Case 1:14-cv-05584-NLH-JS Document 1 Filed 09/08/14 Page 1 of 32 PageID: 1
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`
`
`LITE DEPALMA GREENBERG, LLC
`Michael E. Patunas
`Mayra V. Tarantino
`Two Gateway Center, Suite 1201
`Newark, NJ 07102
`(973) 623-3000
`mpatunas@litedepalma.com
`mtarantino@litedepalma.com
`
`Attorneys for Plaintiff Fresenius Kabi USA, LLC
`
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF NEW JERSEY
`
`
`Civil Action No.:
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`
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`
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`COMPLAINT
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`
`
`:::::::::::::::
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`
`FRESENIUS KABI USA, LLC,
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`
`
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`
`
`
`
`Plaintiff,
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`v.
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`EMCURE PHARMACEUTICALS USA,
`INC. and EMCURE
`PHARMACEUTICALS, LTD.,
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`
`
`
`
`
`
`
`
`
`Defendants.
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`Fresenius Kabi USA, LLC (“Fresenius”) brings this action for patent infringement
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`against Defendants Emcure Pharmaceuticals USA, Inc. and Emcure Pharmaceuticals, Ltd.
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`(collectively “Emcure”).
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`1.
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`This is an action by Fresenius against Emcure for infringement of United States
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`Patent No. 8,476,010 (“the ʼ010 patent”). This action arises out of Emcure’s filing of an
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`Abbreviated New Drug Application (“ANDA”) seeking approval by the United States Food and
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`Drug Administration (“FDA”) to sell generic versions of Diprivan®, an innovative intravenously
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`administered sedative and anesthetic, prior to the expiration of the ʼ010 patent.
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`
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`434941.1
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`

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`Fresenius
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`THE PARTIES
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`2.
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`Fresenius is a Delaware limited liability company with its principal place of
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`business at Three Corporate Drive, Lake Zurich, Illinois 60047. Fresenius Kabi USA, LLC was
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`formerly known as APP Pharmaceuticals, LLC.
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`Emcure
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`3.
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`Upon information and belief, Defendant Emcure Pharmaceuticals Ltd. is a
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`corporation organized and existing under the laws of India, with its principal place of business at
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`Emcure House, T 184, M.I.D.C., Bhosari, Pune, India 411 026.
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`4.
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`Upon information and belief, Defendant Emcure Pharmaceuticals USA, Inc. is a
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`corporation organized and existing under the laws of the State of New Jersey, with its principal
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`place of business in 21/B Cotters Lane, East Brunswick, New Jersey 08816.
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`5.
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`Upon information and belief, Defendant Emcure Pharmaceuticals USA, Inc. is a
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`subsidiary of and is controlled by Emcure Pharmaceuticals Ltd.
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`6.
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`Upon information and belief, both Emcure Pharmaceuticals Ltd. and Emcure
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`Pharmaceuticals USA, Inc. submitted, collaborated and/or acted in concert in the preparation or
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`submission of ANDA No. 206408 (“the Emcure ANDA”).
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`JURISDICTION AND VENUE
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`Subject Matter Jurisdiction
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`7.
`
`8.
`
`This action for patent infringement arises under 35 U.S.C. § 271.
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`This Court has jurisdiction over the subject matter of this action pursuant to 28
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`U.S.C. §§ 1331, 1338(a), 2201, and 2202.
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`434941.1
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`Personal Jurisdiction Over Emcure
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`9.
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`Upon information and belief, this Court has personal jurisdiction over Defendant
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`Emcure Pharmaceuticals Ltd. because Emcure Pharmaceuticals Ltd., through its subsidiaries,
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`affiliates and/or agents, including Defendant Emcure Pharmaceuticals USA, Inc., (1) conducts
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`business in this Judicial District; (2) has engaged in continuous and systematic contacts with
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`New Jersey and/or purposefully availed itself of this forum by, among other things, marketing,
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`making, shipping, using, offering to sell or selling, or causing others to use, offer to sell, or sell,
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`Emcure pharmaceutical products in this Judicial District, and deriving substantial revenue from
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`such activities and (3) has sought approval from the FDA to market and sell its proposed generic
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`Diprivan product throughout the United States, including in New Jersey. Upon information and
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`belief, Emcure Pharmaceuticals Ltd. uses its subsidiaries Heritage Pharma Holdings, Inc. and
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`Heritage Pharmaceuticals Inc. as its sales and marketing infrastructure in the United States.
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`Upon information and belief, Heritage Pharma Holdings, Inc., a wholly-owned subsidiary of
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`Emcure Pharmaceuticals Ltd., maintains a principal place of business in Eatontown, New Jersey.
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`Upon information and belief, Heritage Pharmaceuticals Inc., an indirect subsidiary of Emcure
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`Pharmaceuticals Ltd. and a wholly-owned subsidiary of Heritage Pharma Holdings, Inc.,
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`maintains a principal place of business in Eatontown, New Jersey. Upon information and belief,
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`Defendant Emcure Pharmaceuticals Ltd. also has committed, or aided, abetted, contributed to
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`and/or participated in the commission of, the tortious action of patent infringement that has led to
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`foreseeable harm and injury to Fresenius, which manufactures Diprivan® for sale and use
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`throughout the United States, including the State of New Jersey.
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`434941.1
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`10.
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`Upon information and belief, this Court has personal jurisdiction over Defendant
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`Emcure Pharmaceuticals USA, Inc. because Emcure Pharmaceuticals USA, Inc. (1) is
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`incorporated in and has its principal place of business in this Judicial District; (2) conducts
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`business in this Judicial District; (3) has engaged in continuous and systematic contacts with
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`New Jersey and/or purposefully availed itself of this forum by, among other things, marketing,
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`making, shipping, using, offering to sell or selling, or causing others to use, offer to sell, or sell,
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`Emcure pharmaceutical products in this Judicial District, and deriving substantial revenue from
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`such activities and (4) has sought approval from the FDA to market and sell its proposed generic
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`Diprivan® product throughout the United States, including in New Jersey. Upon information
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`and belief, Defendant Emcure Pharmaceuticals USA, Inc. also has committed, or aided, abetted,
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`contributed to and/or participated in the commission of, the tortious action of patent infringement
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`that has led to foreseeable harm and injury to Fresenius, which manufactures Diprivan® for sale
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`and use throughout the United States, including the State of New Jersey.
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`11.
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`Additionally, Emcure has been previously sued for patent infringement in this
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`district and did not contest personal jurisdiction. See Cephalon, Inc. v. Emcure Pharmaceuticals,
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`Ltd., C.A. No. 14-335-GMS, D. I. 9. Emcure has also purposefully availed itself of the rights
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`and benefits of this Court by asserting counterclaims in lawsuits filed in this Court. See Id.
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`Venue
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`12.
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`Venue is proper in this Judicial District under 28 U.S.C. § 1391 and 1400(b).
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`The Patent-in-Suit: United States Patent No. 8,476,010
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`BACKGROUND
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`13.
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`The ʼ010 patent, entitled “Propofol Formulations with Non-Reactive Container
`
`Closures,” was duly and lawfully issued on July 2, 2013 to inventors Neil P. Desai, Andrew
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`434941.1
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`Yang, and Sherry Xiaopei Ci. The named inventors assigned the ʼ010 patent to APP
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`Pharmaceuticals, LLC, which later changed its name to Fresenius Kabi USA, LLC.
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`Accordingly, Fresenius is the owner of all rights, title, and interest in the ʼ010 patent. The ʼ010
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`patent is listed in the FDA publication “Approved Drug Products with Therapeutic Equivalence
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`Evaluations,” commonly referred to as “The Orange Book” (“Orange Book”) with respect to
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`Diprivan®. The ʼ010 patent will expire on June 1, 2025. A true and accurate copy of the ʼ010
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`patent is attached hereto as Exhibit A.
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`The Diprivan® Drug Product
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`14.
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`Fresenius currently sells, promotes, distributes, and markets Diprivan® (propofol)
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`injectable emulsion in the United States.
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`15.
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`Diprivan® is indicated, generally speaking, for the induction and maintenance of
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`general anesthesia and sedation in certain patient populations.
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`16.
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`Fresenius holds an approved New Drug Application (“NDA”) No. 19627 under
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`Section 505(b) of the Federal Food, Drug and Cosmetic Act, 21 U.S.C. § 355(a) in connection
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`with the Diprivan® 1% (propofol) injectable emulsion product containing 10 mg propofol per 1
`
`ml of emulsion.
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`The Emcure ANDA
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`17.
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`Emcure filed with the FDA an ANDA under 21 U.S.C. § 355(j) seeking approval
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`to manufacture, use, offer for sale, sell in and import into the United States a propofol injectable
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`emulsion containing 10mg propofol per 1 ml of emulsion formulation, in 20 mL, 50 mL and 100
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`mL vials, that Emcure asserts is a generic copy of Diprivan® (“Emcure’s generic Diprivan®
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`products”) prior to the expiration of the ʼ010 patent.
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`434941.1
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`18.
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`19.
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`The FDA assigned the Emcure ANDA the number 206408.
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`Upon information and belief, Emcure filed with the FDA, pursuant to 21 U.S.C. §
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`355(j)(2)(A)(vii)(III), a certification that Emcure would not launch its generic Diprivan®
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`products until after the expiration of U.S. Patents Nos. 5,714,520; 5,731,355; 5,731,356 and
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`5,908,869 (“the ’520, ’355, ’356, and ’869 patents”).
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`20.
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`The ’520, ’355, ’356, and ’869 patents have an expiration date of March 22, 2015 and
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`have pediatric exclusivity with the FDA through September 22, 2015.
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`21.
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`Emcure filed with the FDA, pursuant to 21 U.S.C. § 355(j)(2)(A)(vii)(IV), a
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`certification alleging that the claims of the ʼ010 patent are invalid, unenforceable and/or would
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`not be infringed by the manufacture, use, importation, sale or offer for sale of Emcure’s generic
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`Diprivan® products (“Emcure’s Paragraph IV Certification”). Emcure notified Fresenius of this
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`certification, in a letter dated July 23, 2014 sent by U.S. Mail (“Emcure Notice Letter”).
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`22.
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`In the Emcure Notice Letter, Emcure offered Fresenius confidential access to
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`ANDA No. 206408 on terms and conditions set forth in an attached “Offer of Confidential
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`Access” (“OCA”). The initial OCA provided by Emcure contained various terms and
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`conditions, several of which went above and beyond protections typically afforded in a
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`protective order. For instance, the initial Emcure OCA barred Fresenius in-house counsel from
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`access to the Emcure ANDA.
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`23.
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`Fresenius and Emcure proceeded to negotiate the provisions of the OCA, and a
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`final version of the OCA was executed by both parties on August 18, 2014 which allowed certain
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`Fresenius in-house counsel access to ANDA No. 206408.
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`24.
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`On August 25, 2014, Fresenius received certain abbreviated portions of ANDA
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`No. 206408 from Emcure, pursuant to the OCA.
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`25.
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`On September 4, 2014, after reviewing the sections of ANDA No. 206408 that
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`were provided by Emcure, Fresenius requested further documents and information concerning
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`Emcure’s proposed generic Diprivan® product, including a complete production of the Emcure
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`ANDA. As of the filing of this Complaint, Emcure has begun producing responsive documents,
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`including a production of its voluminous ANDA which was not received until September 5,
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`2014. Fresenius’s counsel has not yet had sufficient time to review all of these documents and
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`other relevant information remains unproduced.
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`26.
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`Given the 45-day statutory deadline to file suit set forth in 21 U.S.C.
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`§ 355(j)(5)(B)(iii) and due to the limited information Fresenius has received from Emcure to
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`date, Fresenius turns to the judicial process and the aid of discovery to obtain, under appropriate
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`judicial safeguards, such information as is required to further confirm their allegations of
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`infringement and to present to the Court evidence that Emcure’s generic Diprivan® products fall
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`within the scope of one or more claims of the ’010 patent.
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`COUNT I FOR INFRINGEMENT OF U.S. PATENT NO. 8,476,010 BY EMCURE
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`27.
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`The allegations of paragraphs 1-26 are realleged and incorporated herein by
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`reference.
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`28.
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`The use of Emcure’s generic Diprivan® products is covered by one or more
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`claims of the ʼ010 patent.
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`29.
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`The commercial manufacture, use, offer for sale, sale, marketing, distribution,
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`and/or importation of Emcure’s generic Diprivan® products would infringe one or more claims
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`of the ʼ010 patent.
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`30.
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`Emcure has infringed the ʼ010 patent by submitting and maintaining the Emcure
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`ANDA before the FDA seeking approval to market Emcure’s generic Diprivan® products
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`containing propofol before the expiration of the ʼ010 patent.
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`31.
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`Upon information and belief, Defendants Emcure Pharmaceuticals USA, Inc. and
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`Emcure Pharmaceuticals Ltd. acted in concert and actively and knowingly caused to be
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`submitted, assisted with, participated in, encouraged, contributed to, aided and abetted, and/or
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`directed the submission and maintenance of the Emcure ANDA to the FDA.
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`32.
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`Defendants Emcure Pharmaceuticals USA, Inc. and Emcure Pharmaceuticals Ltd.
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`induced the infringement of the ʼ010 patent by actively and knowingly aiding and abetting the
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`preparation, submission, and maintenance of Emcure’s ANDA with the Paragraph IV
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`Certification and in the preparation to sell Emcure’s generic Diprivan® product in the United
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`States.
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`33.
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`Emcure was aware of the ʼ010 patent when engaging in these knowing and
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`purposeful activities and was aware that filing Emcure’s ANDA with the Paragraph IV
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`Certification with respect to the ʼ010 patent constituted an act of infringement of the ’010 patent.
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`34.
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`Use of Emcure’s generic Diprivan® products in accordance with and as directed
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`by Emcure’s proposed labeling for that product would infringe one or more claims of the ʼ010
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`patent.
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`35.
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`Upon information and belief, Emcure intends to engage in the manufacture, use,
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`offer for sale, sale, marketing, distribution, and/or importation of Emcure’s generic Diprivan®
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`products with its proposed labeling immediately and imminently upon approval of the Emcure
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`ANDA.
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`36.
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`Upon information and belief, Emcure plans and intends to, and will, actively
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`induce infringement of the ʼ010 patent when the Emcure ANDA is approved, and plans and
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`intends to, and will, do so immediately and imminently upon approval.
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`434941.1
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`37.
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`Upon information and belief, Emcure knows that Emcure’s generic Diprivan®
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`product and the proposed labeling for Emcure’s generic Diprivan® product is especially made or
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`adapted for use in infringing the ʼ010 patent and that Emcure’s generic Diprivan® product and
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`the proposed labeling are not suitable for substantial noninfringing use. Upon information and
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`belief, Emcure plans and intends to, and will, contribute to the infringement of the ʼ010 patent
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`immediately and imminently upon approval of the Emcure ANDA.
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`38.
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`The foregoing actions by Emcure constitute and/or would constitute infringement
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`of the ʼ010 patent, active inducement of infringement of the ʼ010 patent and/or contribution to
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`the infringement by others of the ʼ010 patent.
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`39.
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`Upon information and belief, Emcure acted without a reasonable basis for
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`believing that it would not be liable for infringing the ʼ010 patent, actively inducing infringement
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`of the ʼ010 patent, and/or contributing to the infringement by others of the ʼ010 patent.
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`40.
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`Fresenius will be substantially and irreparably harmed by Emcure’s infringing
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`activities unless the Court enjoins those activities. Fresenius will have no adequate remedy at
`
`law if Emcure is not enjoined from the commercial manufacture, use, offer to sell, sale in, and
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`importation into the United States of Emcure’s generic Diprivan® products.
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`41.
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`Emcure’s activities render this case an exceptional one, and Fresenius is entitled
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`to an award of its reasonable attorney fees under 35 U.S.C. § 285.
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`PRAYER FOR RELIEF
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`
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`WHEREFORE, Fresenius respectfully requests the following relief:
`
`a.
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`A judgment that Emcure’s submission of the Emcure ANDA No. 206408
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`infringes one or more claims of the ʼ010 patent and that the making, using, offering to sell, or
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`selling in the United States, or importing into the United States of Emcure’s generic Diprivan®
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`434941.1
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`products prior to the expiration of the ʼ010 patent will infringe, actively induce infringement,
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`and/or contribute to the infringement of one or more claims of the patent;
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`b.
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`An Order pursuant to 35 U.S.C. § 271(e)(4)(A) providing that the effective date of
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`any FDA approval of Emcure ANDA No. 206408 seeking approval to manufacture, use, offer
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`for sale, sell in and import into the United States a propofol injectable emulsion containing 10mg
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`propofol per 1 ml of emulsion formulation, in 20 mL, 50 mL and 100 mL vials, or any product or
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`compound the use of which infringes the ʼ010 patent, shall be a date that is not earlier than the
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`expiration of the patent;
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`c.
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`An Order permanently enjoining Defendants and all persons acting in concert
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`with Defendants from commercially manufacturing, using, offering for sale, selling, marketing,
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`distributing, or importing Emcure’s generic Diprivan® products, or any other product or
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`compound the use of which infringes the ʼ010 patent, or inducing or contributing to the
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`infringement of the ʼ010 patent until after the expiration of the patent;
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`d.
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`An Order enjoining Defendants and all persons acting in concert with Defendants
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`from seeking, obtaining, or maintaining approval of the Emcure ANDA No. 206408 before the
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`expiration of the ʼ010 patent;
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`e.
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`An award of Plaintiff’s damages or other monetary relief to compensate Plaintiff
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`if Defendants engage in the commercial manufacture, use, offer to sell, sale or marketing or
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`distribution in, or importation into the United States of Defendants’ generic Diprivan® products,
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`or any product or compound the use of which infringes the ʼ010 patent, or the inducement or
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`contribution of the foregoing, prior to the expiration of the patent in accordance with 35 U.S.C. §
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`271(e)(4)(C);
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`f.
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`A judgment that this is an exceptional case and awarding Plaintiff its attorneys’
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`fees under 35 U.S.C. § 285;
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`An award of Plaintiff’s reasonable costs and expenses in this action; and
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`An award of any further and additional relief to Plaintiff as this Court deems just
`
`g.
`
`h.
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`and proper.
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`Dated: September 8, 2014
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`434941.1
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`Respectfully submitted,
`
`LITE DEPALMA GREENBERG, LLC
`
`/s/ Michael E. Patunas
`Michael E. Patunas
`Mayra V. Tarantino
`Two Gateway Center, Suite 1201
`Newark, NJ 07102-5003
`(973) 623-3000
`mpatunas@litedepalma.com
`mtarantino@litedepalma.com
`
`Of Counsel:
`GOODWIN PROCTER LLP
`Daryl L. Wiesen
`John T. Bennett
`Sundar Subramanyam
`Srikanth Reddy
`Jennifer L. Ford
`Todd Marabella
`Exchange Place
`53 State Street
`Boston, MA 02109
`(617) 570-1000
`DWiesen@goodwinprocter.com
`JBennett@goodwinprocter.com
`SSubramanyam@goodwinprocter.com
`SReddy@goodwinprocter.com
`JFord@goodwinprocter.com
`TMarabella@goodwinprocter.com
`
`Attorneys for Plaintiff Fresenius Kabi USA, LLC
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`11
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`CERTIFICATION PURSUANT TO LOCAL CIVIL RULE 11.2
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`Plaintiff Fresenius Kabi USA, LLC, by its attorneys, hereby certifies that the matter in
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`controversy in this action is related to the following action before the United States District
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`Court for the District of Delaware: Fresenius Kabi USA, LLC v. Emcure Pharmaceuticals USA,
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`Inc. and Emcure Pharmaceuticals, Ltd., filed on September 8, 2014 (docket number not yet
`
`assigned).
`
`I hereby certify that the following statements made by me are true. I am aware that if any
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`of the foregoing statements made by me are willfully false, I am subject to punishment.
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`Dated: September 8, 2014
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`
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`LITE DEPALMA GREENBERG, LLC
`
`/s/ Michael E. Patunas
`Michael E. Patunas
`Mayra V. Tarantino
`Two Gateway Center, Suite 1201
`Newark, NJ 07102-5003
`(973) 623-3000
`mpatunas@litedepalma.com
`mtarantino@litedepalma.com
`
`Of Counsel:
`GOODWIN PROCTER LLP
`Daryl L. Wiesen
`John T. Bennett
`Sundar Subramanyam
`Srikanth Reddy
`Jennifer L. Ford
`Todd Marabella
`Exchange Place
`53 State Street
`Boston, MA 02109
`DWiesen@goodwinprocter.com
`JBennett@goodwinprocter.com
`SSubramanyam@goodwinprocter.com
`SReddy@goodwinprocter.com
`JFord@goodwinprocter.com
`TMarabella@goodwinprocter.com
`
`Attorneys for Plaintiff Fresenius Kabi USA, LLC
`
`
`434941.1
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`12
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`Case 1:14-cv-05584-NLH-JS Document 1 Filed 09/08/14 Page 13 of 32 PagelD: 13
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`EXHIBIT A
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`EXHIBIT A
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`Case 1:14-cv-05584-NLH-JS Document 1 Filed 09/08/14 Page 14 of 32 PageID: 14
`case 1:14'CV'05584'NLH'J5 DmmemFlllll’llllfllllfl’flflfllllfillllllllfilllllfllfllllfllilfllllfilfillflllfi
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`USOO8476010B2
`
`(12) United States Patent
`US 8,476,010 B2
`(10) Patent No.:
`Desai et al.
`(45) Date of Patent:
`Jul. 2, 2013
`
`(54) PROPOFOL FORMULATIONS WITH
`NON-REACTIVE CONTAINER CLOSURES
`
`(75)
`
`Inventors: Neil P. Desai, Pacific Palisades, CA
`(US); Andrew Yang, Rosemead, CA
`(US); Sherry Xiaopei Ci, San Marino,
`CA (US)
`
`(73) Assignee: APP Pharmaceuticals LLC,
`Schaumburg, IL (US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 510 days.
`
`(21) Appl.No.:10/616,709
`
`(22)
`
`Filed:
`
`Jul. 10, 2003
`
`(65)
`
`Prior Publication Data
`
`US 2005/0009731 A1
`
`Jan. 13, 2005
`
`(51)
`
`Int. Cl.
`A61K 38/00
`(52) US. Cl.
`USPC .............. .. 435/6; 435/613; 514/5.9; 514/9.3;
`514/13.6; 514/15.2
`
`(2006.01)
`
`(58) Field of Classification Search
`None
`
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,056,635 A
`4,452,817 A
`4,798,876 A
`5,439,686 A
`5,498,421 A
`5,560,933 A
`5,637,625 A
`5,665,382 A
`5,714,520 A
`5,731,355 A
`5,731,356 A
`5,908,869 A
`5,916,596 A *
`5,962,536 A
`6,028,108 A
`6,100,302 A *
`6,140,373 A
`6,147,122 A
`6,150,423 A
`6,177,477 B1
`6,326,406 B1
`6,362,234 B1
`6,399,087 B1 *
`6,469,069 B1
`6,576,245 B1 *
`2002/0006442 A1
`2007/0161601 A1
`2008/0132582 A1
`
`11/1977 Glen et a1.
`6/1984 Glen et a1.
`1/1989 Gould et a1.
`8/1995 Desai et a1.
`3/1996 Grinstaff et a1.
`10/1996 Soon-Shiong et a1.
`6/1997 Haynes
`9/1997 Grinstaff et a1.
`2/1998 Jones et a1.
`3/1998 Jones et a1.
`3/1998 Jones et a1.
`6/1999 Jones et a1.
`6/1999 Desai et a1.
`10/1999 Komer
`2/2000 George
`8/2000 Pejaver et a1.
`10/2000 May et a1.
`11/2000 Mirejovsky et a1.
`11/2000 Carpenter
`1/2001 George et a1.
`12/2001 De Tomaso
`3/2002 Hendler
`................ .. 424/405
`6/2002 Zhang et a1.
`10/2002 Mirejovsky et a1.
`6/2003 Lundgren et a1.
`........... .. 424/400
`1/2002 Mishra et a1.
`7/2007 Desai et a1.
`6/2008 Desai et a1.
`
`................. .. 424/489
`
`.............. .. 514/731
`
`EP
`W0
`W0
`W0
`W0
`W0
`W0
`
`FOREIGN PATENT DOCUMENTS
`0 390 244 A1
`10/1990
`WO 94/18954
`9/1994
`WO 99/00113
`1/1999
`WO 01/64187 A2
`9/2001
`WO 02/45709
`6/2002
`WO 2004/052401 A2
`6/2004
`WO 02/45709 A1
`6/2006
`
`*
`
`OTHER PUBLICATIONS
`
`Sautou-Miranda et a1. , International Journal ofPharmaceutics, 1996,
`130, pp. 251-255.*
`Sautou-Miranda et a1., International Journal or Pharmaceutics, 1996,
`130, pp. 251-255.*
`Sautou-Miranda et a1., International Journal of Pharmaceutics, 1996,
`130, pp. 251-255.*
`Bauer et a1., Pharmazeutische Technologie,: 256-257 (1986).
`Farinotti, Annales Francaises d ’Anesthesie et de Reanimation., 13:
`453-456 (1994).
`Jones, Anaesthesia and Intensive Care, 28(5): 587 (Oct. 2000).
`Naguib et a1., Anesthesiology Abstracts ofScientific Papers Annual
`Meeting,: 1 (Oct. 13, 2003).
`Sautou-Miranda et a1., International Journal of Pharmaceutics,
`130(2): 251-255 (1996).
`Trapani et a1.,InternationalJournalofPharmaceutics, 278(1): 91-98
`(Jun. 18, 2004).
`West Furotec Barrier Film,: 1-2 (Dec. 3, 2003) [http://webarchive.
`org/web/2003 120302363 0/http://www.westpharma.com/pr0ducts/
`flurotec .asp].
`Website, “Melagatran7Comp0und Summary (CID 183797)”, Nov.
`15, 2010, Publisher: http://pubchem.ncbi.nlm.nih.g0v/summary/
`summary.cgi?cid:183797.
`Website, “Pr0p0f017Substance Summary (SID 9726)”, Nov. 15,
`2010, Publisher: http://pubchem.ncbi.nlm.nih.g0v/summary/sum-
`mary.cgi?sid:9726.
`International Searching Authority, “International Search Report and
`Written Opinion for PCT/USO4/020923”, Aug. 18, 2005, Publisher:
`European Patent Office, Published in: EP.
`Arduino, et a1., “Microbial Growth and Endotoxin Production in the
`Intravenous Anesthetic Propofol”, “Infection Control and Hospital
`Epidemiology”, Sep. 1991, pp. 535-539, vol. 12, N0. 9.
`Baker, et a1., “Sulfite Supported Lipid Peroxidation in Propofol
`Emulsions”, “Anesthesiology”, Nov. 2002, pp. 1162-1167, v01. 97,
`N0. 5.
`Benz, et a1., “Electrical Capacity of Black Lipid Films and of Lipid
`Bilayers Made from Monolayers”, “Biochimica et BiophysicaActa”,
`1975, pp. 323-334, vol. 394.
`
`(Continued)
`
`Primary Examiner 7 Jon P Weber
`Assistant Examiner 7 Roy Teller
`(74) Attorney, Agent, or Firm 7 Blanchard & Associates
`
`(57)
`
`ABSTRACT
`
`A sterile pharmaceutical composition for parenteral admin-
`istration of propofol, said composition comprising propofol,
`optionally albumin, and less than about 10% by weight sol-
`vent for propofol, wherein said composition is stored in a
`container having a closure wherein said closure is inert to
`propofol.
`
`70 Claims, No Drawings
`
`

`

`Case 1:14-cv-05584-NLH-JS Document 1 Filed 09/08/14 Page 15 of 32 PageID: 15
`Case 1:14-cv-05584-NLH-JS Document 1 Filed 09/08/14 Page 15 of 32 PagelD: 15
`
`US 8,476,010 B2
`Page 2
`
`OTHER PUBLICATIONS
`
`De Sommer, et a1., “AbstractiA comparative study on the effects of
`propofol
`in emulsion and Intralipid on fat metabolism”, “Acta
`Anaesthesiol Belg”, 1990, pp. 133-138, vol. 41, No. 2.
`Eddleston, et al., “The effect on serum lipid concentrations of a
`prolonged infusion of propofolihypertriglyceridaemia associated
`With pro”, “Intensive Care Med”, 1991, pp. 424-426, vol. 17.
`Gottardis, et al., “Effect of prolonged sedation with propofol on
`serum triglyceride and cholestrerol concentrations”, “Br. J. Anaesth.
`”, 1989, pp. 393-396, vol. 62.
`Langevin, Paul B., “Propofol Containing SulfiteiPotential for
`Injury”, “Chest”, Oct. 1999, pp. 1140-1141, vol. 116, No. 4.
`
`Lindholm, M., “Abstract4Critically ill patients and fat emulsions”,
`“Minerva Anestesiol”, Oct. 1992, pp. 875-879, vol. 58, No. 10.
`Mayhew, et 31., “Characterization of liposomes prepared using a
`microemulsifier”, “Biochimica et Biophysica Acta”, 1984, pp. 169-
`174, vol. 775.
`Mirejovsky, et a1., “Pharmaceutical and antimicrobial differences
`between propofol emulsion products”, “Am J Health-Syst Pharm”,
`Jun. 15, 2000, pp. 1174-1177, vol. 57.
`Sosis, et a1., “Growth of Staphylococcus aureus in Four Intravenous
`Anesthetics”, “Anesth Analg”, 1993, pp. 766-768, vol. 77.
`
`* cited by examiner
`
`

`

`Case 1:14-cv-05584-NLH-JS Document 1 Filed 09/08/14 Page 16 of 32 PageID: 16
`Case 1:14-cv-05584-NLH-JS Document 1 Filed 09/08/14 Page 16 of 32 PagelD: 16
`
`US 8,476,010 B2
`
`2
`
`istered over extended time periods. In addition, compositions
`devoid of fats and triglycerides, with 3% w/v propofol
`(Haynes, US. Pat. No. 5,637,625) are said to be useful for
`sedation over extended periods of time.
`There are two major problems associated with the formu-
`lations described in the above patents: (1) the risk of micro-
`bial contamination due to the high nutrient content and lack of
`antimicrobial preservatives. Studies by Arduino, et al., 1991 ;
`Sosis & Braverman, 1993; and PDR, 1995, have shown that a
`propofol emulsion formulated without preservatives will
`grow bacteria and present a risk of bacterial contamination;
`(2) Hyperlipidemia in patients undergoing long-term ICU
`sedation due to a large amount of fat content. Studies have
`shown that triglyceride overload can become a significant
`problem when a 1% propofol/10% soybean oil emulsion is
`used as the sole sedative for a long period of ICU sedation by
`Gottardis, et al., 1989; DeSoreruer, et al., 1990; Lindholm,
`1992; and Eddieston, et al, 1991.
`To solve the problem of bacterial contamination of propo-
`fol emulsion, the following patented formulations ofpropofol
`have been developed:
`
`10
`
`15
`
`20
`
`1
`PROPOFOL FORMULATIONS WITH
`NON-REACTIVE CONTAINER CLOSURES
`
`FIELD OF THE INVENTION
`
`The invention generally pertains to pharmaceutical formu-
`lations of propofol, an intravenous anesthetic with enhanced
`microbial inhibition. More particularly, the invention pertains
`to propofol formulations that are stored in containers having
`non-reactive, or inert closures.
`
`BACKGROUND OF THE INVENTION
`
`Propofol (2,6-Diisopropylphenol) is a well-known and
`widely used intravenous anesthetic agent. For example, in
`intensive care units (ICU) where the duration of treatment
`may be lengthy, propofol has the advantage of a rapid onset
`after infusion or bolus injection plus a very short recovery
`period of several minutes, instead of hours.
`Propofol is a hydrophobic, water-insoluble oil. To over-
`come the solubility problem, it must be incorporated with
`solubilizing agents, surfactants, solvents, or an oil in water
`emulsion. There are a number of known propofol formula-
`tions, such as disclosed in US. Pat. Nos. 4,056,635, 4,452,
`817 and 4,798,846 all ofwhich are issued to Glen and James.
`Propofol compositions have been the subject of several
`patents. Typically, propofol compositions comprise 1-2% by
`weight propofol, 1-3% or 10-30% of a water immiscible
`solvent such as soybean oil, 1.2% of egg lecithin as a surfac-
`tant, and 2.25% glycerin as a tonicity agent. Variation in pH
`and/or addition of other components allows for various
`advantages and uses. For example, Hendler (U.S. Pat. No.
`6,362,234) uses propofol esters (100 mg-3 gm) in combina-
`tion with anti-migraines to make aqueous, solid and other
`non-aqueous compositions for internal and transderrnal
`delivery, for the treatment of migraines. De Tomaso (US.
`Pat. No. 6,326,406) discloses a composition of pH 4.5-6.5
`comprising 10 mg/ml propofol, 25-150 mg/ml bile salt, a
`lecithin, and preparation with substantially no oxygen. Mix-
`ing propofol with bile acid produces a clear formulation and
`allows for easy detection of foreign particles. For veterinary
`applications, benzyl alcohol and phospholipid free composi-
`tion comprising from 1-30% by weight propofol, wherein the
`aqueous solution is sterile filtered has been used to anesthe-
`tize animals (Carpenter, US. Pat. No. 6,150,423). Higher
`percentages of propofol allow for administration of smaller
`quantities.
`To prevent microbial growth, various components and
`methods of preparation have been discussed. For example,
`Mirejovsky, et al., disclose compositions of pH 4.5-6.4 with
`less than 1% sulfites and 1-2% by weight propofol (US. Pat.
`Nos. 6,469,069 and 6,147, 122); George, et al., disclose 0.15-
`0.25% tromethamine with 1-2% by weight propofol and pH
`8.5-10 (US. Pat. No. 6,177,477); 0.005% EDTA with 1-2%
`by weight propofol and pH 6-8.5 has been used by Jones, et
`al., (US. Pat. Nos. 5,714,520, 5,731,355, and 5,731,356);
`George (U.S. Pat. No. 6,028,108), discloses compositions
`with 0.005-0.1% pentetat that are 1-2% by weight propofol
`and pH 6.5-9.5. Likewise, lowering pH ranges (pH 5-7), using
`egg lecithin (0.2-1%) and soybean oil (1-3%), without pre-
`servatives and 0.1 -6% propofol by weight (Zhang, et al., US.
`Pat. No. 6,399,087), and lowering concentrations of soybean
`oil (1 -3%) to produce stable emulsions and reducing nutrients
`with 1% propofol by weight (Pejaver, et al., US. Pat. No.
`6,100,302), are said to provide protection against microbial
`contamination. Reducing lipid concentrations also reduces
`the chances of fat overload and is ideal for use when admin-
`
`30
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`35
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`40
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`45
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`50
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`55
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`60
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`65
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`25
`
`Patent No.
`
`Inventor
`
`5,637,625
`5,714,520
`6,028,108
`6,100,302
`PCT 99/39696
`PCT 00/24376
`
`Duncan H. Haynes
`Christopher B. 1., et al.
`Mary M. G.
`Satish K. P., et a1.
`Mirejovsky D., et al.
`Mary T., et a1.
`
`Issued
`
`10 Jun. 1997
`3 Feb. 1998
`22 Feb. 2000
`8 Aug. 2000
`12 Aug. 1999
`4 May 2000
`
`The formulations described in US. Pat. No. 5,714,520 is
`sold as DIPRIVAN® and comprises a sterile, pyrogen-free
`emulsion containing 1% (W/v) propofol in 10% (w/v) soy-
`bean oil. The formulation also contains 1.2% (w/v) egg leci-
`thin as a surfactant, 2.25% (w/v) glycerol to make