Case 1:14-cv-00160-RGA Document 1 Filed 02/06/14 Page 1 of 9 PagelD #: 1
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`UNITED STATES DISTRICT COURT
`DISTRICT OF DELA WARE
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`
`
`FRESENIUS KABI USA, LLC,
`
`Plaintiff,
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`v.
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`DR. REDDY'S LABORATORIES, LTD. and DR.
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`REDDY'S LABORATORIES, INC.,
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`
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`Civil Action No.
`
`----
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`Defendants.
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`COMPLAINT
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`Fresenius Kabi USA, LLC ("Fresenius") brings this action for patent infringement
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`against Dr. Reddy's Laboratories, Ltd. and Dr. Reddy's Laboratories, Inc. (collectively and/or
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`individually "DRL'').
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`1. Th.is is an action by Fresenius against Defendants for infringement of United
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`States Patent No. 8,476,010 ("the '010 patent"). This action arises out ofDRL'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
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`®, an innovative intravenously
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`administered sedative and anesthetic, prior to the expiration of the 'O 10 patent.
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`
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`Bass and Spangenberg
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`v.
`Fresenius Kabi USA, LLC
`
`ent No. 8,476,010
`U.S. Pat
`Exhibit 1015
`
`Exh. 1015
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`

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`Case 1:14-cv-00160-RGA Document 1 Filed 02/06/14 Page 2 of 9 Page iD #: 2
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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 ("APP").
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`DRL
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`3.
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`Upon information and belief, Defendant Dr. Reddy's Laboratories, Ltd. ("DRL
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`Ltd.") is a corporation operating and existing under the laws of India, with its principal place of
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`business at 8-2-337, Road No. 3, Banjara Hills, Hyderabad, 500034, India.
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`4.
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`Upon information and belief, Defendant Dr. Reddy's Laboratories, Inc. ("DRL
`
`Inc.") is a New Jersey corporation with its principal place of business at 200 Somerset Corporate
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`Boulevard, Building II, 7th Floor, Bridgewater, NJ 08807.
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`5.
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`On information and belief, Defendant Dr. Reddy's Inc. is a wholly-owned
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`subsidiary of Dr. Reddy's Ltd., and is controlled by Dr. Reddy's Ltd.
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`6.
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`On information and belief, both DRL Inc. and DRL Ltd. submitted, collaborated
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`and/or acted in concert in the preparation or submission of ANDA Number 205067 ("DRL
`
`ANDA").
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`Subject Matter Jurisdiction
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`JURISDICTION AND VENUE
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`7.
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`8.
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`This action for patent infringement arises under 35 U.S.C. § 271.
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`This Court has jurisdliction 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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`2
`
`Exh. 1015
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`Case 1:14-cv-00160-RGA Document 1 Filed 02/06/14 Page 3 of 9 PageiD #: 3
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`Personal Jurisdiction Over DRL
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`9.
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`Upon :information and belief, this Court has personal jurisdiction over DRL, at
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`least because DRL has engaged in continuous and systematic contacts with Delaware and/or
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`purposefully availed jtself of this forum by, among other things, making, shipping, using,
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`offering to sell or selling, or causing others to use, offer to sell, or sell, DRL's pharmaceutical
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`products in this Judicial District, and deriving substantial revenue from such activities.
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`10.
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`Further, DRL has previously admitted in Merck & Co., Inc. v. Dr. Reddy 's Labs,
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`Ltd. , Mo. 04-1313 (GMS) that due to their many contacts with Delaware they were "subject to
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`personal jurisdiction jn this judicial district."
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`Venue
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`11.
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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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`12.
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`The ' 010 patent, entitled "Propofol Formulations with Non-Reactive Container
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`Closures," was duly and lawfully issued on July 2, 2013 to inventors Neil P. Desai, Andrew
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`Yang, and Sherry Xiaopei Ci. The named inventors assigned the ' 0 10 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 '01 0 patent. The ' 010
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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 ' 010 patent will expire on June 1, 2025. A true and accurate copy of the '010
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`patent is attached hereto as Exhibit A.
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`3
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`Exh. 1015
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`Case 1:14-cv-00160-RGA Document 1 Filed 02/06/14 Page 4 of 9 PageiD #: 4
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`The Diprivan® Drug Product
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`13.
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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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`14.
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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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`15.
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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 I
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`ml of emulsion.
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`TheDRLANDA
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`16.
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`DRL filed with the FDA an ANDA under 2I U.S.C. § 355(j) seeking approval to
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`manufacture, use, offer for sale, sell in and import into the United States a propofol injectable
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`emulsion containing I Omg propofol per 1 ml of emulsion that DRL asserts is a generic copy of
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`Diprivan® (" DRL's generic Diprivan® product") prior to the expiration of the '010 patent.
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`17.
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`The FDA assigned the DRL ANDA number 205067.
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`18.
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`By letter dated April11 , 2013, DRL notified Fresenius that it had filed an ANDA
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`seeking approval to market DRL' s generic Diprivan® product prior to the patents then listed in
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`the Orange Book ("DRL Notice Letter").
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`19.
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`The ' 0 10 patent bad not issued at the time DRL submitted its certification under
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`§ 505(j)(2)(A)(vii)(IV) of the Federal Food, Drug and Cosmetic Act.
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`20.
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`DRL is required to amend the patent certification in its ANDA to address the ' 010
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`patent prior to approval of its ANDA but, on information and belief, has yet to do so. Despite
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`4
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`Exh. 1015
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`Case 1:14-cv-00160-RGA Document 1 Filed 02/06/14 Page 5 of 9 PageiD #: 5
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`repeated requests by Plaintiffs counsel, DRL has, to date, refused to disclose whether it will
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`submit a Paragraph IV certification as to the '010 patent.
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`COUNT I FOR INFRINGEMENT OF U.S. PATENT NO. 8,476,010 BY DRL
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`21.
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`The allegations of paragraphs 1-20 are realleged and incorporated herein by
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`reference.
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`22.
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`The use of DRL's generic Diprivan® product is covered by one or more claims of
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`the '0 I 0 patent.
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`23.
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`The commercial manufacture, use, offer for sale, sale, marketing, distribution,
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`and/or importation ofDRL's generic Diprivan® product would infringe one or more claims ofthe
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`'010 patent.
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`24.
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`DRL has infringed the '010 patent by submitting the DRL ANDA to the FDA
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`seeking approval to market DRL's generic Diprivan® product containing propofol before the
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`expiration of the '0 I 0 patent.
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`25.
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`Upon information and belief, Defendants DRL Inc. and DRL Ltd. acted in concert
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`and actively and knowingly caused to be submitted, assisted with, participated in, encouraged,
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`contributed to, aided and abetted, and/or directed the submission of the DRL ANDA to the FDA.
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`26.
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`Defendants DRL Inc. and DRL Ltd. induced the infringement of the '010 patent
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`by actively and knowingly aiding and abetting the preparation and submission of the DRL
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`ANDA and in the preparation to sell DRL's generic Diprivan® product in the United States.
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`27.
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`Upon information and belief, DRL was aware of the '010 patent when engaging
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`in these knowing and purposeful activities and was aware that filing the DRL ANDA constituted
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`an act of infringement of the '0 10 patent.
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`5
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`Exh. 1015
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`Case 1:14-cv-00160-RGA Document 1 Filed 02/06/14 Page 6 of 9 PageiD #: 6
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`28.
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`Use ofDRL's generic Diprivan® product in accordance with and as clirected by
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`DRL's proposed labeling for that product would infringe one or more claims of the '0 10 patent.
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`29.
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`Upon information and belief, DRL intends to engage in the manufacture, use,
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`offer for sale, sale, marketing, distribution, and/or importation ofDRL's generic Diprivan®
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`product with its proposed labeling immediately and imminently upon approval of the DRL
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`AND A.
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`30.
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`Upon information and belief, DRL plans and intends to, and will, actively induce
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`infringement of the '010 patent when the DRL ANDA is approved, and plans and intends to, and
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`will, do so immediately and imminently upon approval.
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`31.
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`Upon information and belief, DRL knows thatDRL's generic Diprivan® product
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`and the proposed labeling for DRL's generic Diprivan® product is especially made or adapted for
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`use in infringing the '01 0 patent andl that DRL's generic Diprivan® product and the proposed
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`labeling are not suitable for substantial noninfringing use. Upon information and belief, DRL
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`plans and intends to, and will, contribute to the infringement ofthe '010 patent immediately and
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`imminently upon approval of the DRL ANDA.
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`32.
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`The foregoing actions by DRL constitute and/or would constitute infringement of
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`the '0 10 patent, active inducement of infringement of the '0 10 patent, and/or contribution to the
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`infringement by others of the '0 10 patent.
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`33.
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`Upon information and belief, DRL acted without a reasonable basis for believing
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`that it would not be liable for infringing the '0 10 patent, actively inducing infringement of the
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`'01 0 patent, and/or contributing to the infringement by others of the '01 0 patent.
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`34.
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`Fresenius will be substantially and irreparably harmed by DRL's infringing
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`activities unless the Court enjoins those activities. Fresenius will have no adequate remedy at
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`6
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`Exh. 1015
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`

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`Case 1:14-cv-00160-RGA Document 1 Filed 02/06/14 Page 7 of 9 PageiD #: 7
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`law ifDRL is not enjoined from the commercial manufacture, use, offer to sell, sale in and
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`importation into the United States ofDRL's generic Diprivan® product.
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`35.
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`DRL's activities render this case an exceptional one, and Fresenius is entitled to
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`an award of their reasonable attorney fees under 35 U.S.C. § 285.
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`PRAYER FOR RELIEF
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`WHEREFORE, Fresenius respectfully requests the following relief:
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`a.
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`A judgment that DRL's submission of the DRL ANDA No. 205067 infringes one
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`or more claims of the '010 patent and that the making, using, offering to sell, or selling in the
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`United States, or importing into the United States ofDRL's generic Diprivan® product prior to
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`the expiration of the '0 10 patent will infringe, actively induce infringement, and/or contribute to
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`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 ofDRL ANDA No. 205067 or any product or compound the use of which
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`infringes the '010 patent, shall be a date that is not earlier than the 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 DRL's generic Diprivan® product, or any other product or compound
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`the use of which infringes the '0 10 patent, or inducing or contributing to the infringement of the
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`'010 pa1i:ent patents 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 DRL ANDA No. 205067 before the
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`expiration of the '010 patent;
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`7
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`Exh. 1015
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`

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`Case 1:14-cv-00160-RGA Document 1 Filed 02/06/14 Page 8 of 9 PageiD #: 8
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`e.
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`An award of Plaintiffs 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 ofDefendants' generic Diprivan® product,
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`or any product or compound the use of which infringes the '010 patent, or the inducement or
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`contribution of the foregoing, prior to the expiration ofthe patent in accordance with 35 U.S.C. §
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`27l(e)(4)(C);
`
`f
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`A judgment that this is an exceptional case and awarding Plaintiff its attorneys'
`
`fees under 35 U.S.C. § 285;
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`An award ofPlaintiff's reasonable costs and expenses in this action; and
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`An award of any further and additional rei ief to Plaintiff as this Court deems just
`
`g.
`
`h.
`
`and proper.
`
`8
`
`Exh. 1015
`
`

`
`Case 1:14-cv-00160-RGA Document 1 Filed 02/06/14 Page 9 of 9 PageiD #: 9
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`Dated: February 6, 2014
`
`Respectfully submitted,
`
`Of Counsel:
`
`Daryl L. Wiesen
`John Bennett
`Sundar Subramanyam
`Sam Sherry
`Todd Marabella
`Jennifer L. Ford
`GOODWIN PROCTER LLP
`Exchange Place
`53 State Street
`Boston, MA 02 109
`(617) 570-1000
`(617) 523-1231 (fax)
`D Wiesen@goodwinprocter.com
`JBennett@goodwinprocter.com
`SSubramanyam@goodwinprocter .com
`S Sherry@goodwinprocter. com
`TMarabella@goodwinprocter.com
`JF ord@goodwinprocter.com
`
`FARNAN LLP
`
`Is/ Brian E. Farnan
`Brian Farnan (BarNo. 4089)
`919 North Market Street
`12th Floor
`Wilmington, DE 19801
`Phone:302-777-0336
`Fax: 302-777-0301
`bfarnan@farnanlaw. com
`
`Auorneys f or Plaintiff
`Fresenius Kabi USA, LLC
`
`9
`
`Exh. 1015
`
`

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`Case 1:14-cv-00160-RGA Document 1-1 Filed 02/06/14 Page 1 of 20 PageiD # : 10
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`EXHIBIT A
`
`Exh. 1015
`
`

`
`Case 1:14-cv-00160-RGA Document 1-~
`
`1111mm 11mmmrmn~1nt1
`
`US0084 7 601 OB2
`
`c12) United States Patent
`Desai et al.
`
`(JO) Patent No.:
`(45) Date of Patent:
`
`US 8,476,010 B2
`Jul. 2, 2013
`
`(54) PROPOFOL FORI\RJL ATIONS WITH
`NON-REACTfVE CONTAI~Il:R C LOSURES
`
`(75)
`
`Inventors: Neil P. D esai, Pacific Pal isades, CA
`(US); Andrew Yang, Rosemead, CA
`(US); S h er ry X iaopei C i , San Marino,
`CA (US)
`
`(73) A~~ignt:t:: A PP Pharmaccutkals LLC ,
`Schaumburg, IL (US)
`
`( *) Notice:
`
`Subject to any d isclaimer, the tenn of this
`patent is ell:tended or adjusted under 35
`U.S.C. 154(b) by SJOdays.
`
`(21) Appl. No.: 10/616,709
`
`(22) Filed:
`
`Jul. 10, 2003
`
`(65)
`
`Prior Public ation Data
`
`US 2005/0009731 A I
`
`Jan . 13, 2005
`
`(51)
`
`Int. C l.
`A61K 38/00
`(52) U.S. C l.
`USPC ................ 435/6; 435/6.13; 514/5.9; 514/9.3;
`514/J3.6; 514/15.2
`
`(2006.01)
`
`(58) F ie ld of C lassific atio n Search
`None
`See application file for complete search history.
`
`(56)
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`(Continued)
`
`Jon P Weber
`Primary Examiner -
`Assistant Examiner - R oy T eller
`(74) Attorney, Agent, or Firm - B la nchard & Associates
`
`(57)
`
`ABSTRACT
`
`A sterile phannaceutical composition for parenteral admin(cid:173)
`istration of propofol , said composition comprising p rop ofol,
`optionally albumin, and less. than aboul 10% by weight sol (cid:173)
`vent for propofol, wherein said composition is. stored in a
`container having a closu re wherein said c losure is inert to
`propofol.
`
`70 Claims, No Drawings
`
`Exh_ 1015
`
`

`
`Case 1:14-cv-00160-RGA Document 1-1 Filed 02/06/14 Page 3 of 20 PageiD # : 12
`
`US 8,476,010 B2
`Page 2
`
`OfHER PUBLICATIONS
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`
`* cited by examiner
`
`Exh. 1015
`
`

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`Case 1:14-cv-00160-RGA Document 1-1 Filed 02/06/14 Page 4 of 20 PageiD #: 13
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`US 8,476,010 B2
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`1
`PROPOFOL FORMULATIO!\S WITH
`NON-REACTIVE CONTAlNER CLOSURES
`
`FIELD OF THE INVENTION
`
`111e invention generaHy pertains to pham1aceutical fonnu(cid:173)
`lations ofpropofo l, 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
`
`5
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`2
`isrered over extended time periods. In addition, compositions
`devoid of fats and triglycerides, with 3% w/v propofol
`(Haynes, U.S. Pat. No. 5,637,625) are said to be useful for
`sedation over extended periods oftime.
`There are two major problems associated with the formu(cid:173)
`lations described in the above patents: (1) the risk of micro(cid:173)
`bial contamination due to the high nutrient con teat and lack of
`antimicrobial preservatives. Studies by Arduino, et al., 1991;
`Sosis & Braverman, 1993; and PDR, 1995, have shown that a
`10 propofol emul sion 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 ammmt of fat conrent. Studies have
`shown that triglyceride overload can become a significant
`15 problem when a 1% propoJol/10% soybean oil emulsion is
`used as the sole sedative for a long period ofiCU sedation by
`Gottardis, et al., 1989; DeSoreruer, et al., 1990'; Lindholm,
`1992; and F.ddieston, et al, 1991.
`To solve the problem of bacterial contamination of propo-
`20 fol emulsion, the following patented formulations of propofol
`have been developed:
`
`Propofol (2,6-Diisopropylphenol) is a well-known and
`widely used intravenous nncsthctic agent. For example, in
`intensive care units (ICU) where the durafion of treatment
`may be lengthy, propofol has the advamage 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(cid:173)
`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(cid:173)
`tions, such as disclosed in U.S. Pat. Nos. 4,056,635, 4,452,
`Rl 7 and 4,79R,R41) all of which are issued to G len and James. 25
`Propofol compositions have been the subject of seveml
`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(cid:173)
`tant, and 2.25% glycerin as a tonicity agent. Variation in pH 30
`and/or addition of othe r components allows for various
`advantages and uses. For example, Hendler (U.S. Pat. No.
`6,362,234) uses propofo·l esters (100 mg-3 gm) in combina(cid:173)
`tion with anti-migraines to make aqueous, solid and other
`non-aqueous compositions for internal and transdermal 35
`delivery, for the treatment of migraines. De To=aso (U.S.
`Pat. o. 6,326,406) discloses a composition of pH 4.5-6.5
`comrrising 10 mg/ml propofol, 25-150 mg/ml bile salt, a
`lecithin, and preparation with substantially no oxygen. Mix(cid:173)
`ing propofol with bile acid produces a clear formulation and 40
`allows for easy dett:ction of foreign particlc,,s. For veterinary
`applications, benzyl alcohol and phospholipjd free composi(cid:173)
`tion comprising from 1-30% by weight propofol, wherein the
`aqueous solution is sterile filtered has been used to anesthe(cid:173)
`tize animals (Carpenter, U .S. Pat. No. 6,150,423). Higher 45
`percentages of propofol allow for administration of smaller
`quantities.
`To prevent microbiaE growth, various components and
`methods of preparation have been discussed. For example,
`Mirejovsky, et aJ., disclose compositions of pH 4.5-6.4 with so
`less ~han 1% sulfites and 1-2% by weight propofol (U.S. Pat.
`Nos. 6,469,069and 6,147, 122); George, eta!., disclose 0.15-
`0.25% tromethamine with 1-2% by weight propofol and pH
`8.5-10 (U.S. 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 55
`a l., (U.S. 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 pHranges(pH 5-7), using
`egg lecithin (0.2-1%) and soybean oil (1 -3%), without pre- 60
`servatives and 0.1-6% pr,opofol by weight (Zhang, et al., U .S.
`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., U.S. Pat. No .
`G,l 00,302), are said to provide protection against microbial 65
`contamination. Reducing lipid concentrations also reduces
`the chances of fat overload and is ideal for use when admin-
`
`Patent No.
`
`Inventor
`
`5,637,625
`5,714,520
`6,028,t08
`6,100,302
`PCT 99/39696
`PCT 00/24376
`
`Dunca.n H. Haynes
`Christop!Jer B. J., et al.
`MaryM. G.
`Satish K. P., eta!.
`Mirejovsky D., et al.
`Mary T., et at.
`
`10 Jun. 1997
`3 Feb. 1998
`22 Feb. 2000
`8 Aug. 2000
`12Aug. 1999
`4May2000
`
`The formu lations described in U.S. Pat. No. 5,714,520 is
`sold as DlPRlYAN® and comprises a sterile, pyrogen-free
`emulsion containing 1% ('V/ v) propofol in 10% (w/v) soy(cid:173)
`bean oil. 1be formulation also confains 1.2% (w/v) egg leci(cid:173)
`thin as a surfactant, 2.25% (w/v) glycerol to make the 1brmu(cid:173)
`lation isotonic, sodium hydroxide to adjust the pH, and EDTA
`0.0055% (w/v) as a preservative. This formulation prevents
`no more than a 10-fold increase against gram negative (such
`as Pseudomonas aeruginosa and Escherichia coli) and gram
`positive (Staphylococcus aureus) bacteria, as well as yeast
`(such as Candida albicans) over a rwenty-four hour period.
`However, EDT.A., which is a metal ion chelato r, removes
`cations like calcium magnesium and zinc. This can be poten(cid:173)
`tially dangerous to some patients with low calcimm or other
`low cation levels, and especially critical for ICU patients.
`To U.S. Pat. No. 6,028,108 the propofol formulation con(cid:173)
`rains pentetate 0.0005% (w/v) as a preservative to prevent
`microbia l contamination. Pentetate is a metal ion chelator
`similar to EDTA and therefore represents the same potential
`danger.
`The fo rmulation described in W.O. Patent No. 99/39696, is
`generic propofol containing 0.25 mg/mL sodium met(cid:173)
`abisulfite as a preservative to prevent microbial growth. At 24
`hours there is no more than a one log increase. Recently, P.
`Langevin, 1999, has expressed concern that generic propofol
`containiug 0.25 mg/mL sodium metabisulfite, jnfu sed at a
`rate of 50 uglkglmin, will result in sulfite administration
`approaching the toxic level (i.e., near the LDSO for rats) in
`about 25 hours.
`Particularly, the addition of sulphites to this drug is worri(cid:173)
`some for: the potential effects to the pediatric population and
`for sulphur allergy to the general population. ln a June 2000
`letter, the manufacturer of metabisulphite-contaiuing propo(cid:173)
`fol emulsion (Gensia Sicor) stated that discoloration and a
`reduction in pi-I occur when the product is exposed to air and
`
`Exh. 1015
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`Case 1:14-cv-00160-RGA Document 1-1 Filed 02/06/14 Page 5 of 20 PageiD #: 14
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`US 8,476,010 B2
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`4
`propofol has been found to occur if the container closure is
`not inert or non-reactive to propofol.
`
`DISCLOSURE OF THE INVENTION
`
`DED\ILED DESCRJPT10N OF THE INVENTION
`
`The invention in one of its embodiments is a sterile phar(cid:173)
`maceutical composition for parenteral admin istration com-
`
`Exh. 1015
`
`s
`
`3
`that both phenomena are caused by the oxidation of sodium
`metahisulphite Mirejovsl<y D. Ghosh M. Reply. (Pharmaceu(cid:173)
`tical and antimicrobial differences between propofol emul(cid:173)
`sion products) (Am J Health-Syst Pharm. 2000: 57: I I 76-7).
`Results show that the yellowing of the commercial metabisul-
`phite-containing propofol emulsion is an oxidized form of
`propofol dimerquininewh.ich is lipid soluble. (U.S. Pat. No .
`6.39'9,087). Recent data also support pro-oxidant activity by
`the sulfite anion resulting in propofol dimcrization and lipid
`peroxidation (Baker er al., Anesthesiology, 96, A472, 2002). 10
`The formulation described in PCT W.O. Parent No .
`00/2-4376 is a formulation having an antimicrobial agent,
`which is a member selected from the group consisting of
`benzyl alcohol and sodium ethylenediamine tetraacetate,
`bcnzcthonium chloride; and benzyl alcohol and sodium ben- 15
`zoate. The formulation contains EDTA, which was men(cid:173)
`tioned as related to the side effect above. Benzyl alcohol is
`linked to adverse reactions reported by Evens and Lopcz(cid:173)
`Herce, et al. The formulation may be unsafe upon adminis(cid:173)
`tration, particularly to those patients who need an extended 20
`period of ICU sedation.
`The fonnulation described in U.S. Pat. No. 5,637,625 is of
`phospholipid-coated microdroplets of propofol, containing
`6.8% propofol with no soybean oil. However, it is believed
`that this formulation may increase injection site pain to an 25
`unacceptable level during administration.
`The formulation described in U.S. Pat. No. 6,100,302 is an
`emulsion of propofol that contains 1-3% of soybean oil to
`prevent against accidental microbial contamination during
`long-term IV infusions due to an increased availability of 30
`propofol.
`Egg lecithin is mainly used in pharmaceutical products as
`a dispersing, emulsifying, and stabilizing agent. The lecithin
`is also used as component of enteral and paranteral nutrition
`formulations, At1hur H. Kibbe, 2000.
`It has been also found that in this invention a propofol
`·]ormulation containing a reduced amount of egg lecithin
`results in a significant increase in the ability to be antimicro(cid:173)
`bial. The soybean oil is also source of nutrition to support the
`microbial growth.
`Thus, it has been fotulll that the preservative-free, opti(cid:173)
`mized propofol formulation of this invention addresses the
`prior art· problems to the point where the problems are elimi(cid:173)
`nated or at the le-ast are substantially reduced.
`It has now been discovered that the propofol in propofol 45
`formulations with reduced oil content is degraded when
`stored in a container with a closure that is not inert to propo(cid:173)
`fol. T he problem of pro-pofol degradation encountered was
`quite unexpected as c losures sealed with a rubber stopper or
`the like are known. For example, U.S. Pat. No . 6,576,245 so
`poin1s out that primary packages such as vials, bottles, car(cid:173)
`tridges, prefilled syringes and the like are typically sealed by
`a rubber stopper or plunger. U .S. Pat. No. 6,576,245 further
`expresses a preference for a rubber material con taining bro(cid:173)
`moblttyl instead of chlorobutyl to improve the stability of low 55
`molecular weight th.rombin inhlbitors in solution. Heretofore,
`however, the art has not w1derstood that the propofol in pro(cid:173)
`polo! formulations is susceptible to degradation due ro expo(cid:173)
`sure to the closure for the container. The fail ure of the art to
`recognize the effect of the container closlllre on propofol
`degradation, it is believed, is due to the fact that the commer(cid:173)
`cially available propofol fonnulation DJPRTVAN® com(cid:173)
`prises 10% (w/v) soybean oil. Applicants have found that at
`the relatively high volume of soybean oil used in prior art
`formulations, the soybean oil apparently protects propofol 65
`from degradation. However, at oil contents (and/or propofol
`solvent contents) lower tban about 10% (w/v), degradation of
`
`Accordingly, the present invention in one of its embodi(cid:173)
`ments provides a sterile formulation of propofol for
`parenteral administration containing a reduced amount of egg
`lecithin and soybean oil triglycerides. T11e formulation is
`preferably comprised of an oil in water emul sion with a mean
`particle size of from about WO to about 300 nanometers in
`diameter, in which the propofol is dissolved in a water-im(cid:173)
`miscible solvent such as soybean oil, and stabilized by a
`surfactant such as egg lecithin. The composition preferably
`has a pH in the range of from about pH 5 to about pH 8. The
`low amount of lecithin and soybean oil in the formulation
`offers a number of advantages. ]n other embodiments of the
`invention, the composition includes protein, such as albumin.
`The presence of protein such as albumin in the propofol
`formulation is also advantageous. The advantages of the fo r(cid:173)
`mulations in accordance with the embodiments of the inven(cid:173)
`tion include:
`(I) eliminating preservatives, such as ED'IA that can result
`in zinc loss due to chelation,
`(2) providing formulations with excellent exhibition of
`antimicrobial activity compa red to fonuu lations with higher
`amount of lecit