`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`ARGENTUM PHARMACEUTICALS LLC
`Petitioner
`
`v.
`
`ALCON RESEARCH, LTD.
`Patent Owner
`
`
`Patent No. 8,268,299
`Issue Date: September 18, 2012
`Title: SELF PRESERVED AQUEOUS PHARMACEUTICAL COMPOSITIONS
`
`
`
`Inter Partes Review No. IPR2017-01053
`
`
`
`PETITION FOR INTER PARTES REVIEW
`UNDER 35 U.S.C. §§ 311-319 AND 37 C.F.R. § 42.100 ET SEQ.
`
`
`
`
`
`
`
`
`
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`

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`Patent No. 8,268,299
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`
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`
`
` Petition for Inter Partes Review
`
`TABLE OF CONTENTS
`
`
`
`
`
`
`I.  MANDATORY NOTICES (37 C.F.R. § 42.8) ......................................................... 1 
`A. 
`REAL PARTIES-IN-INTEREST UNDER 37 C.F.R. § 42.8(B)(1) ............. 1 
`B. 
`RELATED MATTERS UNDER 37 C.F.R. § 42.8(B)(2) ............................. 1 
`C. 
`LEAD AND BACKUP COUNSEL .............................................................. 2 
`D. 
`SERVICE INFORMATION .......................................................................... 2 
`II.  GROUNDS FOR STANDING ............................................................................... 2 
`III.  IDENTIFICATION OF CHALLENGE ................................................................ 2 
`IV.  THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW ................... 3 
`V.  SUMMARY OF ARGUMENTS ............................................................................ 3 
`VI.  CLAIM CONSTRUCTION ................................................................................... 4 
`VII.  PERSON OF SKILL IN THE ART ..................................................................... 7 
`VIII.  CLAIM-BY-CLAIM EXPLANATION OF GROUNDS FOR
`UNPATENTABILITY ........................................................................................ 8 
`A.  GROUND 1: CLAIMS 1, 2, 4-8, 16, 17 AND 20 WOULD HAVE BEEN
`OBVIOUS OVER XIA IN VIEW OF SCHNEIDER AND CHOWHAN .... 8 
`GROUND 2: CLAIM 28 WOULD HAVE BEEN OBVIOUS OVER XIA,
`SCHNEIDER, THE TRAVATAN LABEL AND CHOWHAN ................... 28 
`GROUND 3: CLAIMS 1-23 AND 25-26 WOULD HAVE BEEN
`OBVIOUS OVER XIA, SCHNEIDER, CHOWHAN AND GADD ............ 33 
`D.  GROUND 4: CLAIMS 24 AND 27-28 WOULD HAVE BEEN OBVIOUS
`OVER XIA, SCHNEIDER, THE TL, CHOWHAN AND GADD ............... 51 
`IX.  NO SECONDARY CONSIDERATIONS OF NONOBVIOUSNESS ............... 58 
`X.  CONCLUSION ..................................................................................................... 64 
`
`B. 
`
`C. 
`
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`-i-
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`Patent No. 8,268,299
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` Petition for Inter Partes Review
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`In re Aller,
`220 F.2d 454 (CCPA 1955) .................................................................................. 9, 28
`
`Allergan, Inc. v. Apotex Inc.,
`754 F.3d 952 (Fed. Cir. 2014) ............................................................................ 61, 64
`
`Amneal Pharms. v. Supernus Pharms.,
`IPR2013-00368 (PTAB Dec. 17, 2013) ................................................................... 59
`
`Application of Antonie, 559 F.2d 618 (CCPA 1977) ..................................................... 19
`
`Apotex Corp. v. Alcon Research, Ltd.,
`IPR2013-00428 ........................................................................................................... 1
`
`Apotex Corp. v. Alcon Research, Ltd.,
`IPR2013-00428, Paper 9, 5-6 ................................................................................. 5, 6
`
`In re Applied Materials, Inc.,
`692 F.3d 1289 (Fed. Cir. 2012) ................................................................................ 19
`
`Ex parte Jellá,
`90 USPQ2d 1009 (BPAI 2008) ................................................................................ 63
`
`King Pharms., Inc. v. Eon Labs., Inc.,
`616 F.3d 1267 (Fed. Cir. 2010) ................................................................................ 63
`
`Leapfrog Enterprises Inc. v. Fisher-Price Inc.,
`485 F.3d 1157 (Fed. Cir. 2007) ................................................................................ 60
`
`Media Techs. Licensing, LLC v. Upper Deck Co.,
`596 F.3d 1334 (Fed. Cir. 2010) ................................................................................ 65
`
`Orthopedic Equipment Co., Inc. v. All Orthopedic Appliances, Inc.,
`707 F.2d 1376 (Fed. Cir. 1983) ................................................................................ 61
`
`
`-ii-
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`Patent No. 8,268,299
`
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) ................................................................ 9, 19, 25, 28
`
` Petition for Inter Partes Review
`
`
`
`Prometheus Labs., Inc. v. Roxane Labs., Inc.,
`805 F.3d 1092 (Fed. Cir. 2015) ................................................................................ 64
`
`Santarus, Inc. v. Par Pharm., Inc.,
`694 F.3d 1344 (Fed. Cir. 2012) .......................................................................... 22, 23
`
`In re Susi,
`440 F.2d 442 (CCPA 1971) ...................................................................................... 21
`
`Torrent Pharms. V. Novartis AG,
`IPR2014-00784, Paper 12 (PTAB Sept. 24, 2015) ................................................... 63
`
`Statutes
`
`21 U.S.C. § 352(b) ......................................................................................................... 29
`
`35 U.S.C. § 102(a) and (e) ............................................................................................... 8
`
`35 U.S.C. §102(b) ................................................................................................ 8, 29, 34
`
`35 U.S.C. §§ 311-319 .................................................................................................... 67
`
`35 U.S.C. § 314(a) ........................................................................................................... 3
`
`Other Authorities
`
`37 C.F.R. §§ 42.1-.80, 42.100-.123 ............................................................................... 67
`
`37 C.F.R. § 42.8 ............................................................................................................... 1
`
`37 C.F.R. § 42.8(b)(1) ...................................................................................................... 1
`
`37 C.F.R. § 42.8(b)(2) ...................................................................................................... 1
`
`37 C.F.R. § 42.100(b) ...................................................................................................... 4
`
`37 C.F.R. § 42.104(a) ....................................................................................................... 2
`
`37 C.F.R. § 42.104(b) ...................................................................................................... 2
`
`37 CFR § 42.15(a) ............................................................................................................ 1
`
`-iii-
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`Patent No. 8,268,299
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`37 CFR § 42.6(a)(2)(ii) .................................................................................................. 66
`
` Petition for Inter Partes Review
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`
`
`37 CFR § 42.6(a)(2)(iii) ................................................................................................. 66
`
`37 CFR § 42.10(b) ........................................................................................................... 1
`
`37 CFR § 42.24(a)(1)(i) ................................................................................................. 66
`
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`-iv-
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`Patent No. 8,268,299
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` Petition for Inter Partes Review
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`TABLE OF EXHIBITS
`
`Description
`
`Exhibit
`#
`1001 Kabra et al., U.S. Patent No. 8,268,299, “Self Preserved
`Aqueous Pharmaceutical Compositions” (filed September 20,
`2007; issued September 18, 2012)
`1002 Declaration of Dr. Erning Xia
`
`1004
`
`1003 Xia et al., WO 2005/097067, “Zinc Preservative Composition and
`Method of Use” (filed March 24, 2005; published October 20,
`Chowhan et al., U.S. Patent No. 6,143,799, “Use of Borate-Polyol
`Complexes in Ophthalmic Compositions” (filed July 2, 1998;
`issued November 7, 2000)
`1005 Gadd et al., “Microorganisms and Heavy Metal Toxicity,”
`Microbial Ecology, 4:303-317 (1978)
`FDA Approved Drug Label “TRAVATAN® (travoprost
`ophthalmic solution) 0.004% Sterile” (2001)
`Schneider et al., U.S. Patent No. 6,011, 062, “Storage-Stable
`Prostaglandin Compositions” (Filed February 9, 1999; issued January
`4, 2000)
`File history of U.S. Patent No. 8,268,299
`Joint Claim Construction Statement dated 7/18/2014 in
`Alcon Research, Ltd. v. Mylan Pharmaceuticals, Inc. C.A.
`No. 1:13-cv-01332-SLR
`File history of U.S. Patent No. 8,323,630
`File history of U.S. Patent No. 8,388,941
`Sheftel, “Indirect Food Additives and Polymers: Migration
`and Toxicology,” p. 422 (2000)
`The European Agency for the Evaluation of Medicinal Products,
`Veterinary Medicines Evaluation Unit, “Polyoxyl Castor Oil,
`Polyoxyl Hydrogenated Castor Oil Summary Report” (1999)
`“Antimicrobial Effectiveness Testing,” in The United States
`Pharmacopeia 27: The National Formulary 22, pp. 2148-2150
`Curriculum Vitae of Erning Xia, Ph.D.
`
`1006
`
`1007
`
`1008
`1009
`
`1010
`1011
`1012
`
`1013
`
`1014
`
`1015
`
`
`-v-
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`

`Patent No. 8,268,299
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`
`
`
` Petition for Inter Partes Review
`
`Description
`
`Exhibit
`#
`1016
`
`1017
`
`1018
`
`FORM 6-K, SECURITIES AND EXCHANGE COMMISSION, For
`the month of May 2002, ALCON, INC.
`The Merck Index, An Encyclopedia of Chemicals, Drugs, and
`Biologicals, 13th Ed., (2001), Merck Research Laboratories, 5767,
`8797, 9842.
`Reserved
`
`1019 Kabara and Orth “Chapter 1, Principles for Product Preservation”,
`Preservative-Free and Self-Preserving Cosmetics and Drugs,
`Principles and Practice, (1997) Marcel Dekker, New York.
`Patent Owner Alcon Research, Ltd.’s Response, IPR2013-00428,
`Paper 30.
`
`1020
`
`1021 Declaration of Dr. Yvonne Buys.
`
`1022 Declaration of Dr. Richard P. Parrish, Ex. 2020, IPR2013-00428.
`
`1023 Curriculum Vitae of Dr. Yvonne Buys, M.D.
`
`1024 Kass et al., The Ocular Hypertension Treatment Study: A Randomized
`Trial Determines that Topical Ocular Hypotensive Medication Delays
`or Prevents the Onset of Primary Open-Angle Glaucoma, Clinical
`1025 Mizoue et al., Travoprost with sofZia® preservative system lowered
`intraocular pressure of Japanese normal tension glaucoma with
`minimal side effects, CLIN. OPHTH. 347-354 (2014).
`1026 Bagnis et al., Antiglaucoma drugs: The role of preservative-free
`formulations, Saudi J. of Ophth. 389-394 (2011).
`
`1027 Save big on your TRAVATAN Z® Solution prescription, June 24,
`2008,
`http://web.archive.org/web/20080624220702/http://www.travatanz.com
`
`
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`Description
`
`Exhibit
`#
`1028 Save big on your TRAVATAN Z® Solution prescription, April 1,
`2009,
`http://web.archive.org/web/20090401152511/http://www.travatanz.com
`1029 Save up to $20 on your next four prescriptions with this card, March
`27, 2010,
`http://web.archive.org/web/20100327064125/http://www.travatanz.com
`1030 Pay no more than $25 for each 30-day supply of TRAVATAN Z®
`Solution through December 2011, May 6, 2011,
`http://web.archive.org/web/20110506025033/http://www.travatanz.com
`1031 Pay no more than $25 for each 30-day supply of TRAVATAN Z®
`Solution through March 2013, February 10, 2012,
`http://web.archive.org/web/20120210013546/http://www.travatanz.com
`1032 Save up to $1,300 on your Alcon Medication Refills, Pay as little as
`$25 for each 30-day supply of prescribed eyedrops from Alcon through
`December 2013, June 29, 2013,
`1033 OPENINGS™ Patient Support Program, March 29, 2014,
`http://web.archive.org/web/20140329091929/http://www.myglaucomas
`upport.com/openings-patient-support-program.shtml?
`1034 Openings® Patient Support Program from Alcon, October 31, 2015,
`http://web.archive.org/web/20151031211128/http://www.myglaucomas
`upport.com/get-support.shtml
`1035 OPENINGS® Patient Support Program, March 12, 2016,
`http://web.archive.org/web/20160312083239/http://www.myglaucomas
`upport.com/get-support.shtml?
`1036 OPENINGS® Savings Card, February 22, 2017,
`https://www.myglaucomasupport.com/openings-program-savings-
`card.shtml
`1037 Declaration of Dr. Henry Grabowski, Ex. 2007, IPR2013-00428.
`
`
`
`
`-vii-
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`Patent No. 8,268,299
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`
`
`
`Petition for Inter Partes Review
`
`Argentum Pharmaceuticals, LLC (“Petitioner”) petitions for Inter Partes
`
`Review (IPR), seeking cancellation of claims 1-28 (“challenged claims”) of
`
`U.S. Patent No. 8,268,299 to Kabra et al. (“the ’299 patent”; Ex. 1001),
`
`which is owned by Alcon Research, Ltd. Concurrently filed herewith is a Power
`
`of Attorney pursuant to 37 CFR §42.10(b). The required fee set forth in 37 CFR
`
`§42.15(a) has been paid on-line. The Office is authorized to charge any additional
`
`fees required or credit any overpayments to Deposit Account No. 19-0741.
`
`I. MANDATORY NOTICES (37 C.F.R. § 42.8)
`
`A. Real Parties-In-Interest under 37 C.F.R. § 42.8(b)(1)
`
`Argentum Pharmaceuticals LLC; Intelligent Pharma Research LLC; APS
`
`GP LLC; APS GP Investors LLC; and KVK-TECH, Inc.
`
`B. Related Matters under 37 C.F.R. § 42.8(b)(2)
`
`The ’299 patent has been the subject of the following proceedings: Alcon
`
`Research Ltd. v. Mylan Pharmacuticals, Inc., 1:13-cv-01332; Alcon Research Ltd.
`
`v.Wockhardt Ltd., 1:13-cv-02040; Alcon Research Ltd. v. Micro Labs Ltd., 1:14-
`
`cv-00014; Alcon Research Ltd. v. Watson Laboratories, Inc., 1:14-cv-00647;
`
`Alcon Research Ltd. v. Akorn, Inc., 1:15-cv-00479; Alcon Research Ltd. v. Lupin
`
`Ltd., 1:15-cv-00621; Apotex Corp. v. Alcon Research, Ltd., IPR2013-00428,
`
`settled 7/21/2014 (Paper 60). Petitioner was not a party to any of these cases.
`
`
`-1-
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`

`

`Patent No. 8,268,299
`
`
`
`
`Petition for Inter Partes Review
`
`C.
`
`Lead and Backup Counsel
`
`Lead Counsel
`Michael R. Houston, Ph.D.
`Reg. No. 58,486
`Foley & Lardner LLP
`
`
`
`Backup Counsel
`Joseph P. Meara, Ph.D.
`Reg. No. 44,932
`James P. McParland, Ph.D.
`Reg. No. 69,440
`Foley & Lardner LLP
`
`Backup Counsel
`Tyler C. Liu
`Reg. No. 72,126
`Argentum
`Pharmaceuticals LLC
`
`D.
`
`Service Information
`
`Foley & Lardner LLP, 3000 K St. NW, Suite 600, Washington, DC.
`
`20008. Petitioner consents to service by email at: ARG-travatanZ@foley.com.
`
`II. GROUNDS FOR STANDING
`
`Petitioner certifies under 37 C.F.R. §42.104(a) that the ’299 patent is
`
`available for IPR and that Petitioner is not barred or estopped from requesting an
`
`IPR challenging the claims on the grounds identified in this petition.
`
`III.
`
`IDENTIFICATION OF CHALLENGE
`
`Per 37 C.F.R. §42.104(b) Petitioner requests cancellation of claims 1-28 of
`
`the ’299 patent on the following grounds (pre-AIA):
`
`Ground
`
`References
`
`Claims
`
`1. Obviousness Xia in view of Schneider and Chowhan 1, 2, 4-8, 16, 17, 20
`
`2. Obviousness Xia in view of Schneider, the
`Travatan® Label, and Chowhan
`
`28
`
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`-2-
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`Patent No. 8,268,299
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`Petition for Inter Partes Review
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`3. Obviousness Xia in view of Schneider, Chowhan,
`and Gadd
`4. Obviousness Xia in view of Schneider, the
`Travatan® Label, Chowhan, and Gadd
`
`1-23, 25-26
`
`24 and 27-28
`
`In support of the proposed grounds, this Petition is accompanied by the
`
`declarations of Dr. Erning Xia (Ex. 1002) and Dr. Yvonne Buys (Ex. 1021).
`
`IV. THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW
`
`A Petitioner for inter partes review must demonstrate “a reasonable
`
`likelihood that the petitioner would prevail with respect to at least 1 of the claims
`
`challenged in the petition.” 35 U.S.C. §314(a). This Petition meets that threshold.
`
`For each of the grounds of unpatentability proposed below, there is a reasonable
`
`likelihood that Petitioner will prevail with respect to at least one of the challenged
`
`claims. Indeed, the Board has previously instituted trial against the ’299 patent on
`
`some of the very same art in IPR2013-00428, and should do so again here.
`
`V.
`
`SUMMARY OF ARGUMENTS
`
`The ophthalmic compositions recited in the claims of the ’299 patent are
`
`simply an obvious repackaging of well-known components from prior art
`
`ophthalmic compositions in an attempt to evergreen a patent family. The uses and
`
`properties of the components claimed in the ’299 patent were recognized as of the
`
`earliest possible priority date of the patent. Alcon obtained the ’299 patent by
`
`drafting claims that purport to be complicated – reciting specific ranges of
`
`
`-3-
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`Patent No. 8,268,299
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`Petition for Inter Partes Review
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`concentrations for ingredients, and alleged properties of the claimed composition.
`
`But the claims of the ’299 patent recite subject matter that was both simple and
`
`obvious as of the filing date of the ’299 patent. All of the ranges of
`
`concentrations and properties recited in the claims were known in the prior art.
`
`The ’299 patent purports to be founded on the alleged discovery that ions
`
`interfere with the antimicrobial activity of zinc. But this phenomenon was known
`
`for at least 30 years before the earliest possible priority date of the patent. The
`
`claims also recite that the claimed ophthalmic compositions satisfy standardized
`
`pharmacopeia tests. But these tests were satisfied by compositions having the
`
`claimed components well before the filing date of the ’299 patent.
`
`In sum, the claims of the ’299 patent recite ophthalmic compositions
`
`containing known components used for their known functions and having entirely
`
`expected properties. Further, a person of ordinary skill in the art (“POSA”) would
`
`have had a reasonable expectation of success in preparing the claimed
`
`compositions using known techniques. As Petitioner is reasonably likely to prevail
`
`in showing obviousness over the prior art, inter partes review of the ’299 patent
`
`should be instituted.
`
`VI. CLAIM CONSTRUCTION
`
`Under 37 C.F.R. § 42.100(b), the challenged claims must be given their
`
`broadest reasonable interpretations (“BRI”) in light of the patent specification as
`
`
`-4-
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`Patent No. 8,268,299
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`
`
`Petition for Inter Partes Review
`
`understood by a POSA. The Board has previously construed the following claim
`
`terms exactly as presented here and should do so again. See Apotex Corp. v. Alcon
`
`Research, Ltd., IPR2013-00428, Paper 9, 5-6.
`
`The BRI of the claim term “zinc ions at a concentration of” encompasses
`
`the concentration of zinc salts used to prepare the claimed composition. As
`
`shown in the specification of the ’299 patent, the concentration of zinc ions in
`
`the claimed compositions is equal to the concentration of zinc salt added to
`
`form the composition. See Ex. 1001, 4:41-53. Complete dissociation of zinc
`
`salts into zinc ions is presumed in aqueous compositions at relevant salt
`
`concentrations because zinc salts are highly soluble in water. Ex. 1002 ¶¶22-23.
`
`Claims 24 and 28 recite concentrations of “zinc chloride ionized,” and
`
`claim 27 recites a concentration of “ionized zinc chloride.” These terms are not
`
`used in the specification of the ’299 patent and were not explicitly defined
`
`during prosecution of the ’299 patent. As zinc chloride is not ionized in
`
`ophthalmic compositions, the BRI for “zinc chloride ionized” and “ionized
`
`zinc chloride” encompasses the concentration of zinc chloride added. Ex. 1002
`
`¶24.
`
`The BRI of the claim term “polyol,” as used in the ’299 patent, encompasses
`
`“any compound having at least one hydroxyl group on each of two adjacent carbon
`
`atoms that are not in trans configuration relative to each other.” Ex. 1001, 6:19-
`
`
`-5-
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`

`Patent No. 8,268,299
`
`
`28; Ex. 1002 ¶¶25-26.
`
`
`
`Petition for Inter Partes Review
`
`Based on disclosure in the ’299 patent specification Ex. 1001, 3:27-29), a
`
`POSA would have understood that “self-preserved ophthalmic composition” as
`
`used in the claims of the ’299 patent refers to ophthalmic compositions that do not
`
`contain a conventional antimicrobial preservative, such as benzalkonium chloride
`
`(“BAC”), polyquaternium-1, chlorite, or hydrogen peroxide. Ex. 1002, ¶27. This
`
`meaning is identical to the Board’s previous claim construction of this term.
`
`Apotex, IPR2013-00428, Paper 9, 6.
`
`The specification of the ’299 patent does not define the term “anionic
`
`species.” However, based on the use of the term in the ’299 patent, a POSA
`
`would have understood that "anionic species" refers to negatively charged ions.
`
`Generally, in aqueous solutions, ions are the result of dissolution of ionic
`
`compounds, such as salts. Thus, the BRI of “anionic species” encompasses any
`
`element or molecule that is negatively charged in solution. Ex. 1002 ¶¶28, 31.
`
`The specification of the ’299 patent states that “‘substantially free of
`
`multivalent buffering anions’ means that the composition either does not contain
`
`any multivalent buffering anions or contains an amount of said anions that does not
`
`inhibit the ability of the composition to satisfy specified preservative efficacy
`
`standards (e.g., USP, EP or JP).” Ex. 1001, 5:22-27. Therefore, the BRI for the
`
`claim term "does not contain" multivalent buffering anions or metal cations
`
`
`-6-
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`Patent No. 8,268,299
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`
`Petition for Inter Partes Review
`
`other than zinc encompasses a composition containing multivalent buffering
`
`anions or metal cations other than zinc, so long as the composition also meets
`
`specified preservative efficacy standards. Ex. 1002 ¶¶29-30.
`
`All other terms of all challenged claims are presumed to take on their
`
`ordinary and customary meanings.
`
`VII. PERSON OF SKILL IN THE ART
`
`A POSA is presumed to be aware of all pertinent art and is a person of
`
`ordinary creativity. As of 2006, such a POSA would have had knowledge of the
`
`scientific literature concerning antimicrobial preservation, strategies for inhibiting
`
`microbial growth and the development of ophthalmic formulations, including
`
`knowledge of a wide array of excipients suitable for use in ophthalmic
`
`formulations and their properties. A POSA as of 2006 would typically have (i) a
`
`Ph.D. in microbiology or chemistry (or a related field) with at least a few years
`
`of experience in the development of ophthalmic formulations, or (ii) a BS or MS
`
`in microbiology or chemistry (or a related field) with significant practical
`
`experience (5 or more years) in the development of ophthalmic formulations. A
`
`POSA may work as part of a multi-disciplinary team and draw upon not only his
`
`or her own skills, but also take advantage of certain specialized skills of others
`
`in the team, to solve a given problem. For example, a microbiologist, a
`
`chemist and a physician may be part of the team. Ex. 1002 ¶¶15-17.
`
`
`-7-
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`

`Patent No. 8,268,299
`
`
`
`
`Petition for Inter Partes Review
`
`As evidenced by the references described herein, at least as of September 21,
`
`2006, the earliest possible priority date (“EPPD”) of the ’299 patent, the
`
`subject matter claimed in claims 1-28 was well known to a POSA.
`
`VIII. CLAIM-BY-CLAIM EXPLANATION OF GROUNDS FOR
`UNPATENTABILITY
`
`Claims 1-28 are unpatentable as shown in the detailed grounds for
`
`unpatentability below.
`
`A. Ground 1: Claims 1, 2, 4-8, 16, 17 and 20 Would Have Been
`Obvious Over Xia in view of Schneider and Chowhan
`
`
`Claims 1, 2, 4-8, 16, 17 and 20 would have been obvious over the
`
`combination of Xia, Schneider, and Chowhan. WO 2005/097067 to Xia (Ex.
`
`1003), titled “Zinc Preservative Composition and Method of Use” was published
`
`on October 20, 2005. Xia claims priority to U.S. Appl. No. 10/812,543, filed
`
`March 29, 2004 and qualifies as prior art to the ’299 patent under 35 U.S.C.
`
`§102(a) and (e). The “Schneider” reference, U.S. Patent No. 6,011,062 (Ex. 1007),
`
`issued on January 4, 2000, and
`
`is
`
`titled “Storage-stable prostaglandin
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`compositions.” The Chowhan reference, U.S Patent No. 6,143,799 (Ex. 1004),
`
`titled “Use of Borate-Polyol Complexes in Ophthalmic Compositions,” issued
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`November 7, 2000. Thus, Schneider and Chowhan each published more than one
`
`year before the EPPD of the ’299 patent and therefore qualify as prior art to the
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`’299 patent under §102(b), pre-AIA.
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`-8-
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`Patent No. 8,268,299
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`Petition for Inter Partes Review
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`As shown in the following claim chart and discussed below, the cited
`
`references teach or suggest all of the claimed limitations, and a POSA would have
`
`arrived at the compositions of the claims using only routine experimentation.
`
`“Where the general conditions of a claim are disclosed in the prior art, it is
`
`not
`
`inventive
`
`to discover
`
`the optimum or workable ranges by routine
`
`experimentation.” In re Aller, 220 F.2d 454, 456, (CCPA 1955); see In re
`
`Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003). Further, the concentration
`
`ranges disclosed in Xia, Schneider and Chowhan overlap the claimed ranges of
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`concentrations, establishing a prima facie case of obviousness. See Peterson, 315
`
`F.3d at 1330.
`
`’299 patent
`Claim 1. A multi-
`dose, self-preserved
`ophthalmic
`composition,
`comprising:
`
`Disclosures of Xia, Schneider and Chowhan
`“The present invention relates to a composition that
`includes a preservative-effective amount of a soluble
`zinc compound …. According to one embodiment, the
`composition is an ophthalmic solution… In one
`embodiment, the composition is an eyedrop solution.”
`Ex. 1003, 3.
`“Most preferred are compositions prepared for topical
`administration to the eye” such as Formulation A. Ex.
`1007, 7:7-9; 9:21-42.
`“The ophthalmic compositions of the present
`invention comprise borate-polyol complexes.” Ex.
`1004, 2:4 -12.
`
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`-9-
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`Patent No. 8,268,299
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`Petition for Inter Partes Review
`
`’299 patent
`zinc ions at a
`concentration of 0.04
`to 0.4 mM; and
`
`borate and polyol,
`the borate being
`present in the
`composition at a
`concentration of 0.1
`to 2.0% w/v and
`
`Disclosures of Xia, Schneider and Chowhan
`“Preferably, the zinc compound is selected from the
`group comprising zinc citrate and zinc chloride. . . .” Ex.
`1003, 5.
`“the composition has a minimum of about 0.001 wt.%1
`[0.074 mM ZnCl2]2, about 0.005 wt.% [0.37 mM
`ZnCl2], about 0.01 wt.% or about 0.05 wt.% of a zinc
`compound per total weight of the composition and/or a
`maximum of about 1 wt.%, about 0.5 wt.%, about 0.1
`wt.% or about 0.05 wt.% of the zinc compound per total
`weight of the composition.” Ex. 1003, 5.
`Example 2 of Schneider discloses Formulation A,
`containing 0.3% w/v boric acid and a polyol—
`mannitol. Ex. 1007, 9:21-42.
`Examples 2 and 3 in Xia contain 0.850 wt.% boric
`acid and 0.090 wt.% sodium borate. Ex. 1003, 17-
`18.
`“[C]omfort agents such as … propylene glycol can also
`be added.” Ex. 1003, 14.
`“Preferred polyols are … propylene glycol and
`sorbitol.” Ex. 1004, 3:4-6.
`
`
`1 As admitted by Alcon during prosecution of the ’299 patent, the wt.% (%w/w) is
`
`approximately equal to the % w/v for purposes of the claims. Ex. 1008, 365.
`
`2 The formula for conversion of w/v% (or wt%) to molarity is (w/v% / molar mass)
`
`× 10, and is routine in the art. Ex. 1002 ¶¶46, 50.
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`-10-
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`

`Patent No. 8,268,299
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`
`
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`Petition for Inter Partes Review
`
`’299 patent
`the polyol being
`present in the
`composition at a
`concentration of 0.25
`to 2.5% w/v,
`the polyol
`comprising
`propylene glycol in
`the composition at a
`concentration of
`0.25 to 1.25% w/v
`and
`sorbitol in the
`composition at a
`concentration of
`0.05 to 0.5% w/v;
`wherein
`
`Disclosures of Xia, Schneider and Chowhan
`“Examples of suitable agents which may be utilized to
`adjust the tonicity or osmolality of the formulations
`include … mannitol, dextrose, glycerine, and propylene
`glycol. Ex. 1003. 7:21-25.
`
`“The borate-polyol complexes are utilized in the
`compositions of the present invention in an amount
`between about 0.5 to about 6.0 percent by weight (wt
`%), preferably between about 1.0 to about 2.5 wt %.”
`Ex. 1004, 3:44-47.
`At the minimum concentrations claimed, the
`composition of claim 1 comprises 0.4% w/v borate-
`polyol (0.1% w/v borate + 0.25% w/v propylene
`glycol + 0.05% w/v sorbitol.
`At the maximum concentrations claimed, the
`composition of claim 1 comprises 3.75% w/v borate-
`polyol (2.0% w/v borate + 1.25% w/v of propylene
`glycol + 0.5% w/v sorbitol.
`“The molar ratio of borate to polyol is generally
`between about 1:0.1 to 1:10, and preferably between
`about 1:0.25 and about 1:2.5.” Ex. 1004, 3:15-
`34.
`At the minimum borate and polyol concentrations
`claimed, the composition of claim 1 comprises 0.1% w/v
`borate [16 mM borate] to 0.3% w/v total polyol (0.25%
`w/v propylene glycol + 0.05% w/v sorbitol) [36 mM
`polyol]. The borate to polyol molar ratio in this case is
`1:2.2.
`At the maximum borate and polyol concentrations
`claimed, the composition of claim 1 comprises 2.0%
`borate [330 mM borate] to 1.75% w/v polyol (1.25%
`w/v propylene glycol + 0.5% w/v sorbitol) [194 mM
`polyol]. The borate to polyol molar ratio in this case
`is 1:0.6.
`
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`-11-
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`Patent No. 8,268,299
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`Petition for Inter Partes Review
`
`’299 patent
`(i) the composition
`has a concentration
`of anionic species
`less than 15 mM; and
`
`(ii) the composition
`exhibits sufficient
`antimicrobial
`activity to allow the
`composition to
`satisfy USP 27
`preservative efficacy
`requirements.
`
`Disclosures of Xia, Schneider and Chowhan
` “The aqueous solutions of the present invention are
`typically adjusted with tonicity agents to approximate
`the tonicity of normal lacrimal fluids (approximately
`equivalent to a 0.9 wt.% solution of sodium chloride or
`2.8 wt.% glycerol solution). Ex. 1003, 10.
`“phosphate [an anion] is a good buffer but, when used
`in concentrations generally found in ophthalmic
`formulations, it reduces the antimicrobial activity of
`preservatives.” Ex. 1004, 1:45-48.
`Xia teaches a composition that includes a preservative-
`effective amount of a soluble zinc compound. Ex. 1003,
`3.
`“Based on the acceptance criteria for bacteria or fungus a
`solution is acceptable if the number of viable bacteria
`or fungus recovered per ml is reduced by at least 3.0
`logs at day 14 and after the rechallenge at day 14, the
`concentration of bacteria or fungus is reduced by at
`least 3.0 logs by day 28.” Ex. 1003, 15. These test
`requirements are more stringent than the USP 27
`requirements, explained below.
`“The following general procedure was used for
`evaluating the preservative efficacy (PE) of various eye
`drop solutions against Staphylococcus aureus (ATCC
`6538), Eschrechia [sic] coli (ATCC 8739),
`Pseudomonas aeruginosa (ATCC 9027), Candida
`albicans (ATCC 10231) and Aspergillus niger (ATCC
`16404)…” Ex. 1003, 14. These are the five organisms
`tested in the USP 27. Ex. 1014, 2002-2004.
`“An organism challenge approach based on the British
`Pharmacopoeia (“BP”) 1988 Test for Efficacy of
`Preservatives in Pharmaceutical Products was used to
`evaluate the antimicrobial preservative efficacy of
`Formulations C and D.” Ex. 1004, 9:38-41.
`
`Claims 1 & 4-6: Claim 1 is directed to a multi-dose, self-preserved
`
`
`-12-
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`Patent No. 8,268,299
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`
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`Petition for Inter Partes Review
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`ophthalmic composition containing zinc ions, borate, and polyol (propylene glycol
`
`and sorbitol) at various concentrations and meeting a concentration limit on
`
`anionic species and a preservative efficacy requirement. Claim 4 depends from
`
`claim 1, and adds an effective amount of a therapeutic agent to the composition.
`
`Claim 5 depends from claim 1 and recites
`
`that
`
`the composition further
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`comprises a therapeutic agent selected from the group consisting of bimatoprost,
`
`latanoprost, travoprost and unoprostone. Claim 6 depends from claim 5 and
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`recites that the therapeutic agent comprises travoprost. Because a POSA would
`
`have been motivated to combine Xia, Schneider and Chowhan as described below,
`
`and because these references disclose each of the claimed components within the
`
`claimed concentration ranges, as well as meeting the other claim requirements and
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`teaching how to make such formulations, claims 1 and 4-6 would have been
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`obvious.
`
`Xia discloses that traditional preservatives used in multi-dose, ophthalmic
`
`compositions can cause irritation and discomfort. To remedy that problem, Xia
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`provides self-preserved multi-dose ophthalmic compositions comprising zinc ions
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`(at the claimed concentrations), a therapeutic agent (which alone meets the
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`limitation of claim 4 (Ex. 1002 ¶¶67-68)), borate and propylene glycol (which is a
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`polyol). Ex. 1003, 2-3, 12, 14. The compositions employ less than a preservative-
`
`effective amount of a primary preserva