Case 1:12-cv-08115-ALC-GWG Document 1 Filed 11/07/12 Page 1 of 54
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`ENDO - Ex. 2001
`Amneal v. Endo
`IPR2014-00360
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`

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`of its status as owner of certain of the patents-in-suit, as described in more detail below, and
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`Grunenthal joins this matter as a plaintiff solely for prudential jurisdiction purposes.
`
`3.
`
`Upon information and belief, Amneal Pharmaceuticals, LLC (“Amneal
`
`Pharmaceuticals”) is a limited liability company organized and existing under the laws of the
`
`State of Delaware, having a principal place of business at 440 U.S. Highway 22 East, Suite 104,
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`Bridgewater, NJ 08897.
`
`4.
`
`Upon information and belief, Amneal Pharmaceuticals is a pharmaceutical
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`company engaged in the research, development, production, distribution, and sale of generic
`
`pharmaceuticals throughout the United States, including sales Within this judicial district.
`
`5.
`
`Upon information and belief, Amneal Pharmaceuticals of New York, LLC '
`
`' (“Amneal New York”) is a limited liability company organized and existing under the laws of
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`the State of Delaware, and shares a principal place of business with Amneal Pharmaceuticals”
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`administrative offices at 85 Adams Avenue, Hauppauge, New York 11788.
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`6.
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`Upon information and belief, Amneal New York is a pharmaceutical company
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`engaged in the manufacturing for and the sale of generic prescription pharmaceutical products to
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`Amneal Pharmaceuticals for distribution throughout the United States, including in this judicial
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`district.
`
`NATURE OF ACTION
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`7.
`
`This is an action for patent infringement arising under the Patent Laws of the
`
`United States, 35 U.S.C. § 100, et seq. and the Declaratory Judgment Act, 28 U.S.C. § 2201, et
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`seq.
`
`JURISDICTION AND VENUE
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`8.
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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 and 1338(a) (patent infringement), and 28‘ U.S.C. §§ 2201 and 2202 (declaratory
`
`judgment).
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`9.
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`Venue is proper in this district pursuant to 28 U.S.C. §§ 1391(b) and 1400(b).
`
`10.
`
`Upon information and belief, Amneal Pharmaceuticals conducts its North
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`American operations in part through Amneal New York. Together, Amneal Pharmaceuticals and
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`Amneal New York collaborate in the research, development, manufacture, testing, distribution
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`and/or the sale of a number of pharmaceutical products manufactured and sold pursuant to
`
`approved abbreviated new drug applications within the United States and the State of New York
`
`generally and this judicial district specifically.
`
`11.
`
`This Court has personal jurisdiction over each of the Defendants by virtue of the
`
`fact that, inter alia, they have committed -—— or aided, abetted, planned, contributed to, or
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`participated in the commission of— tortious conduct in the State of New York that has led to
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`foreseeable harm and injury to Endo.
`
`12.
`
`Upon information and belief, Amneal Pharmaceuticals has submitted to FDA
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`paperwork purporting to constitute an Abbreviated New Drug Application (“ANDA”) under §
`
`5050') of the Federal Food, Drug and Cosmetic Act, 21 U.S.C. § 3550) (“ANDA No. 20-4294”.
`
`or “Amneal’s ANDA”), seeking approval to engage in the commercial manufacture, use, and
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`sale of 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, and 40 mg oxymorphone hydrochloride
`
`extended-release tablets, (“Amneals’s ANDA Products” , as a generic version of the drug
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`described in Endo’s sNDA 201655.
`
`13.
`
`Upon information and belief, Amneal both manufactures the Amneal ANDA
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`Products and conductstesting necessary to validate their quality in the State of New York. On
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`further information and belief, Amneal intends to manufacture and test Amneal’s ANDA
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`

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`Products produced for commercial sale in the State of New York.
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`14.
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`Upon information and belief, Amneal New York intends to manufacture generic
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`Opana ER CRF for distribution and sale in this judicial district should Amneal’s ANDA be
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`approved by FDA. Upon information and belief, Amneal Pharmaceuticals intends to distribute
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`and sell generic Opana ER CRF in this judicial district should ANDA No. 20-4294 be approved .
`
`by FDA.
`
`15.
`
`Moreover, Amneal Pharmaceuticals and Amneal New York maintain continuous
`
`and systematic contacts with the State of New York and this District.
`
`16.
`
`Upon information and belief, Amneal Pharmaceuticals and Amneal New York are
`
`registered with the New York State Department of State as corporations actively conducting
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`business within New York and maintain a registered agent within the state.
`
`17.
`
`Upon information and belief, Amneal Pharmaceuticals currently sells significant
`
`quantities of generic drug products in the Southern District of New York. Those products
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`include, for example, generic versions of Percocet®, Ultracet®, and Neurontin®. A list of
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`generic products manufactured and sold by Amneal Pharmaceuticals in the United States can be
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`found at http://wmvarrmealcom/indexphp.
`
`13.
`
`Upon information and belief, Amneal Pharmaceuticals maintains an
`
`administrative office at 85 Adams Avenue, Hauppauge, NY 11788; an oral solids manufacturing
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`facility at 75 Adams Avenue, Hauppauge, NY 11788; an oral solids and softgelsmanufacturing
`
`facility at 50 Horseblock Road, Brookhaven, NY 11719; and an oral solids research and
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`development facility at 50 Horseblock Road, Brookhaven, NY 11719.
`
`19.
`
`Upon information and belief, Amneal New York’s principal place of business is
`
`located at 85 Adams Avenue, Hauppauge, New York 11788.
`
`

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`20.
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`Furthermore, Amneal Pharmaceuticals has been sued as a patent infringer in this
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`Court, asserted counterclaims in this Court, and declined to contest that this Court has personal
`
`jurisdiction over it. See, e.g., Purdue Pharm, L.P., er a]. v. Amneai Pharmaceuticals, LLC, 11-
`
`cv-081 53-SHS-JLC; Pfizer Inc, et at. v, Actavis Inc, et at, 10-cv-8197-(TPG).
`
`21.
`
`Based on the facts and causes alleged herein, and for additional reasons to be
`
`devoloped through discovery, this Court has personal jurisdiction over the Defendants.
`
`FACTUAL BACKGROUND
`
`The Drug Approval Process
`
`22.
`
`A company seeking to market a new drug in the United States must first obtain
`
`approval from FDA, typically through the filing of a New Drug Application (“NBA”). See 21
`
`U.S.C. § 355(a). The sponsor of the NDA is required to submit information on all patents
`
`claiming the drug that is the subject of the NDA, or a method of using that drug, to FDA, and
`
`upon approval, FDA then lists such patent information in its publication, the Approved Drug
`
`Products with Therapeutic Equivalence Evaluations, which is referred to as the “Orange Book.”
`
`See 21 U.S.C. § 355(b)(1) and (c)(2).
`
`23.
`
`On the other hand, a company seeking to market a generic version of a previously
`
`approved drug is not required to submit a full NDA. Instead, it may file an ANDA. See 21
`
`U.S.C. § 3550). The generic drug approval process is considered “abbreviated” because the
`
`generic manufacturer may piggyback on the innovator company’s data and FDA’s prior finding
`
`of safety and efficacy by demonstrating, among other things, that the generic product is
`
`bicequivalent to the previously approved drug (the “listed drug” or “branded drug”).
`
`24.
`
`In conjunction with this “abbreviated” application process, Congress has put in
`
`place a process for resolving patent disputes relating to generic drugs, under which an ANDA
`
`

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`filer must provide certifications addressng each of the patents listed in the Orange Book for the
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`branded drug. See 21 U.S.C. § 3556)(2)(A)(vii); 21 CPR. § 314.94(a)(12). AnANDA filer
`
`may certify, for instance, that it believes a patent is invalid or will not be infringed by the
`
`manufacture, use, or sale of the generic drug for which the ANDA is submitted. See 21 U.S.C. §
`
`3550)(2)(A)(vii)(IV); 21 C.F.R. § 314.94(a)(12)(i)(A)(4). This is know as a “Paragraph IV
`
`Certification.”
`
`25.
`
`The sponsor of an ANDA which is accepted for review by FDA that contains a
`
`Paragraph IV Certification must provide notice (“Paragraph IV Notice”) to both the owner of the
`
`listed patents and the holder of the NDA for the referenced listed drug. The certification must
`
`include a detailed statement of the factual and legal bases for the applicant’s belief that the
`
`challenged patent is invalid or not infringed by the proposed generic product. 21 U.S.C. §
`
`3550)(2)(B); 21 C.F.R. § 314.95.
`
`26.
`
`If the patentee or NDA holder files a patent infringement action within 45 days of
`
`receiving a Paragraph IV Notice from an ANDA filer, final approval of the ANDA is generally
`
`subject to a 30-month stay of regulatory approval. See 21 U.S.C. § 3550)(5)(B)(iii); 21 C.F.R.
`
`§ 314.107(b)(3). The 30-month stay is important to innovator companies, such as Endo and
`
`J Grtinenthal, because it protects them fi-om the severe financial harm that could otherwise ensue
`
`from FDA granting approval to a potentially infringing product without first providing an
`
`opportunity for the innovators to prove infringement and obtain an injunction prohibiting sale of
`
`the infringing product. Put another way, the innovator company is assured of a 30-month period
`
`during which it may try to enforce its intellectual property rights and resolve any patent dispute
`
`before the generic product enters the market. See 21 U.S.C. §I355(i)(5)(B)(iii).
`
`

`

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`Endo’s Opana ER CRF NBA
`
`27.
`
`On December 12, 2011, FDA approved Endo’s Supplemental New Drug
`
`Application (“sNDA”) 201655, under § 505(b) of the Federal Food, Drug and Cosmetic Act, 21
`U.S.C. § 355(b), for a new dosage form of Opana ER which is a crush-resistant tablet that
`
`contains oxymorphone hydrochloride for the relief ofpain (hereinafter, “Opana BR CRF”).
`
`28.
`
`Opana ER CRF is distributed and sold throughout the United States for relief of
`
`moderate to severe pain in patients requiring continuouslaround-the-clock opioid treatment for an
`
`extended period oftime.
`
`THE ’482 PATENT
`
`29.
`
`On December 14, 2010, the PTO duly and legally issued U.S. Patent No.
`
`7,851,482 (“the ’482 Patent"), entitled “Method for Making Analgesics” to Johnson Matthey
`
`Public Limited Company (“Johnson Matthey”) as assignee. Jen-sen Dung, Erno MQ Keskeny,
`
`and James J. Mencel are named as inventors. A true and correct copy of the ’482 Patent is
`
`attached as Exhibit A-
`
`30.
`
`Endo subsequently acquired fiill title to the ’482 Patent, and accordingly, Endo is
`
`now the sole owner and assignee of the ’482 Patent.
`
`31.
`
`Information regarding the Endo 1482 Patth was submitted to FDA for listing in
`
`the Orange Book. Pursuant to 21 C.F.R. § 314.53(e), FDA has listed the ’482 Patent in the
`
`Orange Book with reference to NBA 201655.
`
`32.
`
`Opana ER CRF is covered by one or more claims ofthe ’482 Patent.
`
`THE ’722 PATENT
`
`33.
`
`On June 5, 2012, the PTO duly and legallyissued U.S. Patent No. 8,192,722 (“the
`
`’722 Patent”), entitled “Abuse-Proofed Dosage Form” to Gruenenthal GmbH, also known as
`
`

`

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`Grfinenthal GmbH, as assignee. Elisabeth Arkenau-Marié, Johannes BartltOlOmaus, and
`
`Heinrich Kugelmann are named as inventors. A true and correct copy of the ’722 Patent is
`
`attached as Exhibit B. The ’722 Patent expires on September 15, 2025.
`
`34.
`
`35.
`
`Griinenthal is theassignee and owner of the ’722 Patent.
`
`Endo has an exclusive license to the ’722 Patent from Griinenthal, including a
`
`right to enforce the ’722 Patent.
`
`36.
`
`Information regarding the ’722 Patent was submitted to FDA for listing in the
`
`Orange Book. Pursuant to 21 C.F.R. § 314.53(e),_FDA has listed the ’722 Patent in the Orange
`
`Book in reference to NDA 201655.
`
`37.
`
`Opana ER CRF is covered by one or more claims of the ’722 Patent.
`
`AMNEAL’S ANDA FILING
`
`38.
`
`Upon information and belief, some time before September 21, 2012, Arnneal
`
`submitted to FDA paperwork purporting to constitute an Abbreviated New Drug Application
`
`(“ANDA”) under § 5056) ofthe Federal Food, Drug and Cosmetic Act, 21 U.S.C. § 3556),
`
`seeking approval to engage in the commercial manufacture,use, and sale of 5 mg, 7.5 mg, 10
`
`mg, 15 mg, 20 mg, 30 mg, and 40 mg oxymorphone hydrochloride extended—release tablets
`
`(“Amneal’s ANDA Products”), as a generic version of the products described in sNDA 201655.
`
`39.
`
`In a letter dated September 21, 2012 addressed to Endo and received on or about
`
`September 24, 2012, and in a separate letter addressed to Griinenthal dated October 10, 2012 and
`
`received by Grfinenthal on or about that same day, Amneal purported to notify Plaintiffs that
`
`Amneal had submitted ANDA No. 20-4294, seeking approval to manufacture, use, or sell
`
`Amneal’s ANDA Products before the expiration of the ’482 and ”722 Patents (“Amneal Notice
`
`Letters”).
`
`

`

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`40.
`
`The Amneal Notice Letters claimed that Amneal’s'ANDA included a Paragraph
`
`IV Certification stating that it was Amneal’s opinion that the claims of the ’482 and ’722 Patents
`
`are invalid, unenforceable, or are not infringed by the proposed manufacture, importation, use,
`
`sale, or offer for sale of the Amneal ANDA Products.
`
`41.
`
`This action is being commencedbefore the expiration of forty-five days from the
`
`date Endo and Grfinenthal received the Amneal Notice Letters.
`
`COUNT I: INFRINGEMENT OF THE ’482 PATENT
`
`42.
`
`43.
`
`Endo incorporates each of paragraphs 1-41 above as if set forth fully herein.
`
`The submission of Amneal’s ANDA to FDA, which includes certification under §
`
`5050)(2)(A)(vii)(IV), constitutes infringement of the ’482 Patent under 35 U.S.C. §
`
`271(c)(2)(A).
`
`44.
`Amneal is seeking FDA approval to engage in the commercial manufacture, use,
`or sale ofAmneal’s ANDA Products before the expiration ofthe ’482 Patent. Ifgranted
`
`approval, Amneal intends to launch its ANDA Products before expiration of the ’48.? Patent.
`
`45.
`
`Amneal’s commercial manufacture, offer for sale, or sale of its ANDA Products
`
`would infringe the ’43:: Patent under 35 U.S.C. § 27l(a)-(c).
`
`46.
`
`Any launch by Amneal of its ANDA Products before expiration of the ’482 Patent
`
`would cause Endo to suffer immediate and irreparable harm.
`
`47.
`
`Amncal was aware of the existence of the ‘482 Patent, as demonstrated by its
`
`reference to that patent in the Amneal Notice Letters, and was aware that the filing of its
`
`Paragraph IV Certification with respect to the ”482 Patent would constitute infringement of the
`
`patent.
`
`

`

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`COUNT ll: INFRINGEMENT OF THE ”722 PATENT
`
`I 48.
`
`Endo incorporates each of paragraphs 14] above as if set forth fully herein.
`
`49.
`
`The submission of Amneal’s ANDA to FDA, which includes certification under §
`
`505(j)(2)(A)(vii)(IV), constitutes infringement ofthe ’722 Patent under 35 U.S.C. §
`
`271(c)(2)(A).
`
`I
`
`50.
`
`Amneal is seeking FDA approval to engage in the commercial manufacture, use,
`
`or sale of its ANDA Products before the expiration ofthe ’722 Patent. If granted approval,
`
`Amneal intends to launch Amneal’s ANDA Products before expiration of the ’722 Patent.
`
`51.
`
`Amneal’s commercial manufacture, offer for sale, or sale of its ANDA Products
`
`would infringe the "[22 Patent under 35 U.S.C. § 27l(a)-(c).
`
`52.
`
`Any launch by Amneal of its ANDA Products before expiration of the ’722 Patent
`
`would cause Endo to suffer immediate and irreparable harm.
`
`53.
`
`Amneal was aware ofthe existence of the "[22 Patent, as demonstrated by its
`
`reference to that patent in the Amneal Notice Letters, and was aware that the filing of its
`
`Paragraph IV- Certification with respect to the ’722 Patent would constitute infringement ofthe
`
`patent.
`
`PRAYER FOR RELIEF
`
`WHEREFORE, Plaintiff Endo respectfully requests the following relief:
`
`A.
`
`-A judgment that Defendants have infiinged the ’482 Patent, and a declaration that
`
`Amneal’s connnercial manufacture, distribution, use, and sale of its ANDA Products would
`
`infringe the ’48:! Patent;
`
`B.
`
`C.
`
`A declaration that the ’482 Patent is valid and enforceable;
`
`A judgment that Amneal has infringed the ”722 Patent, and a declaration that.
`
`-10-
`
`

`

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`Amneal’s commercial manufacture, distribution, use, and sale of its ANDA Products would ‘
`
`infringe the ’722 Patent;
`
`D.
`
`E.
`
`A declaration that the "1'22 Patent is valid and enforceable;
`
`An order, pursuant to 35 U.S.C, § 271(c)(4)(A), that the effective date of any
`
`approval of Amneal’s ANDA No. 20-4324 under § 5050) of the Federal Food, Drug and
`
`Cosmetic Act, 21 U.S.C. § 3550'), shall not be earlier than the last expiration date ofthe ’482 and
`
`’722 Patents, including any extensions;
`
`F.
`
`A permanent injunction, pursuant to 35 U.S.C. § 271(c)(4)(B), restraining and
`
`enjoining Amneal, its officers, agents, servants and employees, and those persons in active
`
`concert or participation with any of them, from infringement of the ’482 and ’722 Patents for the
`
`full terms thereof, including any extensions;
`
`G.
`
`An order that damages or other monetary relief be awarded to Endo if Amneal
`
`engages in the commercial manufacture, use, offer to sell, sale, distribution or importation of
`
`Amneal’s ANDA Products, or in inducing such conduct by others, prior to the expiration of the
`
`’482 and ’722 Patents, and any additional period of exclusivity to which Plaintiffs are or become
`
`entitled, and that any such damages or monetary relief be trebled and awarded to Endo with
`
`prejudgment interest;
`
`H.
`
`A declaration that this an exceptional case and an award of reasonable attorneys’
`
`fees pursuant to 35 U.S.C. § 285;
`
`I.
`
`Reasonable attorneys’ fees, filing fees, and reasonable costs of suit incurred by
`
`Enclo and Grtinenthal inthis action; and
`
`J.
`
`Such other and further relief as the Court may deem just and proper.
`
`-11".
`
`

`

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`
`Dated: November 7, 2012
`
`Of Counsel:-
`
`Basil J. Lewris
`Joann M. Neth
`Jennifer H. Roscetti
`
`FINNEGAN, HENDERSON, FARRABOW,
`GARRETT & DUNNER LLP
`
`901 New York Avenue, NW.
`Washington, DC 20001
`(202) 408-4000
`bill.lewfis@finnegan.com
`joarm.neth@finnegan.eom
`jennifer.roscetti@finnegan.com
`
`Anthony C. Tridico
`Avenue Louise 326, Box 37
`Brussels, Belgium B-1050
`01132 2 646 03 53
`
`anthony.tridico@finnegan.com
`
`ATTORNEYS FOR PLAINTIFF
`GRUNENTHAL GMBH
`
`B,W
`
`Joshua I. Sherman
`DECHERT LLP
`1095 Avenue of the Americas
`
`New York, NY 10036
`(212) 698-3500
`joshua.sherman@dechert.com
`
`ATTORNEYS FOR PLAINTIFF
`
`ENDO PHARMACEUTICALS INC.
`
`@‘ 272%
`
`Stephen D. Hoffman (SH 6089)
`WILK AUSLANDER LLP
`
`1515 Broadway, 43rd Floor
`New York, NY 10036
`
`(212) 981-2300
`shoffinan@wilkauslander.com
`
`ATTORNEYS FOR PLAINTIFF
`GRUNENTHAL GMBH
`
`Martin J. Black
`
`Robert D. Rhoad
`DECHERT LLP
`
`Cira Centre
`2929 Arch Street
`
`Philadelphia, PA 19104
`(215) 994-4000
`
`Ann M. Caviani Pease
`Jonathan D. Loeb
`DECHERT LLP
`
`2440 W. El Camino Real
`Suite 700
`
`Mountain View, CA 94040
`(650) 813-4800
`
`ATTORNEYS FOR PLAINTIFF
`
`ENDO PHARMACEUTICALS INC.
`
`_ 12.-
`
`

`

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`Exhibit A
`
`

`

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`Case 1:12—cv-08115-ALC-GWG Document 1
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`
`|l||||11|1|||l|||1|||1|l-||l||||l|||1||| lllll‘lllli|Ill||1|||||l||||ll|ll
`
`U3007851482B2
`
`US 7,851,482 B2
`(10) Patent No.:
`(12) United States, Patent
`Dung et a].
`(45) Date of Patent:
`Dec. 14, 2010
`
`
`(54) DIETHOD FOR MAIflNG ANALGESICS
`
`(75)
`
`Inventors: Jen-Sen Dung, 5001th PA (US);
`Erna M. Keskeny, Wilmington, DE
`(US); James J. Mencel, North Wales, PA
`(US)
`
`(73) Assignee: Johnson Matthey Public Limited
`Compnay, London (GB)
`
`( " ) Notice:
`
`Subject to any disclaimer, theterm ofthis
`patent is extended or adjusied under 35
`U'S‘C‘ 15407)!” 646 days'
`(2,) Appl- No: 111866340
`
`(22) Filed:
`
`Oct. 3, 2007
`
`(65)
`
`Prior Publication Data
`
`US 200310146601 A1
`
`Jun. 19, 2003
`
`.
`
`Foreign Application Priority Data
`(30)
`Dec. 14, 2005
`(GB)
`0524300.:
`
`(51) “It 0-
`(2006.01)
`A6111” 31/435
`(2006.01)
`607.0 489/04
`11.3. C1.
`............................ 5141232; 546145; 546144
`(52)
`58) Field ofClassification Search
`.............. 5141202
`(
`’
`_
`_
`, 545/45: 44
`See apphcatlon file for complete search h1story:
`Rdmm‘ cm"
`U.S. PATENT DOCUMENTS
`
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`'
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`,
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`a cited by examine,-
`
`Primary Examiner%hamgjit S Aulakh
`(74) Atmmey, Agent, or FirnI—RamerPIestia
`
`(57)
`
`'
`
`ABSTRACT
`
`improved analgesic oxymorphone hydmchloride contains
`less than 10 ppm of alpha, beta unsaturated ketoncs and
`pharmaceufica] preparations comprising such oxymorphone
`hydrochloride. Theoxymoxphoue hydrochloride is pmduced
`by reducing a starting matm-ial oxymorphone hydrochloride
`using gaseous hydrogen and under specified acidity, solvent
`.
`.
`.
`system and temperature condmons. A speplfic polymorph of
`'
`btamedh 11 (Indian.
`“Kymmlee hymmde may be 0
`y 3’
`
`21 Claims, 1 Drawing Sheet
`
`

`

`Case 1:12-cv-08115-ALC-GWG Document 1 Filed 11/07/12 Page 15 of 54
`Case 1:12—cv-08115-ALC-GWG Document 1
`Filed 11/07/12 Page 15 of 54
`
`U.S. Patent
`
`‘
`
`Dec. 14, 2010'
`
`Us 7,851,482 B2
`
`In .V
`
`2025303540
`
`1O
`
`15
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`
`Countsls
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`

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`Case 1:12-cv-08115-ALC-GWG Document 1 Filed 11/07/12 Page 16 of 54
`Case 1:12—cv-08115-ALC-GWG Document 1
`Filed 11/07/12 Page 16 of 54
`
`US 7,851,482 B2
`
`1
`METHOD FOR MAKING ANALGESICS
`
`FIELD OF THE INVENTION
`
`This invention concerns an improved method for making
`analgesics, more especially for making the opiate oxymor—
`phone as its hydrochloride.
`BACKGROUND OF THE INVENTION
`
`Oxymorphone, generally administered in the form of its
`hydrochloride salt, is a potent semi-synthetic opiate analge-
`sic, for the relief of moderate to severe pain, and has been
`approved for use since 1959. It can be administered as an
`injectable solution, suppository, tablet or extended release
`tablet. It is desirable to develop high purity forms ofoxymor-
`phone and a method for its synthesis.
`Severalmethcds for synthesising oxymorphonefi-om com-
`pounds iselated from the opium poppy or compounds derived
`therefrom are lotown, for example, starting from morphine,
`thebaine, or from oxycodone. There remains the nwd for
`methods which permit the formation of oxymorphone with
`low contamination of alpha, beta unsaturated ketones. The
`present invention provides an improved oxymorphone prod-
`uct and a method for producing such oxymorphone.
`US. Pat. No. 7,129,248 claims a process for producing
`oxycodone hydrochloride with less than 25 ppm of l4-hy-
`droxycodeinone, by hydrogenating oxycodonc having
`greater than 100 ppm l4-hydroxycodeinone. The synthetic
`route to oxycodone taught inUS’24S starts from thebaine and
`produces l4-hydrcxycodeinone as an intermediate product
`and 8,14—dihydroxy—7,3—dihydrocodeinone as a by-product
`resulting from over-oxidation ofthebaine. During conversion
`of oxycodone free base to the hydrogen chloride salt, the
`by-product may undergo acid-catalysed dehydration and be
`converted into l4-hydroxycodeinone. Thus the final oxyc-
`odone hydrogen chloride salt contains unreacted ] 4-hydroxy-
`codeinone as well as l4-hydroxycodeinone derived from the
`lay—product 8,14—dihydroxy-7,8-dihydrocodeinone. A hydro-
`genation step is claimed to reduce contents of14-hydroxyco-
`deinooe from at least 100 ppm to less than 25 ppm.
`SUMMARY OF THE INVENTION
`
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`The present invention provides an oxymomhone hydro-
`chloride product oontaining less than 10 ppm of alpha, beta
`unsaturated ketones.
`
`45
`
`The invention also provides a method ofpurifyingoxymor-
`phone hydrochloride to yieldan oxymorphone hydrochloride
`product containing less than 10 ppm of alpha, beta unsatur-
`ated ketones, which method comprises reducing a stoning
`material oxymorphonehydrochloride ina strongly acid water
`' and alcohol solvent, using gaseous hydrogen at a temperature
`inthe range from 60 to 70° C. Reduction is suitably carried
`out for a period of at least 20 hours, but in another embodi-
`ment, reduction is carried out for 1 to 20 hours.
`
`BRlEF DESCRIPTION OF THE DRAWINGS
`
`The invention will be described below with referenceto the
`drawing, in which:
`FIG. 1 is the Powder X-Ray Diffraction pattern collected
`for a hydrated oxymorphone hydrochloride product made
`according to Example 3.2D.
`DETAILED DESCRIPTION OF THE INVENTION
`
`50
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`60
`
`65
`
`Preferably, the solvent is ethanol/water, although other
`watermisciblc alcohols, such as isopropanol andn-propano],
`
`2
`
`may be used. The reaction medium is very acidic, preferably
`by incorporatingatleast two equivalents ofhydroch]uric acid.
`A pH ofless than 1 is desirable.
`The reaction temperature is most preferably maintained at
`about 65° C. Hydrogen is conveniently supplied to the reac-
`tion vessel at 2.41 bar pressure.
`The method ofthe invention has been able to reduce start-
`ing material oxymorphone hydrochloride having very high
`(ofthe order of0.3 to 0.5%, or3,000 to 5,000 ppm) content of
`alpha, beta unsaturated ketonec to less than 10 ppm, and in
`many cases to undetectable levels (by HPLC).
`The starting material oxymotphoue hydrochloride may be
`an isolated or non-isolated material. Desirably, it has been
`obtained by the formation of the hydrogen chloride salt by
`heating oxymorphone free base in the presence ofhydrochlo-
`tic acid andan alcohollwater reaction medium. Suitable tem-
`peratures are 60-70” C. It can be seen that the reaction
`medium is ideal for the reduction ofthe method of the inven-
`tion, so that it is generally not necessary to isolate the oxy-
`morphone hydrochloride. Howaver, the starting material oxy-
`morphone hydrochloride may be isolated from the reaction
`medium or may be from another source.
`The oxymorphonefree base is itselfpreferably preparedby
`a reduction of l4-hydroxymorphinone. This may be carried
`out in a single— or two-stage process. The reduction is prefer-
`ably carried out in acetic acid using gaseous hydrogen and a
`palladium on carbon catalyst. Preferred temperamres are of
`the order of30° C. The base is precipitated by adding aqueous
`ammonia (NH40H).
`This reduction may be in the presence of the reaction
`medium to which is added dichloromcthane in methanol
`Florasil and n-propanol.
`The l4¢hydroxymorphincoc itself is most suitably pre-
`pared by hydroxylation of oripavine, using hydrogen perox-
`ide in the presence offormic acid.
`Oripavinc is aknown compound, which is extractablefrom
`poppy straw. The strain developed in Tasmania to be a high-
`Thcbaine—yiclding strain also produces higher than normal
`levels of oripavine.
`The process of the invention is highly flexible, permitting
`many reaction steps to be carried out without isolation of
`intermediate products, whilst still retaining high (ofthe order
`of50%) overall yields from oripavine, as well as markebly
`high purity. Under favourable conditions, the presence of
`alpha, beta unsaturated ketones is undetectable by conven-
`tional means such as HPLC, butthe skilled person can readily
`achieve less than 10 ppm contamination. The process of the
`invention has been successfully carried out at kilogram scale.
`The oxymorphone hydrochloride having less than 10 ppm
`of alpha, beta unsattuated ketones can be incorporated into
`pharmaceutical dosage forms, e.g., by admixtures ofthe oxy-
`morphone hydrochloride having less than 10 ppm of alpha,
`beta unsaturated ketones with conventional excipients, i.e.,
`phannaccufically acceptable organic or inorganic carrier sub-
`stances. For oral fonnulations, the dosage forms can provide
`a sustained release of the active component. Suitable phar-
`maceutically acceptable carriers include but are not limited
`to, alcohols, gum arable, vegetable oils, betray] alcohols,
`polyethylene glycols, gelate, carbohydrates such as lactose,
`amylose or starch, magnesium stearate, talc, silicic acid, vis—
`cous parnfiin, perfume oil, fatty acid monoglyocrides and
`diglyceridcs, pcntacn'ythritol fatty acid esters, hydroxy—mcth—
`ylccllulose, polyvinylpyrrolidone, etc. The pharmaceutical
`preparations can be sterilized and ifdcsired mixed with aux-
`iliary agents, eg, lubricants, disintegrants, preservatives, sta-
`bilizers, wetting agents, emulsifiers, salts for influencing
`osmotic pressure buffers, colouring, devouring andlor aro-
`
`

`

`Case 1:12-cv-08115-ALC-GWG Document 1 Filed 11/07/12 Page 17 of 54
`Case 1:12—cv-08115-ALC-GWG Document 1
`Filed 11/07/12 Page 17 of 54
`
`US 7,851,482 B2
`
`5
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`3
`matic substances and the like. The compositions intended for
`oral use may be prepared according to any method known in
`the art and such compositions may contain one ormore agents
`selected born the group consisting of inert, non-toxic phar-
`maceutically acceptable excipients that are suitable for the
`manufacture oftablets. Such excipients include, for'exarnple
`an inert diluent such as lactose; granulating anddisintegratin