Case 1:14-cv-05144-JBS-KMW Document 1 Filed 08/15/14 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.
`
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`Plaintiffs,
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`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:
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`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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`Page 1 of 20
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`SENJU EXHIBIT 2009
`LUPIN v. SENJU
`IPR2015-01097
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`Case 1:14-cv-05144-JBS-KMW Document 1 Filed 08/15/14 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. 8,754,131 (“the
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`’131 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-05144-JBS-KMW Document 1 Filed 08/15/14 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.
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`The U.S. Patent and Trademark Office (“PTO”) issued the ’131 patent on June 17,
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`2014. The ’131 patent claims, inter alia, formulations of bromfenac for ophthalmic
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`administration. Plaintiffs hold all substantial rights in the ’131 patent and have the right to sue
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`for infringement thereof. Senju is the assignee of the ’131 patent. A copy of the ’131 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 ’131
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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-05144-JBS-KMW Document 1 Filed 08/15/14 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 July 3, 2014, purporting
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`to be a Notice of Certification for ANDA No. 206027 (“Lupin’s notice letter”) under Section
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`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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`’131 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 ’131 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 ’131 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 ’131
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`patent.
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`Case 1:14-cv-05144-JBS-KMW Document 1 Filed 08/15/14 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:
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`1.
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`enter judgment that, under 35 U.S.C. § 271(e)(2), Lupin has infringed at least one
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`claim of the ’131 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
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`United States of Lupin’s generic bromfenac ophthalmic solution before the expiration of the ’131
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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 ’131 patent,
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`or such later date as the Court may determine;
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`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 ’131 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 ’131 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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`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: August 15, 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.
`
`
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`-6-
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`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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`Page 6 of 20
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`

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`Case 1:14-cv-05144-JBS-KMW Document 1-1 Filed 08/15/14 Page 1 of 11 PageID: 7
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`EXHIBIT A
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`Page 7 of 20
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`

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`Case 1:14-cv-05144-JBS-KMW Document 1-1 Filed 08/15/14 Page 2 of 11 PageID: 8
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`11111111111111 111 1111111111 111111111111111111111111111111111111111111111111
`US008754 I 3 I 82
`
`(12) United States Patent
`Sawa et al.
`
`( 10) Patent No.:
`(45) Date of Patent:
`
`us 8,754,131 82
`*Jun.17,2014
`
`(54) AQUEOUS LIQUID PREJ>ARATIO~
`CONTAINING
`2-AMlN0-3-( 4-BROMORF.NZOYI ,)J>IIJ<: NYI .ACETIC
`ACJI)
`
`(7 1) Applicm1t: Scnju Pharmaccutico1l Co., Ltd., Osaka
`(JP)
`
`(72)
`
`Inventors: Shirou Sawa, llyogo (JP); Shuhci
`Fujita, Hyogo (JP)
`
`(73) Assignee: Senju Pharmaceutical Co., Ltd., Osaka
`(.IP)
`
`( *) Notice:
`
`Subjt.'Ct to any disclaimer. the tem1 of this
`patent is extended or adjusted under 35
`lJ .S.C J54(b) by 0 days.
`'Jbis patent is subject to a ten11inal dis(cid:173)
`ciHimer.
`
`(21) Appi.No.: 14/165,976
`
`(22) Filed:
`
`Jan. 28, 2014
`
`(65)
`
`Prior l,ubllcation Ouh1
`
`US 2014/0142183 A I
`
`May 22, 2014
`
`Related U.S. Application Data
`(62) Division of.tpplicaliou No. 13/687.242, 11led on Nov.
`28, 2012, now Pat. No. 1\,669,290. which is a division
`of application No. 13/353,653, filed on Jnn. 19, 2012,
`now i'Ht. N(). X,497,104, which is a division of
`application No. 10/525,006, filed as application No
`PCT/JP2004/000350 on .Jan. 16, 2004, now Pat. No.
`8, 129,431.
`
`(30)
`
`Forcij!n Application Priority Oata
`
`Jan. 21, 2003
`
`(JP) ................................. 2003-012427
`
`(51)
`
`(52)
`
`(58)
`
`(56)
`
`(2006.01 )
`(2006.01)
`(2006.01)
`(2006.01 )
`(2006.01 )
`(2006.01 )
`
`lnt. CL
`AIHN371111
`A61K 311165
`AOIN 37144
`A6/K 31124
`AlliN 371111
`A6JK 31119
`u.s. ('I.
`US!>('
`514/619; 514/535; 5 14/570; 514/61!3
`Field of C lassification Search
`USPC .......................................... 5 14/6 19, 535, 570
`See application file Jor complete search history.
`
`References Cited
`
`U.S. PATENT DOCUMENf S
`
`4.045,576 A
`4,683,242 A
`
`4,910,?2~ ,,
`
`5,110,491 A
`5.475.034 A
`5.540.910 t\
`55SM,X76 A
`
`~ 1977 Welslead, Jr el al
`711987 l'oser
`'\1 1990 Ogawa .:l al
`51 1902 Chcrng-Chyi cl al.
`1211995 Yanni el al.
`7/ 19'J6 Uuy
`911996 ))csai ct al
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`5,597,560 A
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`6,274,609 Bl
`6.319.5 13 Bl
`6,369,1 12 Bl
`6,383,471 Bl
`6,395, 746 B I
`200 1/0056098 AI
`200710082857 A I
`
`Bergamini el al
`1/1997
`Dc~ai cl al.
`2/1997
`811997 Desai cl al.
`!!11999 Sawa
`1211999
`llcllbcrg et al.
`12/2000 De Bn1iju ct al.
`S/2001 Sawa
`S/2001 Yasueda el a!.
`111200 I Dobrozsi
`4/2002 Xia
`5/2002 Chen el al.
`5/2002 Cap,le et al.
`121200 I Sawa
`412007 Sawa
`
`AU
`CA
`EP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`wo
`wo
`WO wo
`
`1'0 1{ 1\l<iN PATI \NT IXX 'LJMI \NTS
`
`707 119
`2 011 18R
`0 306 9!!4
`62-126124
`1-104023
`020H3323
`2-124819
`5-223052
`'J-50379 I
`II-22!S404
`2002-308764
`96114829
`00159475
`01115677
`02111804
`
`9/1995
`<)/(()<)()
`J/19!SlJ
`6/1987
`4/1989
`3'1990
`5/1990
`~11991
`4 · 1')')7
`~1 19!19
`10/2002
`511996
`10/2000
`3/2001
`2/2002
`
`OTHER I'UBLIC'.A:riONS
`
`New Drugs in Jap1u1, 2001, 200 I Edition, Published by Y:1kuji Nippo
`Lid .. May II. 200 I, pp. 27-29, and its English translation of I be
`material ponions.
`ISTA l'hnrm:Jccutic:lls, "~ew Drug Applications Xibrom", htlp If
`www.drugs.comlnd:llxibrom_ 040525.htmt. accessed online Sep.
`19,2007.
`Nolan et al., "'I h.: 'lopicaJ Anti-lnllrumnnloJy and Analgesic Proper(cid:173)
`ties ofBrom!cnic in Rodent~". Agents and Actions. vol. 25. No. 1-2.
`pp. 77-R~. Aug. I<JRR
`
`(Continued)
`
`l .ayla Sonmsh
`Priman• l:'xwniuer
`(74) Anorney. A gem. or Firm Wcndcroth Lind & Ponack,
`L.L.P.
`
`(57)
`
`ABSTRACT
`
`An aqu<.·ous liquid preparation of the present invention con(cid:173)
`taining 2-amino-3-{4-bmmobenzoyl)phenylacetic <Jcid or its
`phanmtCl>logically tu.:ceptablc salt or a hydr<lll' thereof. an
`alkyl aryl polyether alcohol type polymer such as tyloxapnl.
`or a polyethylene glycol fatty acid ester such as polyethylene
`glycol monostearatc is stable. Since even in the c••se where a
`preservative is incorporated into said aqueous liquid prepa(cid:173)
`ration, the preservative exhibits a sufficient preservative
`ell't-ct for a long time, said aqueous liquid prepar<ttiou in the
`form of an eye drop is uscn•l for the treatment of blepharitis,
`conjunctivitis, scleritis. and postoperative
`inflnmmntion.
`Also, the aque<.lUS liquid preparution of the present invention
`in the fom1 of a nasal drop is useful for the lrcatment of
`allel)l.ic rhinitis and inllammatory rhinitis (e.g. chronic rhini(cid:173)
`tis, hypertrophic rhinitis, nasal polyp. etc.).
`
`30 Cloilns, No Drnwln~-:s
`
`Page 8 of 20
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`Case 1:14-cv-05144-JBS-KMW Document 1-1 Filed 08/15/14 Page 3 of 11 PageID: 9
`
`US 8,754,131 B2
`Page 2
`
`(56)
`
`Rl.'fcrcoccs Cited
`
`an JER l'UI3LlCATJONS
`Corrcclcd p:trtwll:nghsh lr:lnslaiiO il of New l)n1gs 10 .lnp:m. 2001.
`200 I Edit10n, Published by Yakuji Nippo Ltd., 'Vlay I I , 200 I, pp.
`27-29, previously submil1ecl on Apr. I I, 2005.
`Complete Enslish lrnnslation of New Dn1gs in Japan, 200 I, 200 I
`Wit ion, Published by Yakuji Nippo Ltd . May II. 200 I. pp. 27-29.
`
`Notice of Opposition dated Feb. 19, 2009 issued by EPO 1n conncc(cid:173)
`lion with 1hc co rrespo nding European pmcnt applicn1ion and Oppo(cid:173)
`siiiOn.
`h11p:llmcdical-dlcllon.:uy.lhcfrccdiclionary.com'pmphylaclic
`accessed Dec. IS, 2009.
`II. Scott el al , "t'omparins lh<· Surli1cc I 'hc111ical Pwpc111cs and the
`Effccl of Salts on the ('loud Poinl of " Conventional Nonionic
`Surfa.Cianl, Oc1oxynol 9 (Triton X-100), and of its Oligomer.
`l'yloxnpol ( I rilon Wl{- 1339)", Journal of ('olio Ill and Interlace SCI(cid:173)
`ence, vol. 205. pp. 496-502, I 998.
`
`Page 9 of 20
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`Case 1:14-cv-05144-JBS-KMW Document 1-1 Filed 08/15/14 Page 4 of 11 PageID: 10
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`US 8,754,131 R2
`
`1
`\QUI.:OUS I.IQUID PJU:PAR .\TIOI'
`CONTAL~ I:"lG
`2- \'\1 1 ~0-3-(4-JlROMOBJ<:'IZOYI.)PH F.~YI •. \ C ETIC
`ACID
`
`:>
`
`IH'JJNICAL J'IELJ.)
`
`2
`In these prior llrtrelcrcnccs. there is no disclosure that alkyl
`aryl polycther alcohol type polymer.; or polyethyknc g.Jyco1
`fatty acid c~tcrs un: ublc to stabilite an a4ucous liqUid prepa·
`rJtion of 2-aminu-3-(4-bromobcOLOyl) phenylacetiC ac1d or
`its pham1acological ly acceptable salt. and mhibit decrease m
`preservative cm.'Ct of bent.alkonium chloride Wld other qua(cid:173)
`ternary ummonium compourlds
`
`DIS< "I OSlJRI · OF rl IF IN\'FNTJON
`
`The prc~cnt mvention relates to an aqu<.'Ous liquid prep<l-
`rat 11111 contuiuing 2-ami no-3-(4-bromobcn~:oyl)phenylacetic
`acid nr a pham1acologically acceptable salt thereof or a 10
`hydrutc then .. '\lf. Mon: purticulurly. the pr<.-:;cnt invention
`relates to an aqueous liquid preparation containing 2-amino-
`3-(4-bmmobcn:royl)phenylacelic acid or a pharmacolot~,i­
`cnlly acccptnblc salt thereof or a hydnllc thereof and lin alkyl 1,
`aryl polycthcr alcoholtypc polymer or a polyethylene glycol
`li111y ncid ustcr.
`
`BACKGROUND ART
`
`UcntJ.>ylphunylacctic acid derivatives including bromfcnnc
`(generic name) of li.1rmula (I):
`
`('()(JH
`
`llr
`
`)ll
`
`It is un ubJ<.'Ct of the pn .. -sent invention to provide an aque(cid:173)
`ous liquid prcp:m.uion comprising 2-ttmino-3-(4-bromoben(cid:173)
`zoyl)phenylacetic acid ora pharmacologicully acceptable salt
`thereof or u hydrutc thereof, which is stable within a pll rongc
`giving 110 irrit<ttionlo eye~ and in which, when u preservative
`such as bcnn1lkoniurn chloride is incorporated therein, pre·
`scrv:uivc eflcct of the prcscrvotivc docs not substantially
`dclcrior.tte.
`Another object of the invention is to provide a method li.1r
`20 stahili:rin~ nn uqucous liquid preparation of 2-amino-3-(4·
`bromobentJ.>yl)pheulylucetic acid or a phannucologicully
`acceptable suit thcr<.:of or u hydmte thereof.
`Fun her obj1.'Ct of the mvention is to prov1dc an aqueous
`liquid preparauon comprisin~ 2-amino-3-( 4-bromohen:r.oyl )
`'' phc.mylacl'liC acHI nr a phannacologtcally acceptable Sillt
`thereof or a hydrate ther<.•ofand a prl-sen:nive "'herein. when
`srx:cillcally a quaternary ammonium salt such as ben:r~'llko­
`nium chloride is incorpc.1rat1.'d :1s •• prescrvati•c. do..'CrC"J'iC in
`prcscrvalivc elli..'Ct ol s;ud pr~cnathe is mhibitcd.
`As a n.:sult of various studies. the inventors of the present
`invcntwn have l\1und th:u, by :tddinp.. Jbr example. an alk-yl
`aryl polyethcr alcnhol type polymer such as tyloxapnl. or a
`polyethylene glycol latty :tcid ester such as polyethylene
`glycol monostcaratc to :tn al)lll'<.lll\ h4u1d prepurauon ol
`3'\ 2-amino-3·( 4-brumobcn:royl)phenylacctic acid or a phamla(cid:173)
`colngicully acceptable s;tlt thereof or u hydratc thcro.."\lf, thl'
`nqucous solution becomes stable withtn a pi I mnge givmg no
`irritmion to eyes. :md chanp.c oft he 2-amino-3-( 4-brumobcn(cid:173)
`zoyl)phenylacctic m.:id over t1mc cm1 he 111hihitcd, and fur-
`40 thermore. when the :lqUI..'\lUS solulion contains a prescrv:ttivc,
`deterioration in the prescrvntivc etk>ct of said preservative
`cw1 be inhibill'd l(lr u long pcrind oftimc. 'l11c inventors nfthc
`present invention have li.Jnhcr studi<.-d extensively and com-
`pleted the pn.:sc11t i nvcntion.
`Namely, the prc.:sent invention relate:. to:
`(I) A11 aqucnus liqo1d preparation comprising 2-amino-3-(4-
`bromohcnmyl)phcnylacctic acid or a phammcologic<tlly
`acccptahlc ~alt thcr<.•of or :1 hydrate th~reof, and an alkyl aryl
`p<>l>·cthcr :llcoholtype polymer or a polyethylene g.lycol fany
`~~~ acid l'Stcr,
`(2) ll1caqueous liquid prcparJtion according to theabo\'c( I).
`wherein the alkyl aryl polyethcr alcohol type polymer has a
`polymem .. atiun dcg.rcc of'\ to 10. the alkyl contains I to IR
`carbon atoms. the :•ryll> a phenyl restdue. and the polycther
`~~ alcnhnl ts represented h> the limnula O(CII,CI 120),1 I 111
`'"h1ch X 1s :111 inli .. I.!.Cr ol 5 to I 00.
`(1 )'Inc aqu<.'Oll> hq\nd prcp;tr.llion uccnrding.to the abo\e (I)
`or (2). whcl'l!in the nlkyl aryl polyether alcohol type polymer
`is tylm..:tpul.
`6u (4) fheaqucous liqllld prepumtionuccurdingtothcabovc( I).
`wherein the carbun numher of the lhtty ,tcid in the polyethyl(cid:173)
`ene glycnl latty ucid e:-.ter ts 12 to I K.
`(5) ll1c aqucuus liquid prcpamtion according to the above (I)
`or (4), wherein the polyethylene glycol fatty acid ester is
`6'i polyethylene glyco I monostearJte,
`(6) The tKill\."\liiS liL)Uid preparation according to any one of'
`the ubovc ( I) to (3 ). wherein the concentration of the alkyl
`
`of which chemical nume is 2-amino-3-(4-bromobcnLoyl)
`phenylucctic acid arc known as disclosed in JP-A-23052/
`1 ?77 and its corr<.':iponding U.S. Pal. No. 4,045,576.
`2-Amino-3-( 4-bromobenzoyl)phcnylacetic acid, its phamla(cid:173)
`eoloj!.ically ucccptuble >alt ru1d a hydr.lle lhen.'ofare known as
`u non sten11dal unti·inllrunmatory agent. and they arc cll'cc(cid:173)
`tivc li!Winst inllummutory dist:<tses of anterior or posterior
`segment nit he eye, such as hlepharitis. conjunctivitis, sclcri·
`tis, and postopcmtivc inllmnmation in the field of ophthal(cid:173)
`nmlogy, and its snclium snit hm; been practically used in the
`form of eye dn1ps ("New Drugs in J:1pan, 200 I", 2001 lldi(cid:173)
`tion, Publi~ho..•d by Yukuji Nippo Ltd., May 11, 2001, p.
`27-21)),
`!"he eye dmp m, mentioned above is <.lcsigned to stabilit.c 4~
`2-umino-3·(4-bnllllllbenzoyl)phenylacetic acid by means of
`addition of a wuter-solublc JXllymer (e.g. polyvinylpyrroli(cid:173)
`done. pnlyvinyl alcohol, etc.) and a sullite (e.g. sodium
`sulfite, potassium sullltc, etc.) (Japanese patent No. 2,683,
`676 and it\ corrcspunding U.S. P<ll No. 4,910,225).
`In uddition, as Wl eye drop other than tbe abo•e-mentioned
`UJW, Jap;ul•.:se patent No. 2. 954,356 (corresponding. to U.S
`Pat. No~ 5.60.~.?29 a1ld 5,65 '\, 972) discloses a stable oph(cid:173)
`thalnue composition which comprisl-:; incorporating an a.nti(cid:173)
`h.K:tenal 4uatcmary ammonium polymer and bone acid into
`an :tc1d1c ophthalm1c agent
`'Inc ac1d1c agent d<.'Scribcd
`thereto 10cludo..'S, !{lr example. 2-amino-3-(4-bromoben/.O)'I)
`phcnylucctic m:id
`l·unhcr. in Japanese patent No. 2.954.356. then: b the
`fnllnwing dcscription-'"[kn~<tlkonium chloride is a widely
`used preservutive in uphthulmil: solutions. llowcvcr, bctll.:l(cid:173)
`lknnium chloride and nthcr 4uatcrnary ammonium com(cid:173)
`pounds :1rc l,l.Cnemlly considered to be incompatible with
`ophthnlmic compositions ofdn1gs with acidic groups, such as
`nonsten1idal anti-inflammatory drugs. T hese preservatives
`lose their ability to function as they form complexes with the
`churgcd dntg compounds".
`
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`
`US 8,754, 131 B2
`
`3
`aryl polyether ulcohol type polymer is sd~.-ctcd li·om a range
`nf minimum concentrdtinn ofO.OJ w/v to maximum concen(cid:173)
`tration of 0.5 w/v
`(7) The aqu~.·ous liquid prcpawtion according to any one of
`the above (I). (2) or (4). wherein the concentration of the
`polyethylene glycol fhtty ucicl ester is selected from orange of
`minimum concentwtion of0.02 w/v% to maximum com:cn(cid:173)
`trarion of 0.1 w/v %,
`(8) The aqueous liquid prcp(lration according to any one of
`the above (I) to (7), wherein the concentration of the HI
`2-amino-3-( 4-bromobcnztJyl)phcnylacct ic <tcid or a pharnw(cid:173)
`colngically acccpwblc snit thereof or a hydrate thereoris 0.0 I
`to 0.5 w/v.
`(9) The ~KJUL'ous liquid prepar:1tion accnrding to any one of
`the above ( I ) to (8), wherein ben·.wlkonium chloride;: is ..:on(cid:173)
`tilincd as a prcservntive,
`( 10) The aqu~.'Ous liquid preparation according to anyone or
`the above (I) to (9). wherein the phamwcologically acccpt(cid:173)
`abJ..: salt of2-amino-3-(4-bmmobcnzoyl)phenylacetic acid is 20
`a sodium salt.
`( II ) ll1c aqueous liquid preparation according to any one of
`the above (I) to (1 0), wherein the pi I ol' the aqueous liquid
`preparation is within <J range of7 to 9,
`( 12) The aqu1-'0us liquid prcp<tr..llion according to the above 2'
`( 1 I), wherein the pi I of the aquem1s liquid preparation is
`within a range of 7.5 to 8.5.
`( 13) The aqueous liquid preparation according to any one nf
`the <.tbove (I) to ( 12), wherein the aqueous liquid prcpar..1tion
`is an eye drop,
`( 14) The aqul.!ous liquid preparation according to :my one or
`the above (I) to ( 12). wherein the aqueous liquid preparation
`i~ a na~n 1 drop.
`(15) An eye drop comprising sodium 2-mnino-3-(4-bro(cid:173)
`mobenzoyl)phenylacetate hydrate and 0_0! to 0.5 w/v% of 35
`tyloxnpol,
`(16) An eye drop comprising sodium 2-amino-3-(4-bro(cid:173)
`mobcnzoyl) phcnylacctnte hydrate and 0.02 to 0. I w/v of
`polyethylene glycol monostearate,
`( 17) A method Jor stabilizing 2-amino-3-(4-bromobenwyl)
`phenylacetic acid or a pham1acologically acceptublc salt
`thereof or a hydrate thcrcofin an aqueous liquid preparation.
`which comprises incorpomting, tyloxapol or polyethylene
`glycol monostcarnte into an :KJUCous liquid prcparminn con- 4'
`t.aining 2-amino-3-(4-bromobcnzoyl)phenylacetic acid or a
`plwnnacologic:illy acceptable wlt thl·ro.'(Jr or a hydntte
`thereoJ: and
`(I R) A method for inl1ibiting decrease in preservative effect of
`a preservative in an aqueous liquid preparation o f 2-amino-
`3-(4-bmmobcnzoyl)phcnylacctic acid or a pharmacologi(cid:173)
`cally acceptable salt thereof or a hydrate thcr..:ot: which com(cid:173)
`prises incorporating
`tyloxapol or polyethylene glycol
`monosteanile into an aqueous liquid prcpamtion containing
`2-amino-3-(4-bromobcn:t..oyl)phenylncctic acid or a phttnml(cid:173)
`colo~cally ;m.:eptable salt thereof or a hydrate thereof <Uld a
`preservative.
`According to the present invention_ u slablc aqueous liquid
`preparation containing 2-amino-3-( 4-bromobenzoyl)pheny(cid:173)
`l:H.:ctic m:itl or a pharmacolo!l.iCtllly acceptable salt thereof or
`a hydrntc thereof can be prep<• red by incorporating an alkyl
`aryl polycthcr alcohol type polymer sucb as tyloxapol. or a
`polyethylene glycol fany ncid e$ter such tiS polyethylene
`glyc.:olmonoste;mttc into an aqueous liquid preparation con- 6'
`taining 2-~mino-1-(4-hromobcnzoyl)phcny lacctic acid or a
`pharmacologically acceptable wlt tbcti.'Of or a hydrutc
`
`4
`thereof. Also. an aqueous liquid preparation of the present
`invention, wherein a preservative is incorpon•tecl, has a suf(cid:173)
`!lcicnt prcscrvntivc ..:!feet.
`Therefore, the aqut.'OUS liquid preparation of the present
`invention is advantogcously used as fill eye drop for the treat(cid:173)
`ment ot; tor example, blepharitis. conjunctivitis. scleritis. and
`postoperative inHammation. In addition, such aqueous liquid
`preparation cm1 be used as a nasal drop for the treutmcnt nf.
`for example, allergic rhinitis and ioflammatory rhinitis (e.g.
`chmnic rhinitis, hypertrophic rhinitis, nasal polyp, etc.).
`The phanm1cologically acceptable salt of 2-amino-3-(4-
`bromobcn;wyl)phcnylacctic acid includes, for cxumplc. m1
`t \ alkali metal salt such as soditu11 salt and potussium salt. and
`an alkaline earth metal salt such as calcium salt and magne(cid:173)
`sium snh. among which sodium salt i~ especially preferable.
`2-A.mino-3-(-t-bromobenzoyl)phenylacctic e~cid and its
`pham1acologically acceptable salt can be prepared according
`to the method us deticribed in .IP-A-23052/ 1 977 (correspond(cid:173)
`ing to U.S. Pat. No. 4,045,576) or by a similar method thereof.
`These compounds cun be obtained as their hydmt..: depending
`on synthetic conditions and recrystallization conditions 'Inc
`hydrate includes l/2 hydr.1tc, I hydriltc, nnd 1/2 hydmte,
`among, which 3/2 hydrate is prdbrable.
`ln the aqueous liquid preparation of the present invention,
`the content (concentration range) or 2-amino-3-( 4-bro-
`30 mobenmyl)phenylacctic acid or a phan11acologicully accept(cid:173)
`able salt ther~.·ofor a hydmtc thereof is usually ubout 0.01 to
`0.5 w/v %. preterably about 0.05 to 0.2 w/v %, cspcciully
`about 0.1 w/v % . and it is preferable to appropriately vary the
`content depending on the purpose of usc and the degr1.-c of
`disease to be treated.
`'l11c c.:<Jrbon number of' the alkyl in th.: an alkyl aryl poly(cid:173)
`ether alcohol type polymer which is a non-iunic surfactant
`us<:d us a stabilizer fi1r 2-amino-3-(4-bromobcnzoyl)phcny-
`40 )acetic acid or a pharmacologically acceptable salt thcr1.'0J' or
`a hydrate thereof is approximately l to 18. Specifically, the
`alkyl group includes. for example, methyl, ethyl, propyl. iso(cid:173)
`propyl, cyclopropyl. butyl. isobutyl. sec-butyl, tert-butyl.
`cyclobutyl. pentyl. jsopentyl, ncopcntyl. tcrt-pentyl. !-ethyl(cid:173)
`propyl, 4-methylpentyl, 1.1-dimethylbutyl. 2,2-dimcthylbu(cid:173)
`l ,2-dimcthylbutyl. 2-cthylbutyl. cyclopentyl. hexyl.
`tyl,
`cyclohcxyl, hepty 1.
`isohcptyl, octyl.
`isoot·tyl. nonyl.
`isononyl, dccyl, isoclccyl, undccyl. isoundccyl, dodecyl. isod-
`,11 odecyl, tridecyl, isotridecyl, tctradccyl. isotetradccyl, penta(cid:173)
`decyl. isopcnt<tdccyl, hcxadccyl. isobcxadccyl. hL'ptadccyl,
`isoheptadecyl, octadecyl, isooctadecyl, and isomers thereof.
`umong which nctyl nnd its isomer (e.g. tsnt)ctyl, scc-nctyl,
`1-methylheptyl, 1-ethylhexyl. 2-ethylhexyl, 1-propylpcntyl,
`11 I ,5-dimcthylhcxyl, 1,1,3,3-terramcthylbutyl, etc.) arc prclcr(cid:173)
`nble, and I, I ,3,3-tetnu11cthylbutyl which is an isomcrnfoctyl
`groups is especially preferable.
`The uryl in the alkyl aryl polyethcr alcohol type polymer
`can be prefembly a phenyl residue. Hu: pol yet her alcohol can
`60 be represented by the formula 0(('1 1i'I120),Il in which X is
`an intcg,crnf5 to 100, prclcranly 5 tn 30, mnre prcfcranly H to
`I 0. The average polymeri7alion degree is preJerably about 3
`to 10.
`Among the abovc-111entioncxf <tlkyl aryl ]X>lyethcr alcohol
`type polymers, tyloxapol having the f()l]owing formula is
`csp~.-cially preferable.
`
`Page 11 of 20
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`Case 1:14-cv-05144-JBS-KMW Document 1-1 Filed 08/15/14 Page 6 of 11 PageID: 12
`
`US 8,754,131 B2
`
`5
`
`C'll'
`
`('(('HJ)l
`
`(Cfi)CI!;O) l<l l
`R
`X 8-10
`'" ... 6
`
`The farty acid of the po lyethylene glycol fatty acid ester
`which is a non-ionic surfuwmt used as a stabilizer ltlr
`2-amino-3-(4-bromobenzoyl)phenylacetic acid or a phamla(cid:173)
`cologically acceptable salt thereof or a hydrate thereof can be
`preferably a lhtty acid having the carbon number of I 2 to I R.
`Specific examples of such polyethylene glycol fatty 11cid
`esters arc polyethylene glycol monoste<mlle (e.g. polyoxyl 8
`stearate, polyoxyl 40 stearate, etc.). polyethylene glycol
`monolmmtte, polyethylene glycol monoolcat..:, polyethylene 2'
`glycol diisostearate, polyethylene glycol dilaurate, polyeth(cid:173)
`ylene glycol dioleate, and the like. Among these compotmds,
`polyethylene glycol monostearate is preferable, and polyoxyl
`40 stcaratt! is ~!Specially preft!rable. The polyoxyl 40 stearate
`is a monostearic acid ester of an ethylene oxide condensed JO
`polymer, and can be represenwd by the formula C 171 I ,~COO
`(C 'I li'l 120).,1 I which is a non-ionic surfactant <Jnd n is about
`40.
`Although the l'Ontent (conccutrati<ln range) of the alkyl
`aryl polyether alcohol type polymer in the aqueous liquid
`prcpmation of the present invention depends on the kind of
`compounds used. the minimum concentration is about 0.01
`wlv and the maximum concentration is about 0.5 wlv %. With
`respect to the tyloxapol content (concentration range). ft1r
`example, the minimum content is about 0.01 w/v%, 0.02 wlv 41!
`or0.03 w/v %. and the maximum content is ilbout 0.05 w/v %,
`0. I wlv %. 0.3 wlv% or 0.5% wlv. and prelcrably the mini(cid:173)
`mum content is about 0.02 wlv %and the maximum content
`is about 0.05 w/v %.
`Allbaugh the content (conccntrution mngc) of the polyeth- 4)
`ylene glycol fatty acid ester in the aqueous liquid preparation
`of the present invention depends on the kind of compounds
`used, it is within a range nf about 0.02 wlv% of minimum
`concentration to a bout 0. I w/v% of maximum concentration.
`For cxampk. the content (concentration range) of polyethyl(cid:173)
`ene glycol monostcamte is within a range ofabout 0.02 w/v of
`minjmum content to about 0. I w/v Llfmaximum content. and
`prcli.!mbly within a nmgc of about 0.02 w/v% of the mini(cid:173)
`mum content to about 0.05 wlv o f the nmximtm1 content.
`'ll1c incorporation ratio of tyloxapol in the aqueous liquid
`preparation of the invention is within a rangeofthe minimum
`content of about 0.1 or 0.2 part by weight to the maximum
`content ofabout 0.5. I. 3 or 5 parts by weight, relative to I part
`by weight of2-amino-3-(4-bromobeuzoyl)phenylacdic acid
`or its phannacologically acceptable salt or a hydrate thereof.
`·n1c incorponttinn r.ttio of polyethylene ~~olycol monostem(cid:173)
`ate in the aqm.:ous liquid preparation of the present invention
`is within a range of the minimum content of about 0.2 part by
`weight to the m:1ximum content of nbout 0.5 or I part by
`w