Case 1:14-cv-00667-JBS-KMW Document 1 Filed 01/31/14 Page 1 of 6 PageID: 1
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF NEW JERSEY
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`Civil Action No.:
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`SENJU PHARMACEUTICAL CO., LTD.,
`BAUSCH & LOMB, INC. and BAUSCH &
`LOMB PHARMA HOLDINGS CORP.
`
`
`Plaintiffs,
`
`v.
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`LUPIN, LTD. and LUPIN
`PHARMACEUTICALS, INC.,
`
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`Defendants.
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`COMPLAINT FOR PATENT INFRINGEMENT
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`Plaintiffs Senju Pharmaceutical Co., Ltd., Bausch & Lomb Incorporated and Bausch &
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`Lomb Pharma Holdings Corp. (collectively “Plaintiffs”) by way of Complaint against
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`Defendants Lupin, Ltd. and Lupin Pharmaceuticals, Inc. (collectively “Lupin”) allege as follows:
`
`THE PARTIES
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`1.
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`Plaintiff Senju Pharmaceutical Co., Ltd. (“Senju”) is a corporation organized and
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`existing under the laws of Japan, with a principal place of business at 2-5-8, Hirano-machi,
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`Chuo-ku, Osaka 541-0046, Japan.
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`2.
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`Plaintiff Bausch & Lomb Incorporated (“B+L”) is a corporation organized and
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`existing under the laws of New York, with a place of business at 1400 North Goodman St.,
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`Rochester, New York 14609. B+L is the registered holder of approved New Drug Application
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`No. 203168, which covers Prolensa®.
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`3.
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`Plaintiff Bausch & Lomb Pharma Holdings Corp. (“B+L Pharma Holdings”) is a
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`corporation organized and existing under the laws of Delaware, with a place of business at 700
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`#23581246 v1 (140859.2)
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`Page 1 of 18
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`SENJU EXHIBIT 2007
`LUPIN v. SENJU
`IPR2015-01097
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`

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`Case 1:14-cv-00667-JBS-KMW Document 1 Filed 01/31/14 Page 2 of 6 PageID: 2
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`Route 202/206, Bridgewater, New Jersey 08807. B+L Pharma Holdings is a wholly-owned
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`subsidiary of B+L.
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`4.
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`Upon information and belief, defendant Lupin, Ltd. is a corporation organized and
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`existing under the laws of India, having a corporate headquarters at C/4 Laxmi Towers, Bandra
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`Kurla Complex, Bandra (E), Mumbai 400 051.
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`5.
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`Upon information and belief, defendant Lupin Pharmaceuticals, Inc. is a
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`corporation organized and existing under the laws of Virginia, having a principal place of
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`business at 111 S. Calvert Street, 21st Floor, Baltimore, MD 21202. Upon information and belief,
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`Lupin Pharmaceuticals, Inc. is a wholly-owned subsidiary of Lupin, Ltd.
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`NATURE OF THE ACTION
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`6.
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`This is an action for infringement of United States Patent No. 8,129,431 (“the
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`’431 patent”), arising under the United States patent laws, Title 35, United States Code, § 100 et
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`seq., including 35 U.S.C. §§ 271 and 281. This action relates to Lupin Ltd.’s filing of an
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`Abbreviated New Drug Application (“ANDA”) under Section 505(j) of the Federal Food, Drug,
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`and Cosmetic Act (“the Act”), 21 U.S.C. § 355(j), seeking U.S. Food and Drug Administration
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`(“FDA”) approval to market generic Bromfenac Ophthalmic Solution 0.07% (“Lupin’s generic
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`bromfenac ophthalmic solution”).
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`JURISDICTION AND VENUE
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`7.
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`8.
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`This Court has subject matter jurisdiction under 28 U.S.C. §§ 1331 and 1338(a).
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`Upon information and belief, this Court has jurisdiction over Lupin, Ltd. Upon
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`information and belief, Lupin Ltd. is in the business of manufacturing, marketing, importing and
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`selling pharmaceutical drug products, including generic drug products. Upon information and
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`belief, Lupin Ltd. directly manufactures, markets and sells generic drug products throughout the
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`United States and in this judicial district, and this judicial district is a likely destination for
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`Case 1:14-cv-00667-JBS-KMW Document 1 Filed 01/31/14 Page 3 of 6 PageID: 3
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`Lupin’s generic bromfenac ophthalmic solution. Upon information and belief, Lupin Ltd.
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`purposefully has conducted and continues to conduct business in this judicial district.
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`9.
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`Upon information and belief, this court has jurisdiction over Lupin
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`Pharmaceuticals, Inc. Upon information and belief, Lupin Pharmaceuticals, Inc. directly, or
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`indirectly, manufactures, markets and sells generic drug products, including generic drug
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`products manufactured by Lupin Ltd., throughout the United States and in this judicial district.
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`Upon information and belief, Lupin Pharmaceuticals, Inc. purposefully has conducted and
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`continues to conduct business in this judicial district.
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`10.
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`Upon information and belief, venue is proper in this judicial district under 28
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`U.S.C. §§ 1391(c) and (d), and § 1400(b).
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`COUNT FOR PATENT INFRINGEMENT
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`11.
`
`The U.S. Patent and Trademark Office (“PTO”) issued the ’431 patent on March
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`6, 2012. The ’431 patent claims, inter alia, formulations of bromfenac for ophthalmic
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`administration. Plaintiffs holds all substantial rights in the ’431 patent and have the right to sue
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`for infringement thereof. Senju is the assignee of the ’431 patent. A copy of the ’431 patent is
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`attached hereto as Exhibit A.
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`12.
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`B+L is the holder of New Drug Application (“NDA”) No. 203168 for Prolensa®,
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`which the FDA approved on April 5, 2013. In conjunction with NDA No. 203168, the ’431
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`patent is listed in the FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations
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`(“the Orange Book”).
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`13.
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`Bromfenac Ophthalmic Solution 0.07% is sold in the United States under the
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`trademark Prolensa®.
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`14.
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`Upon information and belief, Lupin Ltd. filed with the FDA ANDA No. 206027,
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`under Section 505(j) of the Act and 21 U.S.C. § 355(j).
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`Case 1:14-cv-00667-JBS-KMW Document 1 Filed 01/31/14 Page 4 of 6 PageID: 4
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`15.
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`Upon information and belief, Lupin Ltd.’s ANDA No. 206027 seeks FDA
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`approval to sell in the United States Lupin’s generic bromfenac ophthalmic solution, intended to
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`be a generic version of Prolensa®.
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`16.
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`Bausch & Lomb received a letter from Lupin Ltd. dated December 19, 2013,
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`purporting to be a Notice of Certification for ANDA No. 206027 (“Lupin’s notice letter”) under
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`Section 505(j)(2)(B)(ii) of the Act, 21 U.S.C. § 355(j)(2)(B)(ii), and 21 § C.F.R. 314.95(c).
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`17.
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`Lupin’s notice letter alleges that Lupin Ltd. has submitted to the FDA ANDA No.
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`206027 seeking FDA approval to sell generic bromfenac ophthalmic solution, intended to be a
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`generic version of Prolensa®.
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`18.
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`Upon information and belief, ANDA No. 206027 seeks approval of Lupin’s
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`generic bromfenac ophthalmic solution that is the same, or substantially the same, as Prolensa®.
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`19.
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`Under 35 U.S.C. § 271(e)(2), Lupin Ltd. has infringed at least one claim of the
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`’431 patent by submitting, or causing to be submitted to the FDA, ANDA No. 206027 seeking
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`approval for the commercial marketing of Lupin’s generic bromfenac ophthalmic solution before
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`the expiration date of the ’431 patent.
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`20.
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`Upon information and belief, Lupin’s generic bromfenac ophthalmic solution
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`will, if approved and marketed, infringe at least one claim of the ’431 patent.
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`21.
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`Upon information and belief, Lupin Ltd. will, through the manufacture, use
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`import, offer for sale and/or sale of Lupin’s generic bromfenac ophthalmic solution, directly
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`infringe, contributorily infringe and/or induce infringement of at least one claim of the ’431
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`patent.
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`Case 1:14-cv-00667-JBS-KMW Document 1 Filed 01/31/14 Page 5 of 6 PageID: 5
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`22.
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`Upon information and belief, Lupin Ltd.’s actions relating to ANDA No. 206027
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`complained of herein were done with the cooperation, the participation, the assistance of, and at
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`least in part for the benefit of Lupin Pharmaceuticals, Inc.
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`WHEREFORE, Plaintiffs respectfully request that the Court enter judgment in their
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`favor and against Defendants on the patent infringement claim set forth above and respectfully
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`request that this Court:
`
`1.
`
`enter judgment that, under 35 U.S.C. § 271(e)(2), Lupin has infringed at least one
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`claim of the ’431 patent through Lupin Ltd.’s submission of ANDA No. 206027 to the FDA to
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`obtain approval for the commercial manufacture, use, import, offer for sale and/or sale in the
`
`United States of Lupin’s generic bromfenac ophthalmic solution before the expiration of the ’431
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`patent;
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`2.
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`order that the effective date of any approval by the FDA of Lupin’s generic
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`bromfenac ophthalmic solution be a date that is not earlier than the expiration of the ’431 patent,
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`or such later date as the Court may determine;
`
`3.
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`enjoin Lupin from the commercial manufacture, use, import, offer for sale and/or
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`sale of Lupin’s generic bromfenac ophthalmic solution until expiration of the ’431 patent, or
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`such later date as the Court may determine;
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`4.
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`enjoin Lupin and all persons acting in concert with Lupin from seeking, obtaining
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`or maintaining approval of Lupin Ltd.’s ANDA No. 206027 until expiration of the ’431 patent;
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`5.
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`declare this to be an exceptional case under 35 U.S.C. §§ 285 and 271(e)(4) and
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`award Plaintiffs costs, expenses and disbursements in this action, including reasonable attorneys
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`fees;
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`#23581246 v1 (140859.2)
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`Page 5 of 18
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`Case 1:14-cv-00667-JBS-KMW Document 1 Filed 01/31/14 Page 6 of 6 PageID: 6
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`6.
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`award Plaintiff such further and additional relief as this Court deems just and
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`proper.
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`Dated: January 31, 2014
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`Respectfully submitted,
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`
`
`s/ John F. Brenner
`John F. Brenner
`PEPPER HAMILTON, LLP
`Suite 400
`301 Carnegie Center
`Princeton, New Jersey, 08543-5276
`(609) 951-4193
`brennerj@pepperlaw.com
`
`Attorneys for Plaintiffs
`SENJU PHARMACEUTICAL CO., LTD.,
`BAUSCH & LOMB, INC. and BAUSCH & LOMB
`PHARMA HOLDINGS CORP.
`
`
`
`
`
`
`
`
`Of Counsel:
`Bryan C. Diner
`Justin J. Hasford
`FINNEGAN, HENDERSON,
`FARABOW, GARRETT & DUNNER, LLP
`901 New York Avenue, NW
`Washington, DC 20001-4413
`(202) 408-4000
`
`
`
`
`
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`#23581246 v1 (140859.2)
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`Page 6 of 18
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`Case 1:14-cv-00667-JBS-KMW Document 1-1 Filed 01/31/14 Page 1 of 9 PageID: 7
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`EXHIBIT A
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`Page 7 of 18
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`

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`Case 1:14-cv-00667-JBS-KMW Document 1-1 Filed 01/31/14 Page 2 of 9 PageID: 8
`
`' 111111111111111111111111111111111111111111 11111 11111 11111111111111111111111
`US00812943182
`
`c12) United States Patent
`Sawa et al.
`
`(JO) Patent No.:
`(45) Date of Patent:
`
`us 8,129,431 82
`Mar.6,2012
`
`(54) AQUEOUS LIQUID PREPAHATION
`CONTAINING 2-AMTNO-
`J-( 4-BilOMOBENZOYI ,)Pil F. NYI .AC:ntC
`ACfl)
`
`(75)
`
`inventors: Shirou Sawa, Kobe (JP); Sbubei Fujita,
`Kakogawa (JP)
`
`(73)
`
`Assignee: Senju Pharmaceutical Co., Ltd., Osaka
`(JP)
`
`( *)
`
`Notice:
`
`Subject to any disclaimer, the tenn of this
`patent is ex1ended or ndjusted 1mder 35
`U .S.C. I 54(b) by 604 days.
`
`(21) Appl.No.:
`
`10/525,006
`
`(22) PCT F iled:
`
`Jan. 16,2004
`
`(86) PCT No.:
`
`J>C T /.1 P2004/000J50
`
`§371 (c)( J).
`(2). (4) Date: Mar. 28, 2005
`
`(87) PCT Pub. No.: W02004/064828
`PC'T Pub. Date: May 8, 2004
`
`(65)
`
`Prior Publication l)atu
`
`US 2005/0239895 A I
`
`Oct. 27,2005
`
`(30)
`
`Foreign Application Priority Data
`
`Jan. 21, 2003
`
`(JP) ................................... 2003- 12427
`
`(5 1)
`
`(52)
`(58)
`
`(56)
`
`Int. CJ.
`!lOIN .?7118
`(2006.0 I)
`AOIN 37144
`(2006.01)
`(2006.01 )
`A01N37/JO
`(2006.01)
`A6/K 311165
`A61K 31124
`(2006.01 )
`A61K 31119
`(2006.01)
`514/619; 514/535: 51 4/570; 514/6 18
`U.S.CI.
`Field of C lassification Search . ...... ..... .. .... 514/567,
`5 14/619, 535, 570; 424/486
`Sec application file for complete s-earch history.
`
`References C ited
`
`U.S. PATENT DOCUMENTS
`!:1/ 1977 Wclstcad. Jr. ct al.
`4,045,576 A
`4,683,242 A
`7/ 1987 Poser
`4,910,225 A
`311990 Ognwa ct al.
`5,110,493 A
`511992 Chcrng-Chyi ct al.
`5,475,034 A •
`1211995 Yanni ctal .................... 5 14/6 19
`5,540,930 A •
`7/ 1996 Guy et al. ..................... 424/427
`l/1997 Berp;unini ctal.
`5.597,560 A
`5,603,929 A •
`211997 Desai et al. ................ 424/78.04
`5,653,972 A
`81 1997 Desai et al.
`1211999 llclllx:rgctal ............... 5 14/432
`5,998,465 A •
`6,319,513 Bl •
`1112001 Dobro<.si ...................... 424/434
`6,369, 112 Bl •
`4/2002 Xia ............................... 514/635
`
`6,383,471 Bl
`6.395,746 Rl
`2007/0082857 A I •
`
`5/2002 Chen et al.
`5/2002 Cnglc ct nl.
`4/2007 Sawa .............................. 514/ 35
`
`i\U
`CA
`n>
`JP wo
`wo
`WO
`WO
`wo
`
`FOREIGN PATENT DOCUMENTS
`911995
`707 119
`2 013 188
`9/ 1990
`5-223052
`811993
`11-228404
`8/1999
`511996
`96114829
`3/200 1
`01115677
`WO 0 1115677 A2 +
`3/200 1
`WO 0115677 A2 +
`3/200 1
`2/2002
`02113804
`OTJJER PUOLJCA'TIONS
`
`lSTi\ Pharmaceuticals; "New Drug Appl-cations: Xibrom", http://
`www.dmgs.com/nd:v'xibrom 040525.html, ncccss~-d online Scp.
`19, 2007.•
`Nolan, et al.; The topical anti-inflammatory and analgesic properties
`ofbromfcnic in rodents:; Agents and Act ions; Aug. 1988; 25(1-2):77-
`85. abstract. •
`Nolan, et al. ("lbc topic! a antj-inflammatOJy and analgesic proper(cid:173)
`til's of bromfcnac in rodents"; 1988; Agents and Actions; 25( 1·2):
`77-85.•
`New Drugs in Japan, 2001,2001 Edition, Published byYakuji Nippo
`Ltd., May I I , 200 1, pp. 27·29. and its English trnnslation of the
`material portions.
`Corrected partial English translation of New Drugs in Japan, 200t,
`200 I Edition, Published by Yakuji Nippo Lrd., May II, 2001, pp.
`27-29, previously submitted on Apr. ll, 2005.
`Complete English translation of New Dmgs in Japan, 2001, 2001
`Edition, Published by Y.~kuji N ippo Ltd., May 11 , 2001, pp. 27-29.
`Noti~c of Opposition dated Feb. 19, 2009 imoed by Epo in conn~'<: lion
`with the corresponding European patent application and Opposition.
`hllp://med icnl-clictionary.thcfn:edictionruy.comlprophylact ic. nc·
`ccssed Dec. 15, 2009.
`
`*cited by examiner
`
`Primary Examiner Sn .. -cni P<Jdmambhan
`Assislanl Examiner Layla Soroush
`(74) Allomey, Age111, or /•inn Wcnderoth, I .ind & Ponack,
`L.L.P.
`
`(57)
`
`A llSTRACT
`
`An aqueous liquid pn::paration of the present invention con(cid:173)
`taining 2-amino-3-( 4-bromobcnzoyl)phenylacetic acid or its
`pharmacologically .acceptable salt or a hydrate thereof~ an
`alk-yl aryl polyether alcohol type polymer such as tyloxapol,
`or a polyethylene g lycol f1•tty acid esliJr such as polyethylene
`glycol monostearatc is stable. Since even in the case where a
`pres-ervative is incorporated into soid Dqueous liquid prepn(cid:173)
`ration, the preservative exhibits a ; ufficient preservative
`efJcct for a long time, said aqueous liquid preparation in the
`form of an eye drop is useful for the treatment of blepharitis,
`conjunctivitis, scleritis, and postoperative inflammation.
`Also, the aqueous liquid prepamtion 0fthc present invention
`in the fo rm of a o.asol drop is useful for the treatment of
`allergic rhinitis and inllmnmatory rhinitis (e.g. chronic rhini(cid:173)
`tis, hypertrophic rhinitis, nasal polyp, ctc.).
`
`22 Claims, No Drawings
`
`Page 8 of 18
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`

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`Case 1:14-cv-00667-JBS-KMW Document 1-1 Filed 01/31/14 Page 3 of 9 PageID: 9
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`US 8, 129,431 B2
`
`1
`AQUEOUS LIQUIJ) PIU:J>ARATION
`CONTAINING
`2-AMJN0-3-(4-U ROMOBENZOYl,)POE~LACF.TlC
`ACIJ)
`
`2
`nonsteroidal anti-inflallliDatory drugs. These preservatives
`lose their ability to Jimction as they fbrm complexes with the
`charged dntg compounds".
`In these prior ar1 references, there is no disclosure that alb.')' I
`aryl polyether alcohol type polymers or polyelllylcnc glycol
`fatty acid esters arc able to stabilize an aqu<.:ous liquid prcpa(cid:173)
`r<llion of 2-mnino-3-(4-bromobcnzoyl)phenylacetic acid or
`its pharmacologically acceptable salt, und inhibit decrease in
`prescrvatiw em~ct ~lfbenzaJkonium chloride and other qu<t-
`10 ternary ammonium compounds.
`
`DISCLOSURE OF THE INVENTION
`
`'l11is application is a U.S. national stage of International
`Application No. PCTIJP2004/000350 filed Jan. 16, 2004.
`
`TECl iN1CAL FJELD
`
`The present invention relates to an aqueous liquid pn.:pa(cid:173)
`ration containing 2-amino-3-(4-bromobenzoyl)pbenylacetic
`acid or a pharmacologically acceptable salt thereof or a
`hydrate thereof. More particularly, the present invention
`relates to an aqueous liquid preparation containing 2-amino-
`3-(4-bmmobcnzoyl)phcnylacetic acid or a pharmacologi(cid:173)
`cally acceptable salt thereof or a hydrate thereofond till alkyl
`aryl polyether alcohol type polymer or a polyethylene glycol
`fat1y acid ester.
`
`BACKGROUND ART
`
`Benzoylphenylacetic acid derivatives including bromfenac
`(generic n!lme) of fom111la (I):
`
`COOH
`
`Br
`
`15
`
`It is an object of the present invent ion to provide an aque-
`ous Equid preparation comprising 2-amino-3-(4-bromoben(cid:173)
`zoyl)phenylacetic acid or a pharmacologiclllly acceptable salt
`thereof or a hydrate thcrcol~ which is stable within a pH range
`giving no irritation to eyes and in which, when a preservative
`20 such as benzalkonium chloride is incorporated therein, pre(cid:173)
`servative effect of the preservative does not substantially
`deteriorate.
`Aoother object of the invention is to provide a method lbr
`stabilizing an aqueous liquid preparation of 2-amino-3-(4-
`H bromobenzoyl)phc:nylacctic acid or a pharmacologically
`acceptable salt thereof or a hydrate thereof.
`Further object of the invention is to provide an aqtteous
`liquid preparation comprising 2-amuto-3-( 4-bromobcuzoyl)
`phenylacetic acid or a phannacologically acceptable salt
`JO thereof or a hydrate thereof and a preservative, wherein, when
`sp<..>eilically a quaternary mnmoniwn salt such as benzalko(cid:173)
`nium chloride is incorporated as a preservative, decrease in
`preservative effect of said preservative is inhihitcd.
`As a result of various studi<:s, the inventors of the present
`invention have found that, by adding, for exan1plc, an alkyl
`aryl polycther alcohol type polymer such as tyloxapol, or a
`polyethylene glycol fat1y acid ester such as polyethylene
`glycol monostcaratc to an aqm:ous liquid preparation of
`40 2-amino-3-(4-bromobcnzoyl)phcnylacetic acid or a phanna(cid:173)
`cologically acceptable salt thereof or a hydrate thereol~ the
`aqueous solution becomes stable within a pfl mngc giving no
`irritation to eyes, and change of the 2-amino-3-(4-bmmobcn(cid:173)
`wyl)phenylacetic acid over time can be inhibited, and fur-
`45 thcnnorc, when the aqueous solution c:onl!lins a preservative.
`deterioration in the preservative effect of said preservative
`can be inhibited fbr a long period o ftirnc.111c inventors oft he
`present invention lwve further studied extensively and com-
`pleted the present invention.
`Namely, the present invention relates to:
`(I) An aqueous liquid preparation comprising 2-amino-3-( 4-
`bromobenzoyl)pbcnylacetic acid or a pharmacologically
`acceptable salt thereof or u hydr.lte thereof, and an alkyl
`aryl polyether alcohol type polymer or a polyethylene gly(cid:173)
`col fatty acid ester,
`(2) llle aqueous liquid preparation according to the above (I).
`wherein ll1e alk')'l aryl polyether alc:ohol type polymer has
`a polymerization degree of3 to 10, the all-')'1 contains I to
`18 carbon atoms, the aryl is a phenyl residue. and the
`polycthcr alcohol
`is
`represented by
`the
`formula
`O(Cli2CII20) .. 1 I in which X is llll integer of 5 to I 00,
`(3) The aqueous liquid preparation according to the a hove (I)
`or (2), wherein the alkyl aryl polyether alcohol type poly(cid:173)
`mer is tyloxapol,
`65 ( 4) The aqueous liquid prcpariltion according to the above ( I),
`wherein the carbon numberofthe f<ttty acid in the polyeth(cid:173)
`ylene glycol liltty acid ester is 1 2 to 18,
`
`35
`
`of which chemical name is 2-amino-3-(4-bromobenzoyl)
`phenylacetic acid arc known as disclosed in JI'-A-23052/
`1977 and its corresponding U.S. Pat. No. 4,045,576.
`2-Amino-3-(4-bromobenzoyl)phenylacetic !lcid. its pharma(cid:173)
`cologically acceptahle salt and a hydrate thereof arc known us
`a non-steroidal anti-inllammatory agent, and they arc cfl'<:c(cid:173)
`tivc against inflammatory diseases of auterior or posterior
`segment oft be eye. such as blepharitis, conjunctivitis. scleri-
`tis, and postoperative inllallliDation in the field of ophthal(cid:173)
`mology, and its sodium salt has been pmctically used in the
`form of eye dmps ("New [)rugs in J<tpWl, 2001 ", 2001 Edi(cid:173)
`tion, Published by Yakuji Nippo Ltd., May II, 2001, p.
`27-29).
`'!11c eye dmp as mentioned above is designed to stabilize
`2-amino-3-( 4-bromobenzoyl)pbenylacetic acid by means of
`addition of a water-soluble polymer (e.g. polyvinylpyrroli- 50
`done, polyvinyl alcohol, etc.) and a sulfite (e.g. sodium
`sulfite, potassium sulfite. etc.) (Japanese patent No. 2,683,
`676 and its corresponding U.S. Pat. No. 4.9 1 0,225).
`In addition, as an eye drop other than the above-mentioned
`one, Japanese patent No. 2,954,356 (corresponding to LJ.S. 55
`Pat. Nos. 5,603,929 and 5,653,972) discloses a stable oph(cid:173)
`thalmic composition which comprises incorporating an anti(cid:173)
`bacterial quaternary mnmonium polymer and boric acid into
`au acidic ophthalmic agent. The acidic agent described
`therein includes, for example, 2-amino-3-( 4-bromobenzoyl) 60
`phenylacetic acid.
`Further, in Japanese patent No. 2,954,356, there is the
`following description "Benzalkonium chloride is a widely
`used pn.:scrvativc in ophLh;llm.ic solutiOilll. llowcvcr, bcn7a(cid:173)
`lkonium chloride and other quaternary ammonium com(cid:173)
`pounds are generally considered to be incompatible with
`ophthalmic compositions of drugs with acidic !I,I'Oups, such as
`
`Page 9 of 18
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`Case 1:14-cv-00667-JBS-KMW Document 1-1 Filed 01/31/14 Page 4 of 9 PageID: 10
`
`us 8,129,431 82
`
`3
`(5) The aqueous liquid preparation according to the above (I)
`or (4), wherein the polyethylene glycol fatty acid ester is
`polyethylene glycol monostearate,
`(6) The aqueous liquid preparation according to any one of
`the above (1) to (3), wherein the concentration oft he alkyl
`aryl polyether alcohol type polymer is selected from a
`rdnge of minimum concentnllion of 0.01 w/v% to maxi(cid:173)
`mum concentration of0.5 w/v %,
`(7) The aqueous liquid preparation according to any one of
`the above (1), (2) or (4), wherein the concentration of the to
`polyethylene glycol fatty acid ester is sck'Cted from a range
`of minimum concentration o f 0.02 w/v % to maximum
`concentration of0.1 w/v %,
`(8) The aqueous liquid preparation according to uny one of
`the above (I) to (7), wherein the cum;eutrdtion of the 15
`2-amino-3-(4-bromobenr.oyl)phenylacetic acid or a phar(cid:173)
`macologically ucccptablc salt thereof or a hydrate thereof
`is O.QI to 0.5 w/v %,
`(9) The aqueous liquid preparation according to any one of
`the above (I) to (8), wherein benzalkonium chloride is 20
`contained as a preservative,
`( l 0) The aqtu .. 'OUS liquid preparation according to anyone of
`the above (I) to (9). wherein the pham1acologically accept(cid:173)
`able salt of2-amiuo-3-(4-bromobenzoyl)phenylacetic acid
`is a sodium s11lt,
`( l l) The aqueous liquid preparation according to any one of
`the above (1) to ( 10), wherein the pH of the aqueous liquid
`preparation is within a range of7 to 9,
`( 12) The aqueous liquid pn.:pamtion according to the above
`(II), wherein the pH of the aqueous liquid preparation is 30
`within a range of7 .5 to 8.5,
`(13) The aqueous liquid preparation according to any one of
`the above (1) to ( 12), wherein the aqueous liquid prepara(cid:173)
`tion is an eye drop,
`(14) The aqueous liquid preparation according to any one of 35
`the above ( I) to ( 12), wherein the aqueous liquid prepara(cid:173)
`tion is a nasal drop.
`(15) A11 eye dmp comprising sodium 2-amino-3-(4-bro(cid:173)
`mohenzoyl)phenylacetate hydrate and 0.01 (() 0.5 w/v% nf
`tyloxapol,
`(I o) An eye drop comprising sodium 2-amino-3-( 4-bro(cid:173)
`mobcnzoyl)phcnylacctnte hydrate and 0.02 to 0.1 w/v% of
`polyethylene glycol monos tellTale,
`(17) A method for stabilizing 2-amino-3.-(4-bromobcr17.oyl)
`phenylacetic acid or a pharmacologically :.~cecptable salt 45
`thereof or a hydrate thereof in an aqueous liquid prcpam(cid:173)
`tion, which comprises incorporating tyloxapol or polyeth(cid:173)
`ylene glycol monostearate into an aqueous liqnid prepant(cid:173)
`tion containing 2-amino-3-(4-bromobcnzoyl)phenylacetic
`acid or a pharmacologically acceptable salt thereof or a so
`hydrate thereof, <Uld
`( 18) A method for inhibiting decrease in preservative effect of
`a preservative in an aqueous liquid prepar<:~tion of2-amino-
`3-(4-bromobenzoyl)phenylacetic acid or a phMmacologi(cid:173)
`cally acceptable salt thereof or a hydrate thereof, which ss
`comprises incorporating tyloxapol or polyethylene glycol
`monosteanlle into an aqueous liquid preparation contain(cid:173)
`ing 2-amino-3-( 4-bromoben:r.oyl)phenylacctic acid or a
`ph<~nnacologically acceptable salt tht!reof or a hydrate
`then::of and a preservative.
`According to the prcseut iuvcntion, a stuble uqucous liquid
`preparation containing 2-amino-3-( 4-bromobcnzoyl)pheny(cid:173)
`lacetic acid or a pharmacologically acceptable salt thereof or
`a hydrate thereof can be prep:m:d by incorporating au alkyl
`aryl polyether alcohol type polymer sucb as tyloxapol, or a 65
`polyethylene glycol fatty acid ester such as polyethylene
`glycol monostcaratc into an aqueous liquid preparation con-
`
`4
`taining 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a
`phannacologically acceptable salt thereof or a hydrate
`thereof. 1\lso, an aqueous liquid preparation of the present
`invention, wherein .a preservative is incorporated, has a sui~
`ficient preservative eJTect.
`11terefore, the aqu-.'Ous liquid pn.:paration of the present
`invention is advantageously used as an eye drop for the treat(cid:173)
`ment of, lor example, blepharitis, conjunctivitis, scleritis. and
`postoperative inflammation. In addition, such aqueous liquid
`preparation can be used as a nasal drop for the treatment of,
`fhr example, allergic rhinitis and inflammatory rhinitis (e.g.
`chronic rhinitis. hypenropbic rhinitis. nasal polyp, etc.).
`The pham1acologically accepwblc sail of 2-amino-3-(4-
`bromobcnzoyl)phenylacctic acid includes, for example, an
`alkali metal salt such as sodium salt and potassium salt, and
`an alkaline earth metal salt such as ct~lcium salt and magne(cid:173)
`sium salt, among which sodium salt is especially prefcrdblc.
`2-Ami.no-3-(4-bromobenzoyl)pbcnylacetic acid and its
`pharmacologic<Jlly acceptable salt can be prcpan.:d according
`to the method as described in .TP-A-2305211977 (correspond(cid:173)
`ing to U.S. Pnt. No. 4,045,576)orby a similar method thereof.
`These compounds c.an be obtained as their hydrate depending
`2' nn synthetic conditions and recry~tal l i7ation conditions. 'l11e
`hydrate includes J/2 hydrate, I hydrate, and 3/2 hydnttc,
`among which 3/2 hydrate is preferable.
`In the aqueous liquid preparation of' the present invention,
`the content (concentration range) of 2-amino-3-(4-bro(cid:173)
`moben7.oyl)phenylacctic acid or a phannacologically accept(cid:173)
`able salt thereof or a hydrate thereof is usually about 0.0 I to
`0.5 w/v %, preferably about 0.05 to 0.2 w/v %, especially
`about 0.1 w/v 'Vc>, and tl is preferable tn appropriately vary the
`content depending on the purpose of use and the degree of
`disease to be treated.
`"lbe carbon number of the alkyl in the au alkyl aryl poly(cid:173)
`ether alcohol type polymer which is a non-ionic surfactant
`used as a stabilizer for 2-amino-3-(4 .. bromobcnzoyl)phcny-
`40 !acetic acid or a pharmacologically acceptable salt thereof or
`a hydrate thereof is approximately l to 18. Specifically, the
`<~lkyl gmup includes, for example. methyl, ethyl, propyl, iso(cid:173)
`propyl, cyclopropyl, butyl, isobutyl. sec-butyl, !crt-butyl,
`cyclobutyL pcntyl, isopentyl, ncopcntyl, tert-pcntyl, 1-cthyl(cid:173)
`propyl, 4-metbylpentyl, J,J-dimethylbutyl, 2,2-dimcthylbu(cid:173)
`tyl, 1 ,2-dimcthylbutyl, 2-cthylbutyl, cyclopcntyl, hcxyl,
`cyclobexyl, heptyl.
`isoheptyl, octyl,
`isooctyl. oonyl,
`isooooyl, decyl, isodecyl, undecyl. iso:mdecyl, dodecyl, isod-
`odccyl, triJecyl, isotridecyl, wtmdt:cyl, isotctr<~decyl, penta(cid:173)
`Jc..'Cyl, isopcntadccyl, hexadc..'Cyl, isohexadecyl, hcptadccyl,
`isobeptadecyl. octadc..'Cyl, isooctadccyl, and isomers thereof,
`among which octyl and its isomer (e.g. isooctyl, sec-octyl,
`1-mcthylheptyl, 1-cthylhcxyl, 2-ethylhexyl, 1-propylpcutyl,
`l ,5-dimcthylhcxyl, I , I .),3-tctrnmcthylbutyl, etc.) arc prelcr(cid:173)
`ablc, and I, I ,3,3-tetnmlcthylbutyl which is an isomer ofoctyl
`groups is especially preferable.
`The <Jry) in the alkyl aryl polycther alcohol type polym.:r
`can be preferably a phenyl residue. 'lb-: polyether alcohol can
`be reprc..'Sented by the fom1ula O(CI 12Cll20).l I in which X is
`an integer of'S to 100, prefer..tbly 5 to 30, more preferably 8 to
`J 0. The average polymeri:z.ation deg!'E'e is preferably about 3
`to 10.
`Among the above-mentioned alkyl aryl polycther alcohol
`type polymers, tyloxapol having the following formula is
`especially preli.mtblc.
`
`60
`
`Page 10 of 18
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`

`
`Case 1:14-cv-00667-JBS-KMW Document 1-1 Filed 01/31/14 Page 5 of 9 PageID: 11
`
`US8, 129,43 1 8 2
`
`5
`
`R (CII2CIIt>> xH
`,.- 8- 10
`Ill 6
`
`5
`
`6
`weight to the maximum content of ;tbotn 0.5 or I rart by
`weight, relative to I part by weight of 2-amino-3-(4-bro(cid:173)
`mobcn:t.oyl)phcnylacctic acid or it~ pham1acologically
`acceptable salt or a hydrate thereof.
`The preservative used in the present invention includes, for
`exmnple, qumern:tl)' wnmonium salts (e.g. benzalkonium
`chloride, benzcthonium ch loride, etc.), chlorhexidinc glu(cid:173)
`conate, and the like, among which bcnn1lkonium chloride is
`10 especially prefemble.
`Further, so long as the purpose of tlte present invention is
`achieved. conventional various additives such as ismonics,
`buffers, thickners, stabilizers, chelating agents, pH control(cid:173)
`ling agents, perfumes and the like may be appropriately added
`1 s to thcaqm .. 'Ous liquid preparation of the present invention. The
`isotonics include sodium chloride, pntnssimn chloride, glyc(cid:173)
`erine, mannitol, sorbitol, boric acid, glucose, propylene gly(cid:173)
`col and the like. The buJTers include, for example. phosphate
`buffer. bomte buffer, citrate butler. tartarJtc buller, acetate
`2u butler. boric actd. borax, amino actds. and the like. 'Inc thick(cid:173)
`ners include polyvinylpyrrolidone. carboxymcthylcellulose.
`carboxypropylccllulosc, hydroxyethylccllulosc, hydn,x(cid:173)
`ypropylcellulose, hydroxypropylruethylccllulose, polyvinyl
`<~ lcohol, sodium polyacrylate, and the like. The stabilit~ers
`include sullitcs such as sodium sulfite und the like. Thechclat(cid:173)
`ing agents include sodium edctatc, so:lium citrate, condens"-d
`sodium phosphate and the like. The pi I controlling agents
`include hydrochloric acid. sodium hydroxide, phosphoric
`Jo acid, acetic acid and the like. The pufumcs include 1-mcn(cid:173)
`thol, bornt...'OI, camphor, Pucalyptus oil, and the like.
`With respect to the concentrations of the above various
`additives in the aqueous liquid preparation of lhc prc>enl
`invention, the isotonic is incorporated into an osmotic pres-
`35 sure ratio of about 0.8 to 1.2, and the concentrations of the
`buffer and the thickncr to be added nrc about 0.0 I to 2 w/v%
`and 0.1 to 10 w/v %. respectively.
`The pll of the aqueous liquid preparation of the present
`invention is adjusted to about 6 10 9, preferably about 7 to 9,
`especially about 7.5 to 8.5.
`So longus I he purpose of the prescut invenlion is achieved,
`other same or ditlcrcnt kind of active ing.rcdicnts may be
`appropriately udd'-'<.1.
`'lbcaqll'-'OUS liquid prepantlion oftlte present invention can
`be prepared by per sc known method nr according to the
`method as described in the Jarancs...: l'harmacopocia, 14'h
`Edition, General R11les for Prepnmtions. Solutions or Opb-
`so lhalmic solutions.
`'I be aqueous liquid preparation oflhe present invention can
`be appli"-d to warm-blooded animals such as htunan. rat.
`mouse, rabbit, cow. pig. dog. cat. and the like.
`The aquc.."'us liquid preparation ofthc present invention can
`be prepared easily by dissolving the above-mentioned com(cid:173)
`ponents in, for example, distilled water or sterile purified
`water. For example, the aqueous liquid preparation in the
`form of an eye drop can be used for the treatment of in1lam-
`60 matory diseases in anterior or posterior segment of the eye
`such <Is blepharitis, conjunctivitis, scleriti~. postoper<Itive
`innammation, and the like. The dose of the aqueous liquid
`preparation containing 0.1 w/v% of sodium 2-amino-3-(4-
`bromobcnt.oyl)phcnylacetatc hydrate is, for example, admin-
`65 istered to an adult 3 to 6 times daily in an amount of I to 2
`drops per one time. Depending on the degree of diseases,
`frequency of dosing, is appro