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.
`
`LUPIN, LTD. and LUPIN
`PHARMACEUTICALS, INC.,
`
`
`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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`SENJU EXHIBIT 2007
`LUPIN v SENJU
`IPR2015-01100
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`PAGE 1 OF 18
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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
`
`7.
`
`8.
`
`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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`#23581246 v1 (140859.2)
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`PAGE 2 OF 18
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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.
`
`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
`
`(“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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`#23581246 v1 (140859.2)
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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
`
`patent.
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`#23581246 v1 (140859.2)
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`PAGE 4 OF 18
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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
`
`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
`
`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
`
`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.
`
`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;
`
`4.
`
`enjoin Lupin and all persons acting in concert with Lupin from seeking, obtaining
`
`or maintaining approval of Lupin Ltd.’s ANDA No. 206027 until expiration of the ’431 patent;
`
`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
`
`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,
`
`
`
`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
`
`
`
`
`
`
`#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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`Case 1:14—cv—OO667—JBS—KMW Document 1-1 Filed 01/31/14 Page 1 of 9 Page|D: 7Case 1:14—cv—OO667—JBS—KMW Document 1-1 Filed 01/31/14 Page 1 of 9 Page|D: 7
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`
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`EXHIBIT AEXHIBIT A
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`
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`PAGE 7 OF 18PAGE 7 OF 18
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`PAGE 7 OF 18
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`Case 1:14-cv-00667-JBS-KMW Document 1-1 Filed 01/31/14 Page 2 of 9 PageID: 8
`Case 1:14—cv—OO667—JBS—KMW Document 1-1
`Filed O1/31/14 Pafie 2 of 9 Pafie|D: 8
`MWWWWWMMWMW
`WWWM
`
`US008l29«’-13lB2
`
`(12) United States Patent
`
`Sawa et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,129,431 B2
`Mar. 6, 2012
`
`(54) AQUEOUS LIQUID PRl§l’.*\R.~\'I‘lON
`CONTAIN} NG 2_AMlN0_
`3_{4_BRONl0BENz0Y.[‘}P"EN.YLi\CE,”(:
`ACID
`
`(75)
`
`inventors: Shirou Sawa. Kobe-(J1-‘);SlJuhei Fujita.
`mwwet
`(73) Assig,t1ee: Se-nju Pharmaceutical (.'o.. lltdu‘ Osaka
`(JP)
`
`( "‘ ) Notice:
`
`Subject to any tlisclailncr. the term ol‘ this
`patent is extended or atiitlsted under 35
`U.S.(‘. 151-lfb) by 604 days.
`
`(21) App1.No.:
`
`10J'S25,006
`
`(22) PCT Filed:
`
`Jan. 16.. 2004
`
`(86) PCT No.2
`
`I’( T'l‘!J l"20041'll0ll35ll
`
`§ 37"] (C}(l).
`(2). (4) Date.’
`
`Mar. 28, 2005
`
`(87) PCT Pub. No; W02004J064828
`
`l’("l‘ Pub. Date.’ May 8.. 2004
`
`(65)
`
`(30)
`
`Prior Publication Data
`
`US 200510239895 Al
`
`Oct. 27', 2005
`
`Foreign Application Priority Data
`
`Jun. 21. 2003
`
`(JP)
`
`2003-1242?
`
`(51)
`
`Int. Cl.
`AWN}?/I8
`(2006.01)
`AOIN.i'?/44
`(2006.01)
`AOIN.?7XIO
`(2005.01)
`AGIK 31/165
`(2006.01)
`(2006.01)
`/161K 31.04
`(2006.01)
`A6IK 31/19
`5141619: 514535: 514.570: 5140118
`(52) U.S. (Tl.
`(58)
`Field of(L'lassification Search
`5l4.’S6?.
`5140319. 535. 570;
`-1241'-436
`Set: application lilo for complete searclt history.
`
`(56)
`
`References Cited
`
`U .S. PATl"'.NT D()(.‘UM1'~IN'l‘S
`-4.U45.5?t’i A
`8"'|‘9".-"F W<:lstca.d..1r. ctatl.
`4.683.242 A
`?.~"l§}S'.-' Poser
`4.910.225 A
`3.51990 Ogawa at :11.
`5.110.493 A
`S.«"|9‘)2
`(.‘hemg—(.'hyi ct :11.
`514E619
`5,425,034 A "‘ 131995 Y:1n.niet ai.
`.
`.. 424."-42?
`5,540,930 A "‘
`‘H1996 Guyet al.
`
`i.-'']‘)‘)".'' Bergaminiet
`.
`5.591560 A
`.............. .. 4241"7"X.lJ4
`5.603.929 A ’“
`2."l99'."
`l)t2S.tiiu1. al.
`5,653,972 A
`3.-“I997 Dcsai U1. al.
`“
`5,998,465 .-’\
`l2."I99$} Hellberg i.-12.1.
`6.319.513 Bl “
`|lr"3UD]
`l)ob11J'./.5i
`6,369,112 BI “
`4.-"2002 Xia
`
`514.-“#432
`424:’-434
`5l4.9'G3-5
`
`,.
`
`PAGE 8 OF 18
`
`A
`514-“.35
`
`(“hen at al.
`5103002
`R1
`{Tagle et al.
`5.-£21102
`.
`. 4 1 H1 *
`4.-2001 Sawa
`200?.-008285? Al
`FORl7.'lGN PATl_':NT l)(}(.‘1lMl'€N'l'S
`70? I I9
`E‘-‘E1995
`2 013 [88
`951990
`300
`we
`
`AU
`CA
`ii
`
`W0
`WT]
`W0
`
`3.-2001
`W001.-"[5072 A2 *
`_";'2lJUl
`\-VU 0115677 A2 "‘
`212002
`02113804
`OTIIER PIJ'l'3l.lCA'i'lONS
`
`ISTA I’l1aIrna.ct:utical5j. "New Drug Appi.ca.tions: Xibrom", htlp:..-‘.-'
`vtt'v.'W.dnIgs.cotm'nda.-'xibrom 040525.hI.ml. accessed online Sop.
`I9. 2007.‘
`Nolan. el 241.; The topical a.nti—infla.Inmatorya.nda.n:1igc5ic properties
`ofbi'om1L‘nit.' in rodents: Agentsand At.‘tions:ALIg. 1988: 25{'1—21.'?‘T—
`85. &|b5l.ra.L:t.*
`Nolan. et at. (_“'|'he topicla anti -inflatnntatory and analgesic proper-
`ties of bromfenau: in |'ot|<:ut5": 1933', Agents and Actitins. 25(1-2):
`T’?—85.“
`New l)I'ugs in Japan. 200l.200l Edilion.I'ublisl1ed by‘s’akuji Nippo
`Ltt‘1.. May 11, 2001.. pp. 2?-29. and its English Inmslation of the
`material portions.
`{Ioneeled partial English translation 0|‘ New Dmgs in Japan, 2001.
`2001 Edition. Published by Yi|.l('|.{il Nippo 1.td.. May II. 2001. pp.
`22-29. previously submitted on Apr. 1 l. 2005.
`{Iomplcte lrlnglish translation of New Drugs in Japan. 200i. 200!
`litiition, PtJblishet1h)’Y.1kujiNippt: l.td.. May 1 1, 2001. pp. 22-29.
`-.\loLit:e offlpposilion dated Feb. I‘). 200.‘) issued by 1-Ipo in connection
`with the corresponding European patent 3|:-pl.lCEi.llt)I1 and Opposition.
`hllp:i’."rnet'lica]—dictionary.IltefreedictionaJ'y.con1Jprophy1.=tc£ic_:tc-
`ceased Dec. 15. 2009.
`
`"‘ cited by examiner
`
`Sreeui l’ad1nanablJau
`
`Pr.I'mar_t-' 1_’xa.rm‘m'r
`./i.t':;is.trtr:! ]:'.rm:r:i1*:e'r
`
`l .ayla Sorouslt
`(T4) .»Ii‘rormr_i'. A'gc.'.'2.t. or firm Wcndemth, 1 ind 8:. Pona-ck,
`L1. .1’.
`
`(57)
`
`.-\BS'l‘RA( :1‘
`
`An aqtleotls liquid preparation of the present invention con-
`taining 2—amit1o—3—(4—brontobenmyljphenylacetic acid or its
`pltarntacologically acceptable salt or :1 hydrate thereof. an
`alkyl aryl polyetlier allcoltol type polymer such as tyloxupol.
`or a polyethylene glycol fatty acid ester such as polyethylene
`glycol moiiostearate is stable. Since even in the east: wiiere a
`preservative is incorporated into said aqueous liquid prepa-
`ration,
`the preservative exhibits a suflicieilt preservative
`effect for a long time. said aqueous liquid preparation in the
`form oliart eye drop is useful for the tteattnent ollblepharilis.
`cotijunctivitis. sclerilis. and postoperative inllammation.
`Also. the aqueous liquid preparation C-fthe present invention
`in the form of a nasal drop is u.~'efL.l
`for the ll'£:'3lmBl11 of
`ullergjt.‘ rhinitis tund ititlatntiiatory rhinitis (e.g. chronic rhini-
`tis. ltypcrtroplzic rliinilis. nasal polyp. clan).
`
`22(.‘lain1s, No l)rawings
`
`PAGE 8 OF 18
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`US 8,129,431 B2
`
`1
`AQUEOUS LIQUID PRl*JPARA'l'ION
`C()N'l"AlNl-NG
`2-AMINO-3-(4-BROMOBENZ.0YL)PIIENYLAC IC'l‘[(?
`.-\(TI D
`3
`
`This application is at US. national stage of lnterrtatiortal
`Application No. t‘Cl}'JI’2004f0t)0350 filed Jan. I6. 2004.
`
`'FEt‘HNI(.TAI. I’IljLD
`
`The present invention relates to an aqueous liquid prepa-
`ration containing 2—amino-3-[4-bromobenzoyl)phenylacetic
`acid or an pharmacologically acceptable salt thereof or a
`hydrate thereof. More particularly.
`the present
`invention
`relates to an aqueous liquid preparation containing 2-amii1o-
`3-(4-bromobe|m)yl)phcny1acctic acid or a pharmacologi-
`caily acceptable salt tliercolior a hydrate thereof and an alkyl
`aryl polycther alcohol type polymer or a polyethylene glycol
`fatty acid ester.
`
`BACKGROUND ART
`
`i0
`
`15
`
`Bciimylplieriylacetic acid derivatives including bromfenac
`(generic name) offormula (I):
`
`35
`
`U
`
`N113
`
`(Tilt)! I
`
`Br
`
`of which chenrtical name is 2-amino-3-(4-brot11oben2‘.oyl]
`phenyiacelic acid are known as disclosed in ll’-A—2?>(l52i’
`i977 and its corresponding U.S. Pat. No. 4,045,575.
`2-.’\tnino-3-(4-bromobenxoy I )phe11ylace1ic acid, its pharma-
`coiogically acceptable salt and :1 hydrate thereofare known as
`a non-steroidal anti~intlani.n1atory agent. and they are effec-
`tive against inflammatory diseases of anterior or posterior
`segntertt ofthe eye. such as blepharitis. conjunctivitis. scien-
`tis, and postoperative iriilainrnation in the field of ophthal-
`niology. and its sodium salt has been practically used in the
`form ofcye drops (“New Drugs in Japan. 2001“. 2001 I7.d.i-
`tion, Published by Yakuji Nippo Ltd., May I], 20101, p.
`27-29).
`'lhe eye drop as mentioned above is designed to stabilize
`2—an1ino—3—{4~broit1obeimoy|)plienytacetic acid by means of
`addition of a water-soluble polymer (e. g. polyviriylpyrroli-
`done. polyvinyl alcohol, etc.) and a Sulfite (cg. sodium
`sultite, potassium sullitc. etc.) (Japanese patent No. 2,683.
`675 and its corresponding US. Pat. No. 4.910.225).
`in addition. as an eye drop other than the above—n'ientioneCl
`one. Japanese patent No. 2,954,356 (corresponding to l.J.S.
`Pat. Nos. 5.603.929 and 5.653.9?2) discloses a stable oph-
`thalmic composition which comprises incorpot"ating an anti-
`bacterial quaternary tI.l]'lI’t10l'li‘t.1l‘]‘l polymer and boric acid into
`an acidic ophtlralmie agent. The acidic agent described
`therein includes. for example, 2-amino—3—[4—bron1obenz.oyl}
`phenylacetic acid.
`Furtlier,
`in Japanese patent No. 2,954,356, there is the
`following, description
`“fienzalkonium chloride is a widely
`used preservative in ophthalmic solutions. tlowever. ben7a-
`lkonium chloride and other quaternary anunonitun com-
`pounds arc generally considered to be incompatible with
`ophthalmic compositions ofdrugs with acidic groups, such as
`
`30
`
`35
`
`4o
`
`45
`
`_‘iU
`
`6U
`
`65
`
`2
`
`nonsteroidal anti—in.flan1n1atory drugs. These preservatives
`lose their ability to futiction as they forrn complexes with the
`charged drug conipounds".
`In these prior art references, there is no disclosure that alkyl
`aryl polyether alcohol type polymers or polyethylene glycol
`fatty acid esters are able to stabilize an aqueous liquid prepa-
`ration of 2-amino-3-(4-bromobcnzoyljphenylacctic acid or
`its pharmacological ly acceptable salt. and inhibit decrease in
`preservative ellccl of benzalkonittrn chloride and other qua-
`ternary atrtmonium compounds.
`
`I)ISC‘.l,t')Sll'RE OF‘ Tl-IF. ll‘lVlv".N'l'l()N
`
`It is an object ofthe present invention to provide an aque-
`ous liquid preparation comprising 2-ami11o-3-(4-broniobem
`zoyl}phenylacetic acid ora pharmacological Iy acceptable salt
`thereofor a hydrate thereof. which is stable within a pH range
`giving no irritation to eyes and in which. when a preservative
`such as benraikonium chloride is incorporated therein, pre-
`servative effect of the preservative does not substantially
`deteriorate.
`
`Another object of the invention is to provide a method for
`stabilizing an aqueous liquid prcpamtion of 2-:trnino-3-(4-
`bromoben'z.oyljplienylacctic acid or a pharmacologically
`acceptable salt thereof or a hydrate thereof.
`Further object of the invention is to provide an aqueous
`liquid preparation cornprising. 2—amit'|o—3—(4—broniobeIi:e:oyl)
`phenylacetic acid or a phannacologically acceptable salt
`thereofor a hydrate thcrcofand :1 preservative, wherein. when
`specifically a quaternary ammoniutn salt such as benzalko-
`niutn chloride is incorporated as at preservative. decrease in
`preservative effect of said preservative is inhibited.
`As a result of various studies. the inventors of the present
`invention have found that, by adding, for example. an alkyl
`aryl polyethcr alcohol type polymer such as tyloxapol. or a
`polyethylene glycol fatty acid ester such as polyethylene
`glycol rnonostearatc to an aqueous liquid preparation of
`2-3n'tino—3~(4-bromobcnzoyl)phcnylacetic acid or a pharma-
`cologically acceptable salt thereof or a hydrate thereof, the
`aqueous solution becomes stable within a pH range giving no
`irritation to eyes. and change ofthc 2-:i1'l1iEtt)-3-[4-bl'0l'tl0l)CI1-
`myijtphenylaeetic acid over time can be iltltibited. and litr-
`thcrinore, when the aqueous solution cotttains a preservative.
`deterioration in the preservative effect of said preservative
`can be inhibited for a long period o ftime. The inventors ofthe
`present inverttimi have thither studied extensively and corn-
`pletcd the present invention.
`Namely, the present invention relates to:
`[ l)An aqueous liquid preparation comprising 2—amii1o—3—(4—
`brotltobertzoyllphenylacetic acid or a pharrnacologically
`acceptable salt thereof or a hydrate thereof. and an alkyl
`aryl polyethcr alcohol type polymer or a polyetliylcite gly-
`col tatty acid ester,
`(2) The aqueous liquid preparation according to the above( 1).
`wherein the alkyl aryl polyether alcoliol type polymer has
`it polymeriaation degree ot'3 to It). the alkyl contains l to
`13 carbon atoms. the any} is a phcnyl residue. and the
`polycrher
`alcohol
`is
`represented
`by
`the
`tomiuln
`()(CH2(.‘I'i20)_,.Ii in which X is an integer of S to 100.
`(3) The aqueous liquid preparation according to the above (I)
`or (2), wherein the alkyl aryl polyether alcohol type poly-
`mer is tylo:-capo}.
`(4 ) "lite aqueous liquid preparation according to the above (1 ),
`wherein the carbon number of the fatty acid in the polyeth-
`ylene glycol fatry acid ester is I2 to I8,
`
`PAGE 9 OF 18
`
`PAGE 9 OF 18
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`

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`Case 1:14—cv—OO667—JBS—KMW Document 1-1 Filed 01/31/14 Page 4 of 9 Page|D: 10
`
`US 8,129,431 B2
`
`4
`taining 2-atnino—3—(-Lbromobenzoylipheuylacetic acid or a
`pharrnacologjcally acceptable salt
`thereof or a hydrate
`thereof. Also, an aqueous liquid preparation of the present
`invention. wherein a preservative is irtcorporated. has a suf-
`licient preservative effect.
`
`5
`
`Therefore. the aqueous liquid preparation of the present
`invention is advantageously used as an eye drop for the treat-
`ment of, lhrexamplc, blepharitis. conjunctivitis. scleritis. and
`postoperative inilatnmation. In addition, such aqueous liquid
`preparation can be used as El nasal drop for the treatment of.
`for example, allergic rhinitis and infitminuittiry rhinitis (e.g_
`chronic rhinitis. hypettrophjc rhinitis, nasal polyp, etc.).
`The pharruacologically acceptable salt of 2-an1iuo-3-(4-
`bromohenmoyl)phenylacetic acid inciudes, for example, an
`alkali metal salt such as sodium salt and potassium salt, and
`an alkaline earth metal salt such as calcium salt and tnag,ne—
`sititn salt. among which sodium salt is especially preferable.
`2-Amino-3-(4-bromobenzoy])pl1enylacetic acid and its
`pharrnacologically acceptable salt can be prepared according
`to the method as described in Jl’-A-23052.’ 1 9?? (correspond-
`ing to US. Pat. No. 4.0-45,576) or by a si111ilar method thereof.
`These conipounds can be obtained as their hydrate dependi ng
`' on synthetic conditions and recrystalliration conditions. The
`hydrate includes U2 hydrate.
`1 hydrate. and 3K2 hydrate.
`among wllich 3J2 hydrate is preferable.
`In the aqueous liquid preparation o l' the present invention,
`the content
`[concentration range) of 2-arnino-3-[4-brw
`tnoben7.oyl)phenylacetic acid om pliarniacoiogically accept-
`able salt thereof or a hydrate thereof is usually about 0.0] to
`0.5 wfv %._ preferably about 0.05 to 0.2 wfv "/0. especially
`about U_l wlv "0, and it is preferable to appropriately vary the
`content depending on the purpose of use and the degree of
`disease to be treated.
`
`I5
`
`St:
`
`3
`(5) The aqueous liquid preparation according to the above (1)
`or (4). wherein the polyethylene glycol fatty acid ester is
`polyethylene glycol monostearate,
`(G) The aqueous liquid preparation according to any one of
`the above ( l] to (3). wherein the concentration ofthe alkyl
`aryl polycther alcohol
`type polymer is selected from a
`range of minimum coiicentiation of 0.01 wtv % to maxi-
`mum concentration of 0.5 wt’v "/9.
`(T) The aqueous liquid preparation according to any one of
`the above [1]. (2) or (4). wherein the concentration of the in
`polyethylene glycol fatty acid ester is selected from arange
`of minimum concentration of (1.02 wfv % to maximunit
`concentration of 0.1 wtv %,
`(8) The aqueous liquid preparation according to any one of
`the above (1) to (7), wherein the concentration of tl1e
`2-arnino-3-(4-broniobenmyliphcnylacetic acid or a phar-
`macologically acceptable salt thereof or a hydrate tltereof
`is 0.0] to 0.5 wlv ‘Va,
`(9) The aqueous liquid preparation according to any one of
`the above
`to
`wherein benzalkonium chloride is 20
`contained as a preservative.
`(10) The aqueous liquid preparation according to anyone of
`the above (1) to (9). wherein the pharmacc-logically accept-
`able salt of2-amino-3 -(4-bromobenzoyliphenylacetic acid
`is :1 sodium salt,
`(1 1 ) The aqueous liquid preparation according to any one of
`the above (1 ) to (10), wherein the pH ofthe aqueous liquid
`preparation is within a range of? to 9,
`(12) The aqueous liquid preparation according to the above
`[1 1). wherein the pll of the aqueous liquid preparation is
`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-
`tion is an eye drop,
`(14) The aqueous liquid preparation according to any one of
`the above (I) to (12), wherein the aqueous liquid prepara-
`tion is a nasal drop.
`(15) An eye drop comprising sodium 2-atnino-3-(4-bro-
`mobenzoyl)pheny|acetate hydrate and 0.01 to t). 5 wtv "/E: of
`tyloxapol.
`(In) An eye drop comprising sodium 2-iI111ilIl0-3-{4-lJl'[t-
`nlobenzoyl)phenylacetate hydrate and 0.02 to ti. 1 wiv "’/o of
`polyethylene glycol monostearate.
`(17) A method for stabilizing 2-amino-3-(4-bromobenroyl)
`phenylaeetic acid or u phamiacologically acceptable salt
`thereof or a hyclrate thereof in an aqueous liquid prepara-
`tion. which comprises incorporating tyloxapoi or polyeth-
`ylene glycol ntonostearate into an aqueous liquid prepara-
`tion containing 2-amino-3-(4-hroniobenzoyDphetiylacetic
`acid or a pliarmacologically acceptable salt tltereof or a
`hydrate thereof. zuid
`(18)); method for inhibiting decrease in preservative effect of
`at preservative in an aqueous liquid preparation of2—amino-
`3-(4-brontobettzoylJphenylacetic acid or a pharmacologi-
`cally acceptable salt thereof or a hydrate thereof. which _
`comprises incorporating tyloxapol or polyethylene glycol
`nionosteamte into an aqueous liquid preparation contain-
`ing 2—at:t1ino—3-(4~bronJobenzoyl)ph-anylacetic acid or a
`phartnacologically acceptable salt thereof or at hydrate
`thereof and a preservative.
`According to the present invention. at stable aqueous liquid
`preparation containing 2—atniino-3-(4-bromobenzoy|)pheny-
`lacetic acid or a phartnacologically acceptable salt thereof or
`{I hydrate thereofcan be prepared by incorpomting an alkyl
`aryl polyether alcohol type polymer such as tyloxapol. or a
`polyethylene glycol fatty acid ester such as polyethylene
`glycol inonostcaratc into an aqueous liquid preparation con-
`
`4U
`
`45
`
`50
`
`60
`
`65
`
`The carbon number of the alkyl in the an alkyl aryl poly-
`ethcr alcohol type polymer which is a non-ionic surfactant
`used as a stabilizer for 2-amino-3-(4--bromoben2oyl)pheny-
`lacetic acid or a pharmacologically acceptable salt thcreofor
`a hydrate thereofis approximately 1 to 13 Specifically. the
`alkyl group includes. for exzxniple, methyl. ethyl, propyl. iso-
`propyl, cyclopropyl, butyl.
`isobutyl. sec—butyI.
`tert-butyl.
`cyclobutyl. pentyl. isopentyl. neopentyl, tert-pentyl. I-ethyl-
`prtopyl. 4-tnethylpentyl. 1,1-dimelhylbutyl. 2_.2-diniethylbu-
`tyl, 1.2-dimethylbutyl, 2-ethylbutyl. cyciopentyl. hexyl.
`cyclohexyl.
`heptyl,
`isoheptyl,
`octyl,
`isooctyl.
`nonyl.
`isononyl. decyl. isodecyl. undecyl. isoundecyl, dodeey1.isod—
`odecyl. tridecyl. istitiidecyl. tetmdec} 1. isotetradecyl. penta-
`decyl. isopentadecyl, hexadecyl. isohexadecyl. heptadecyl.
`isoheptadecyl. octadecyl. isooctadecyl. and isomers thereof.
`among which octyl and its isomer (cg. isooctyl. seccctyl.
`l-mcthylheptyl, 1-ethylliexyl. 2-cthylhcxyl. l-propylpenlyl.
`l,5-dimethylhcxyl, I,13,3-tetrantetliylbutyl, etc.) are preter-
`able. and 1,1.3,3-tetraniethylbutyl which is an isomer ofoctyl
`groups is especially preferable.
`
`The aryl in the alkyl aryl polyethci‘ alcohol type polymer
`can be preferably a phenyl residue. The polyether alcohol can
`be represented by the formula O(("l l:('_' l l_.,(J),‘lI in which X is
`an integer of'5 to 100. preferably 5 to 30. more preferably 8 to
`10. The average polynteriration degree is preferably about 3
`to 10.
`
`Among, the above-mentioned alkyl aryl polyethcr alcohol
`type polymers, tyloxapol having the following formula is
`especially preferable.
`
`PAGE 10 OF 18
`
`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
`Case 1:14-CV-00667-JBS-KMW Document 1-1 Filed 01/31/14 Page 5 of 9 PagelD: 11
`
`U’!
`
`US 8,129,431 B2
`
`6
`
`
`
`t'C‘ll3CI-I3O).1:H
`'
`R.
`x - 9- -l[J
`U1‘: 6
`
`The [ally acid of the polyethylene glycol fatty acid ester
`which is a non-ionic surfactant used as a stabilizer for
`
`2—antino-3-(4—hromoben7toyl)phenylacetic acid or a pharma-
`cologjcally acceptable salt thereofor a hydrate thereofcan be
`preferably a fatty acid having the carbon number of 12 to E8.
`Specific examples of such polyethylene glycol fatty acid
`esters are polyethylene glycol rnonostearate (e. g. p-olyoxyl 8
`stearate, polyoxyl 40 stearate, ete.). polyethylene glycol
`monolaurate. polyethylene glycol monooleate. polyethylene
`glycol diisosteamte. polyethylene glycol dilaurate. polyeth-
`ylene glycol dioleate. and the like. Among these compounds.
`polyethylene glycol nionostearule is preferable. and polyoxyl
`40 stearate is especially preferable. The polyoxyl 40 stearatc
`is a monostearic acid ester of an ethylene oxide condensed
`polymer. and can be represented by the l‘orn1ulaC1.,ll35CO()
`l_('l l_,_(.'| 120),} l which is a non-ionic surfactant and n is about
`40.
`
`Although the content (concentration range) of the alkyl
`uryl polyether alcohol type polymer in the aqueous liquid
`preparation oi" the present invention depends on the kind of
`coinpotlnds used. the otinirnum concentration is about 0.01
`wtv "/o and the ntaximunt concentration is about 0.5 wlv %.
`With respect to the tyloxapol content (concentration range).
`for exzuuple. the I1'lll'lll‘l1Lti']'.t content is about 0.01 wfv %, 0.02
`wfv % or 0.03 wfv ‘Va. and the ntainxintum content is about
`
`0.05 wlv %. 0.l wlv "/0, 0.3 wfv % or 0.5% wiv, and preferably
`the minimum content is about 0.02 wfv ‘Va and the maximum
`content is about 0.05 wiv %.
`
`Although the content (concentration range) otithe polyeth-
`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 of about 0.02 wlv % of minimum
`concentration to about 0.} w/v %ol‘tnaxiniurn concentration.
`For example. the content (concentration range) of polyethyl-
`ene glycol monostearate is within a range ofabout 0.02 wfv %
`of rrlinimum content to about 0.] wlv of maximum content.
`and preferably within a range of about 0.02 wlv % of the
`ntinii11ui11 content to about 0.05 wfv "/6 of the maximunt
`content.
`
`The incorporation ratio of tyloxapol in the aqueous liquid
`preparation ofthc invention is within a range of the minimum
`Colllent of about 0.1 or 0.2 part by weight to the nlaxiinutn
`content ofahout 0.5. 1, 3 or 5 parts bywcight_ relative to I part
`by weight of2-antino—3-(4-bromobenzoyhphenylacetic acid
`or its pharrnacologically acceptable salt or a hydrate thereof.
`The incorporation ratio of polyethylene glycol rnonostear-
`ate in the aqueous liquid preparation of the present invention
`is within a range ofthe minimum content of about 0.2 part by
`
`weight to the rnaximum content ol about 0.5 or 1 part by
`vvcight. relative to l part by weight of 2-amino-3-(4-bro
`rnobenmyl)phen_vlacetic
`acid or
`its pliarinacologically
`acceptable salt or a hydrate thereof.
`The preservative used in the present invention includes. for
`example. quaternary armnoniurn salts (cg.
`l1'K3tl?2IlliUl'llt.lIIl
`chloride. hen’/ethoniurn chloride, etc.), chlorhexidine glu-
`eonate. and the like. among which henralkonium chloride is
`especially preferable.
`
`Further. so long as the purpose of the present invention is
`achieved, conventional various additives such as isotonics.
`bulfers. Llticktters. stabilizers. chelating agents, pH control-
`ling agents. perfumes zuid the like may be appropriately added
`to the aqueous liquid preparation ofthc present invention. The
`isotonics include sodium chloride. potassium chloride. glyc-
`urine, It'lEIt‘tt'li1t)l_. sorbitol, bor