also been
`
`used to solubilize higher concentrations of olopatadine in aqueous solution and
`
`prevent precipitation or crystallization. Id. ¶¶ 38-40. Combinations of
`
`hydroxypropyl methylcellulose and cyclodextrin derivatives further enhance
`
`olopatadine solubility and the solution stability. Id. 34. Utilizing cyclodextrins
`
`provided other desirable benefits, such as increasing the effectiveness of drug
`
`delivery to the conjunctiva of the eye. Id. ¶ 82; Ex. 1014 at 149. Polyethylene
`
`glycols have also been long used to enhance olopatadine solublility and as
`
`viscosity enhancers with cyclodextrins. Ex. 1002 ¶¶ 27-28, 41-43.
`
`In the U.S., olopatadine-containing compositions have been commercially
`
`available under the brand names PATANOL® and PATADAY® as 0.1 % and 0.2%
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`sterile ophthalmic solutions (respectively), both marketed by Alcon. Id. ¶ 24.
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`PATANOL® is indicated for the treatment of signs and symptoms of allergic
`
`
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`4
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`conjunctivitis and PATADAY® for the treatment of ocular itching associated with
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`Patent No. 8,791,154
`Petition For Inter Partes Review
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`eye allergy. Id. According to its labeling information, each mL of PATANOL®
`
`contains olopatadine hydrochloride (equivalent to 0.1% olopatadine), 0.01%
`
`benzalkonium chloride (BAC), and unspecified amounts of sodium chloride,
`
`dibasic sodium phosphate, hydrochloric acid and/or sodium hydroxide (to adjust
`
`pH) and purified water. Id. Each mL of PATADAY® solution contains
`
`olopatadine hydrochloride (equivalent to 0.2% olopatadine), inactives such as
`
`0.01% benzalkonium chloride, and unspecified amounts of polyvinylpyrrolidinone
`
`(aka povidone), dibasic sodium phosphate, sodium chloride, edentate disodium,
`
`hydrochloric acid/sodium hydroxide (to adjust pH) and purified water. Id..
`
`Alcon’s Olopatadine Evergreening Strategy
`
`2.
`Alcon has long attempted to control the market for olopatadine-containing
`
`compositions by obtaining new patents that cover trivial changes to the
`
`formulation, strength, and delivery system of the original olopatadine drug. The
`
`chart below illustrates Alcon’s Orange Book listed patents that utilize olopatadine.
`
`
`
`5
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`
`Patent No. 8,791,154
`Petition For Inter Partes Review
`
`Alcon’s Olopatadine Products
`
`Product
`Trade
`Name
`
`Olopatadine
`(free base)
`Conc.
`
`Orange
`Book
`Patents
`
`Publication
`or Issue
`Date
`
`Patent Expiry
`(according to
`Orange Book)
`
`PATANOL
`
`PATADAY
`
`0.1%
`
`0.2%
`
`PATANASE
`
`0.6%
`(spray)
`
`5,641,805
`
`6/24/1997
`
`12/06/2015
`
`6,995,186
`
`3/20/2003
`
`5/12/2024
`
`7,402,609
`
`7/21/2005
`
`12/19/2022
`
`7,977,376
`
`6/21/2007
`
`8,399,508
`
`12/15/2011
`
`8/02/2023
`
`3/17/2023
`
`0.7%
`
`8,791,154
`
`11/22/2012
`
`5/19/2032
`
`PAZEO
`
`
`Hayakawa: The first Alcon patent directed to olapatadine compositions is
`
`U.S. Patent No. 5,641,805 (Ex.1008; “Hayakawa”) covering PATANOL®, which
`
`published on June 24, 1997 and was assigned to Alcon Laboratories, Inc. and
`
`Kyowa Hakko Kogyo Co., Ltd. Hayakawa discloses and claims preparation of eye
`
`drops including olopatadine (i.e., “Compound A”) concentrations of up to about 5
`
`w/v%. Id. at 6:30-44, Claims 2, 6. As discussed by Dr. Bielory and Dr. Xia in
`
`more detail in their declarations, Hayakawa indicates that formulations containing
`
`up to 5 wt% olopatadine are useful for treatment of allergic conjunctivitis. Ex.
`
`1002 ¶ 72; Ex. 1003 ¶29. Across the claimed olopatadine concentration range of
`
`0.0001 to 5 w/v%, Hayakawa recommends the use of standard ophthalmic
`
`excipients such as glycerin, boric acid and polyvinylpyrrolidone among others, and
`
`
`
`6
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`does not mention any solubility or stability issues at such concentrations. Ex. 1008
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`Patent No. 8,791,154
`Petition For Inter Partes Review
`
`at 6:50-58, Claims 2, 6; Ex 1002 ¶¶ 72.
`
`Hayakawa also discloses that olopatadine has both antihistamine activity, as
`
`well as human conjunctival mast cell stabilizing activity that allows it to be
`
`administered as infrequently as once or twice a day. Ex. 1008 at 3:18-23, Table 1;
`
`Ex. 1003 ¶ 29. The effects of olopatadine on histamine release from human
`
`conjunctival tissue mast cells upon anti-human IgE challenge were predictive of
`
`the in vivo effect of 0.1 %w/v olopatadine on passive conjunctival anaphylaxis in
`
`rats. Ex. 1008 at 5:57-6:29. The rat assay indicated that topically applied
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`olopatadine effectively reduced local allergic response by 86% over control. Ex.
`
`1003 ¶ 29.
`
`When Alcon tried to enforce the Hayakawa patent, the Federal Circuit found
`
`all claims that were not limited to about 0.1 w/v% olopatadine to be invalid as
`
`obvious. Alcon Research, Ltd. v. Apotex, Inc., 687 F.3d 1362, 1366-70 (Fed. Cir.
`
`2012). In its opinion, the Court found that the therapeutically effective amount of
`
`olopatadine recited by claim 1 encompassed the range of 0.0001–5 w/v%, as
`
`recited in dependent claims 2 and 6. Id. at 1367-68. Because the prior art
`
`disclosed olopatadine compositions overlapping with this range, claims having
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`therapeutically effective amounts other than specifically about 0.1% were held
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`obvious. Id. at 1368.
`
`
`
`7
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`

`Yanni II: Alcon continued to pursue patents directed to olopatadine-
`
`Patent No. 8,791,154
`Petition For Inter Partes Review
`
`
`
`containing solutions. WO 01/54687 (Ex. 1021, “Yanni II”; assigned to Alcon
`
`Universal Ltd.) was published August 2, 2001 and purports to claim an
`
`olopatadine-containing composition “suitable for use by patients wearing contact
`
`lenses.” Ex. 1021 at 1:1-7, Claim 1. Yanni II also discloses using olopatadine up
`
`to 5 w/v% in the topically administrable compositions. Id. at 1:17-19; Claim 2.
`
`Like Hayakawa, Yanni II does not disclose any solubility or stability issues at any
`
`concentration of olopatadine, and recommends the use of standard ophthalmic
`
`components such as boric acid, hydroxypropylmethylcellulose,
`
`polyvinylpyrrolidone, mannitol, and many others. Id. at 4:30-5:24.
`
`Castillo I and II: U.S. Pat. No. 6,995,186 (Ex. 1006, “Castillo”), which is
`
`listed as covering PATADAY®, issued February 7, 2006, to Alcon, Inc., and
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`discloses topical solutions for treating allergic or inflammatory disorders of the eye
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`that include approximately 0.2-0.6% olopatadine and an amount of PVP or
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`polystyrene sulfonic acid sufficient to “enhance” the stability of the solutions. Ex.
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`1006 at 2:13-22, 3:42-46. Such solutions are taught to be effective as once-a-day
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`products. Id. Castillo teaches that tonicity agents (e.g. mannitol) and buffering
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`agents (e.g. borates) may be included in the solutions. Id. at 3:57–4:8.
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`PATADAY and the Castillo patent differ little from PATANOL and the
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`Hayakawa patent. The primary difference is that PATADAY contains 0.2%
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`olopatadine rather than PATANOL’s 0.1% (Ex. 1003 ¶31), and Castillo reports
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`Patent No. 8,791,154
`Petition For Inter Partes Review
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`using solubilizing agents such as PVP to achieve clear solutions free of precipitates
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`even at the highest tested olopatadine hydrochloride concentrations of 0.665%.
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`Ex. 1006 at 2:64-65, Tables 12-13; Ex. 1002 ¶¶ 32, 56. Castillo’s experiments also
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`show that inclusion of PEG 400 can help promote olopatadine stability/solubility.
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`Ex. 1006 at Tables 5-6 (compare formulations R and S); Ex. 1002 ¶¶ 28-29.
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`U.S. Patent No. 7,402,609 (Ex. 1049, “Castillo II”) is a continuation of
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`Castillo and contains the same disclosure.
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`Singh I and II: U.S. Pat. No. 7,977,376 (Ex. 1047, “Singh I”) is a
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`continuation-in-part of Castillo II. U.S. Pat. No 8,399,508 (Ex. 1048, “Singh II”)
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`is a continuation from both Singh I and Castillo II. Both cover PATANASE®, a
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`nasal formulation of olopatadine. Ex. 1003 ¶40. The new disclosure over Castillo
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`II teaches nasal compositions with approximately 0.6% olopatadine that do not rely
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`on a polymeric ingredient, such as polyvinylpyrrolidone, as a “physical stability
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`enhancing agent.” Ex. 1047 at 2:15-22; 5:11-19. Instead, the nasal compositions
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`use a phosphate salt to maintain a pH of 3.5-3.95 which aids in solubilizing
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`olopatadine in the presence of sodium chloride. Id. at 2:22-25. Thus, the
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`differences between PATANASE and PATADAY are the concentration of
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`olopatadine (0.6 w/v% versus 0.2 w/v%) and the use of low pH to solubilize
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`olopatadine rather than a polymeric agent, such as polyvinylpyrrolidone.
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`Patent No. 8,791,154
`Petition For Inter Partes Review
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`The ’154 Patent
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`B.
`The ’154 Patent (which is listed in the Orange Book as covering Alcon’s
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`PAZEO® product, containing 0.7 w/v% olopatadine) discloses ophthalmic
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`compositions for treatment of allergic conjunctivitis that purportedly includes a
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`“relatively high” concentration of olopatadine solubilized in aqueous solution. Ex.
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`1001 at 3:23-28; see Ex. 1002 ¶¶ 16-21; Ex. 1003 ¶¶ 17-23. “Relatively high”
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`olopatadine concentrations are described as at least 0.50 w/v% to no greater than
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`1.5 w/v% olopatadine. Id. at 3:48-53. The ophthalmic compositions are purported
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`to include a “unique set of excipients” for solubilizing olopatadine while
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`maintaining comfort “and/or” efficacy such as symptoms associated with late
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`phase allergic conjunctivitis. Id. at 3:28-35. The aqueous ophthalmic solutions
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`claimed by the ’154 Patent include one of three cyclodextrin derivatives:
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`hydroxypropyl-β-cyclodextrin (“HP-β-CD”), hydroxypropyl--cyclodextrin (“HP-
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`-CD”), or a sulfoalkyl ether-β-cyclodextrin (“SAE- β-CD”). Id. at 4:45-52. The
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`’154 Patent describes sulfobutyl ether-β-cyclodextrin (“SBE- β-CD”) as a
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`particular SAE- β-CD. Id., 4:51-52. The claimed solutions further include
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`polyvinylpyrrolidone (“PVP”) as well as polyethylene glycol (“PEG”) with a
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`molecular weight of 300 to 500, where a PEG with a molecular weight of 400
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`(“PEG 400”) is preferred. Id. at 6:8-40. Consistent with Castillo, PVP and PEG
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`are each purported to aid in solubilizing olopatadine. Id. at 5:65-67; 6:22-24. The
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`’154 Patent further teaches that the solutions may include hydroxypropylmethyl-
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`Patent No. 8,791,154
`Petition For Inter Partes Review
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`cellulose (“HPMC”) to aid in solubilizing olopatadine. Id. at 6:48-50; 7:34-37.
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`The ophthalmic compositions of the ’154 Patent are purported to
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`“surprisingly” show significant reduction in late phase symptoms and early phase
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`redness, to “surprisingly” solubilize the relatively high olopatadine concentration
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`and be stable for extended periods of time, and to still exhibit efficacy despite
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`inclusion of cyclodextrins such as HP--CD. Id. at 11:17-50.
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`However, as shown herein, the claimed ophthalmic compositions of the ’154
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`Patent and methods for using them would have been obvious to a person of
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`ordinary skill in the art and do not provide any unexpected results or advantages.
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`C. Level of Ordinary Skill in the Art
`A person of ordinary skill in the art (“POSA”) at the time of filing of the
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`’154 Patent typically would have had: (i) an M.D., Pharm. D. or Ph.D. in
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`chemistry, biochemistry, pharmaceutics, or in a related field in the biological or
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`chemical sciences, and have at least about two years of experience in treatment of
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`ocular diseases and developing formulations used to treat ocular diseases,
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`including topical eye pharmaceuticals; (ii) a Master’s degree in chemistry,
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`biochemistry, pharmaceutics, or in a related field in the biological or chemical
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`sciences, and have at least about five years of experience in treatment of ocular
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`diseases and developing formulations used to treat ocular diseases, including
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`topical eye pharmaceuticals; or (iii) a bachelor’s degree in pharmacy, chemistry,
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`Patent No. 8,791,154
`Petition For Inter Partes Review
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`biochemistry or in a related field in the biological or chemical sciences, and have at
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`least about ten years of experience in treatment of ocular diseases and developing
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`formulations for treating ocular diseases, including topical eye pharmaceuticals.
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`Ex. 1002 ¶¶ 12-13; Ex. 1003 ¶¶ 12-13. The descriptions are approximate, and a
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`higher level of education or specific skill may make up for less experience, and
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`vice-versa.
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`As evidenced by the art in this field (see In re GPAC Inc., 57 F.3d 1573,
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`1579 (Fed. Cir. 1995) (noting that the level of ordinary skill can be evidenced by
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`the prior art references themselves)), the POSA here would have an understanding
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`of the basis of ocular allergy including knowledge of the structure and constitution
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`of conjunctiva of the eye, IgE antigen stimulated histamine release, cell-based and
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`animal models and assays for assessing effectiveness of ophthalmic treatments, and
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`knowledge of ophthalmic formulation excipients. Furthermore, the ’154 Patent
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`and much of the prior art discussed herein involves the development of ophthalmic
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`pharmaceutical compositions to treat ocular allergic conjunctivitis. Ex. 1001 at
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`2:41-42. Thus, the POSA will also have experience in developing ophthalmic
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`pharmaceutical formulations for the treatment of ocular allergic conjunctivitis. Ex.
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`1002 ¶ 14; Ex. 1003 ¶14; cf. Daiichi Sankyo Co., Ltd. v. Apotex, Inc., 501 F.3d
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`1254, 1257 (Fed. Cir. 2007).
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`Lastly, a POSA typically would work as part of a multidisciplinary team and
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`Patent No. 8,791,154
`Petition For Inter Partes Review
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`
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`draw upon not only his or her own skills, but also take advantage of certain
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`specialized skills of others in the team to solve a given problem. Ex. 1002 ¶ 15;
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`Ex. 1003 ¶15. For example, a clinician having experience in treating allergic
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`disorders of the eye with topical pharmaceuticals would be part of the team. Id. A
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`formulations chemist with knowledge of a wide array of excipients suitable for use
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`in ophthalmic formulations and their properties would also be part of the team. Id.
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`The hypothetical POSA will be aware of such specialized knowledge as applicable
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`to various aspects of the claimed invention. E.g., AVX Corp. v. Greatbatch, Ltd.,
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`IPR2014-00697, Paper 60 at 3 (PTAB Jan. 11, 2016).
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`D. Claim Construction Under 37 C.F.R. § 42.104(b)(3)
`Claim terms in inter partes review are given their “broadest reasonable
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`construction in light of the specification.” 37 C.F.R. § 42.100(b). Any claim term
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`that lacks a definition in the specification is therefore given a broad interpretation.
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`For the purposes of this proceeding, claim terms are presumed to take on their
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`plain and ordinary meaning in view of the specification. Petitioners’ discussion
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`herein relies on the plain and ordinary meaning of the claim terms to a POSA in
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`light of the specification at the time of the filing of the ’154 Patent, and therefore
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`Petitioners’ analysis falls well within the standard set by 37 C.F.R. § 42.100(b),
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`and is consistent with Phillips v. AWH Corp., 415 F.3d 1303, 1313-14 (Fed. Cir.
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`Patent No. 8,791,154
`Petition For Inter Partes Review
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`2005)(en banc).
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`Solely for purposes of this proceeding, the following discussion proposes
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`constructions of certain claim terms. Any claim terms not included below are to be
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`interpreted in accordance with their plain and ordinary meaning in light of the
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`specification, as understood by one of ordinary skill in the art.
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`Claims 1, 4, 8, and 21 -- Preamble
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`1.
`The preambles of claims 1, 4, 8 and 21 each recite “An aqueous ophthalmic
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`solution for treatment of ocular allergic conjunctivitis, the solution comprising ….”
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`The bodies of the claims (including the dependent claims) go on to define the
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`compositional limitations of the solutions claimed, without any reference back to
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`the preamble description. The ’154 Patent nowhere teaches that the recited
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`“intended use” imparts any structural differences to the claimed solutions, beyond
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`the express compositional limitations in the claims.
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`Where, as here, the claim body fully sets forth all the limitations of the
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`claimed invention, and the preamble merely states the purpose or intended use of
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`the invention, rather than any distinct definition of any of the claimed invention’s
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`limitations, the preamble is non-limiting. Pitney Bowes, Inc. v. Hewlett-Packard
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`Co., 182 F.3d 1298, 1305 (Fed. Cir. 1999); see also Rowe v. Dror, 112 F.3d 473,
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`478 (Fed. Cir. 1997) (“[W]here a patentee defines a structurally complete invention
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`in the claim body and uses the preamble only to state a purpose or intended use for
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`Patent No. 8,791,154
`Petition For Inter Partes Review
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`the invention, the preamble is not a claim limitation”). In addition, neither the
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`Patent Owner nor the Examiner relied on the preamble during prosecution to
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`distinguish the claimed invention from the prior art (see Ex. 1009 at 56-65, 94-108,
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`126-143), which likewise confirms the preamble’s non-limiting nature. Catalina
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`Mktg. Int’l v. Coolsavings.com