V.
`
`‘
`
`A
`
`C,
`
`1
`
`AlVlNEAL PHARMACEUTICALS,
`LLC and AMNEAL
`Case 1:12-cv-08115-TPG-GWG Document 3 Filed 11/14/12 Page 1 of 106
`PHARMACEUTICALS OF NEW
`YORK, LLC,
`'
`
`Defendants.
`
`AMENDED COMPLAINT
`
`Plaintiffs Endo Pharmaceuticals Inc. (“Endo”) and Griinenthal GmbH (“Gr1‘inenthal”) for
`
`their Complaint against Defendants Amneal Pharmaceuticals, LLC and Amneal Pharmaceuticals
`
`of New York, LLC (collectively, “Amneal”), alleges as follows:
`
`PARTIES
`
`1.
`
`Plaintiff Endo is a Delaware corporation, having its principal place of business at
`
`lOO Endo Boulevard, Chadds Ford, Pennsylvania 19317. Endo is a specialty Pharmaceuticals
`
`company engaged in the research, development, sale and marketing of prescription
`
`pharmaceuticals used, among other things, to treat and manage pain. Endo markets and
`
`distributes OPANA® ER, an innovative crush—resistant opioid (alternatively referred to herein as
`
`“Opana ER CRF”).
`
`2.
`
`Plaintiff Griinenthal GmbH (“Gri'1nenthal”) is a corporation organized and
`
`existing under the laws of Germany, having an address at 52078 Aachen, Zieglerstafle 6, North
`
`Rhine—Westaphalia, Germany.
`
`ENDO - Ex. 2002
`
`Amneal v. Endo
`
`|PR2014-00360
`
`ENDO - Ex. 2002
`Amneal v. Endo
`IPR2014-00360
`
`

`
`4.
`
`Upon information and belief, Amneal Pharmaceuticals is a pharmaceutical
`
`Case 1:12-cv-08115-TPG-GWG Document 3 Filed 11/14/12 Page 2 of 106
`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 Yor ”) is a limited liability company organized and existing under the laws of
`
`the State of Delaware, and shares a principal place of business with Amneal Pharmaceuticals’
`
`administrative offices at 85 Adams Avenue, Hauppauge, New York 11788.
`
`6.
`
`Upon information and belief, Amneal New York is a pharmaceutical company
`
`engaged in the manufacturing for and the sale of generic prescription pharmaceutical products to
`
`Amneal Pharmaceuticals for distribution throughout the United States, including in this judicial
`
`district.
`
`NATURE OF ACTION
`
`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
`
`seq.
`
`JURISDICTION AND VENUE
`
`8.
`
`This Court has jurisdiction over the subject matter of this action pursuant to 28
`
`U.S.C. §§ 1331 and 133 8(a) (patent infringement), and 28 U.S.C. §§ 2201 and 2202 (declaratory
`
`judgment).
`
`

`
`and/or the sale of a number of pharmaceutical products manufactured and sold pursuant to
`
`Case 1:12-cv-08115-TPG-GWG Document 3 Filed 11/14/12 Page 3 of 106
`approved abbreviated new drug applications within the United States and the State of New York
`
`generally and this judicial district specifically.
`
`I 1.
`
`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
`
`participated in the commission of —— tortious conduct in the State of New York that has led to
`
`foreseeable harm and injury to Endo.
`
`12.
`
`Upon information and belief, Amneal Pharmaceuticals has submitted to FDA
`
`paperwork purporting to constitute an Abbreviated New Drug Application (“ANDA”) under
`
`§ 5050) of the Federal Food, Drug and Cosmetic Act, 21 U.S.C. § 3556) (“ANDA No. 20-4294”
`
`or “Amneal’s ANDA”), 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, (“Amneals’s ANDA Products”), as a generic version of the drug
`
`described in Endo’s SNDA 201655.
`
`13.
`
`Upon information and belief, Amneal both manufactures the Amneal ANDA
`
`Products and conducts testing necessary to validate their quality in the State of New York. On
`
`further information and belief, Amneal intends to manufacture and test Amneal’s ANDA
`
`Products produced for commercial sale in the State of New York.
`
`14.
`
`Upon information and belief, Amneal New York intends to manufacture generic
`
`

`
`15.
`
`Moreover, Amneal Pharmaceuticals and Amneal New York maintain continuous
`
`and systematic contacts with the State ofNew York and this District.
`Case 1:12-cv-08115-TPG-GWG Document 3 Filed 11/14/12 Page 4 of 106
`
`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
`
`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
`
`include, for example, generic versions of Percocet®, U1tracet®, and Neurontin®. A list of
`
`generic products manufactured and sold by Amneal Pharmaceuticals in the United States can be
`
`found at http://www.amneal.corn/index.php.
`
`18.
`
`Upon information and belief, Amneal Pharmaceuticals maintains an
`
`administrative office at 85 Adams Avenue, Hauppauge, NY 11788; an oral solids manufacturing
`
`facility at 75 Adams Avenue, Hauppauge, NY 11788; an oral solids and softgels manufacturing
`
`facility at 50 Horseblock Road, Brookhaven, NY 11719; and an oral solids research and
`
`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.
`
`20.
`
`Furthermore, Amneal Pharmaceuticals has been sued as a patent infringer in this
`
`Court, asserted counterclaims in this Court, and declined to contest that this Court has personal
`
`

`
`Case 1:12-cv-08115-TPG-GWG Document 3 Filed 11/14/12 Page 5 of 106
`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 (“NDA”). 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)(l) 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
`
`bioequivalent 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
`
`filer must provide certifications addressing each of the patents listed in the Orange Book for the
`
`branded drug. See 21 U.S.C. § 355(j)(2)(A)(vii); 21 C.F.R. § 314.94(a)(l2). An ANDA filer
`
`

`
`25.
`
`The sponsor of an ANDA which is accepted for review by FDA that contains a
`
`Case 1:12-cv-08115-TPG-GWG Document 3 Filed 11/14/12 Page 6 of 106
`Paragraph TViCertification 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. 2l U.S.C. §
`
`355(i)(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. § 355(j)(5)(B)(iii); 21 CFR.
`
`§ 3 l4.l07(b)(3). The 30-month stay is important to innovator companies, such as Endo and
`
`Grtinenthal, because it protects them from 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. § 355(j)(5)(B)(iii).
`
`Endo’s Opana ER CRF NDA
`
`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
`
`

`
`extended period of time.
`
`Case 1:12-cv-08115-TPG-GWG Document 3 Filed 11/14/12 Page 7 of 106
`THE ENDO PATENTS
`
`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 M. 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 full title to the ’482 Patent, and accordingly, Endo is
`
`now the sole owner and assignee of the ’482 Patent.
`
`31.
`
`Information regarding the Endo ’482 Patent 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 NDA 201655.
`
`32.
`
`On November 13, 2012, the PTO duly and legally issued U.S. Patent No.
`
`8,309,122 (“the ’122 Patent”), entitled “Oxymorphone Controlled Release Formulations” to
`
`Endo Pharmaceuticals, Inc. as assignee. Huai—Hung Kao, Anand R. Baichwal, Troy McCall, and
`
`David Lee are named as inventors. A true and correct ‘copy of the ’ 122 Patent is attached as
`
`Exhibit B.
`
`33.
`
`Endo is the sole owner and assignee of the ’ 122 Patent.
`
`34.
`
`Information regarding the Endo ’122 Patent has been submitted to FDA for listing
`
`

`
`’722 Patent”), entitled “Abuse-Proofed Dosage Form” to Gruenenthal GmbH, also known as
`
`Case 1:12-cv-08115-TPG-GWG Document 3 Filed 11/14/12 Page 8 of 106
`Griinenthal GmbH, as assignee. Elisabeth Arkenau-Mario, Johannes Bartholomaus, and
`
`Heinrich Kugelmann are named as inventors. A true and correct copy of the ’722 Patent is
`
`attached as Exhibit C.
`
`37.
`
`On November 13, 2013, the PTO duly and legally issued US. Patent No.
`
`8,309,060 (“the ’060 Patent”), entitled “Abuse-Proofed Dosage Form” to Gruenenthal GmbH,
`
`also known as Griinenthal GmbH, as assignee. Elisabeth Arkenau-Marié, Johannes
`
`Bartholomaus, and Heinrich Kugelmann are named as inventors. A true and correct copy of the
`
`’060 Patent is attached as Exhibit D.
`
`38.
`
`Griinenthal is the assignee and owner of the ’722 and ’060 Patents (“the
`
`Grfinenthal Patents”).
`
`39.
`
`Endo has an exclusive license to the Grtinenthal Patents from Griinenthal,
`
`including a right to enforce the Griinenthal Patents.
`
`40.
`
`Information regarding the Griinenthal Patents 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 with reference to NDA 201655.
`
`41.
`
`Opana ER CRF is covered by one or more claims of each of the Griinenthal
`
`Patents.
`
`

`
`seeking approval to engage in the commercial manufacture, use, and sale of 5 mg, 7.5 mg, 10
`
`Case 1:12-cv-08115-TPG-GWG Document 3 Filed 11/14/12 Page 9 of 106
`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.
`
`43.
`
`In a letter dated September 21, 20l2 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 Grtinenthal 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”).
`
`44.
`
`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.
`
`45.
`
`This action was commenced before the expiration of forty—five days from the date
`
`Endo and Grijnenthal received the Amneal Notice Letters. This Amended Complaint adds two
`
`new Counts asserting infringement of the ’122 and ’060 patents which issued after the Complaint
`
`was filed.
`
`COUNT I: INFRINGEMENT OF THE ’482 PATENT
`
`46.
`
`Endo incorporates each of paragraphs 1-45 above as if set forth fully herein.
`
`

`
`or sale of Amneal’s ANDA Products before the expiration of the ’482 Patent. If granted
`
`Case 1:12-cv-08115-TPG-GWG Document 3 Filed 11/14/12 Page 10 of 106
`approval, Amneal intends to launch its ANDA Products before expiration of the ’482 Patent.
`
`49.
`
`Amneal’s commercial manufacture, offer for sale, or sale of its ANDA Products
`
`would infringe the ’482.Patent under 35 U.S.C. § 271(a)-(c).
`
`50.
`
`Any launch by Amneal of its ANDA Products before expiration of the ’482 Patent
`
`would cause Endo to suffer immediate and irreparable harm.
`
`51.
`
`Amneal 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.
`
`COUNT II: INFRINGEMENT OF THE ’722 PATENT
`
`52.
`
`Endo incorporates each ofparagraphs 1-45 above as if set forth fully herein.
`
`53.
`
`The submission of Amneal’s ANDA to FDA, which includes certification under §
`
`505(j)(2)(A)(vii)(lV), constitutes infringement of the "722 Patent under 35 U.S.C. §
`
`27l(e)(2)(A).
`
`54.
`
`Amneal is seeking FDA approval to engage in the commercial manufacture, use,
`
`or sale of its ANDA Products before the expiration of the ’722 Patent. If granted approval,
`
`Amneal intends to launch Amneal’s ANDA Products before expiration of the " 722 Patent.
`
`55.
`
`Arnneal’s commercial manufacture, offer for sale, or sale of its ANDA Products
`
`-10-
`
`

`
`reference to that patent in the Amneal Notice Letters, and was aware that the filing of its
`
`Case 1:12-cv-08115-TPG-GWG Document 3 Filed 11/14/12 Page 11 of 106
`Paragraph IV Certification with respect to the ’722 Patent would constitute infringement of the
`
`patent.
`
`COUNT III: INFRINGEMENT OF THE ’122 PATENT
`
`58.
`
`Endo incorporates each of paragraphs l-45 above as if set forth fully herein.
`
`59.
`
`The submission of Amneal’s ANDA to FDA constitutes infringement of the ’ l22
`
`Patent under 35 U.S.C. § 27l(e)(2)(A).
`
`60.
`
`Amneal is seeking FDA approval to engage in the commercial manufacture, use,
`
`or sale of its ANDA Products before the expiration of the ’122 Patent. If granted approval,
`
`-
`
`Amneal intends to launch its ANDA Products before expiration of the ’ 122 Patent.
`
`61.
`
`Amneal’s commercial manufacture, offer for sale, or sale of its ANDA Products
`
`would infringe the ’ 122 Patent under 35 U.S.C. § 27l(a)—(c).
`
`62.
`
`Any launch by Amneal of its ANDA Products before expiration of the ’ 122 Patent
`
`would cause Endo to suffer immediate and irreparable harm.
`
`COUNT IV: INFRINGEMENT OF THE ’()60 PATENT
`
`63.
`
`' Plaintiffs incorporate each of paragraphs l-45 above as if set forth fully herein.
`
`64.
`
`The submission of Amneal’s ANDA to FDA constitutes infringement of the ’060
`
`Patent under 35 U.S.C. § 27l(e)(2)(A).
`
`65.
`
`Amneal is seeking FDA approval to engage in the commercial manufacture, use,
`
`-11-
`
`

`
`67.
`
`Any launch by Amneal of its ANDA Products before expiration ofthe ’06(l Patent
`
`would cause Endo and Griinenthal to suffer immediate and irreparable harm.
`Case 1:12-cv-08115-TPG-GWG Document 3 Filed 11/14/12 Page 12 of 106
`
`PRAYER FOR RELIEF
`
`WHEREFORE, Plaintiffs Endo and Griinenthal respectfully request the following relief:
`
`A.
`
`A judgment that Defendants have infringed the ’482 Patent, and a declaration that
`
`Amneal’s commercial manufacture, distribution, use, and sale of its ANDA Products would
`
`infringe the ’482 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
`
`Arnneal’s commercial manufacture, distribution, use, and sale of its ANDA Products would
`
`infringe the ’722 Patent;
`
`D.
`
`C.
`
`A declaration that the ’722 Patent is Valid and enforceable; A
`
`A judgment that Amneal has infringed the ’ 122 Patent, and a declaration that
`
`Amneal’s commercial manufacture, distribution, use, and sale of its ANDA Products would
`
`infringe the ’ 122 Patent;
`
`F.
`
`G.
`
`A declaration that the ’ 122 Patent is valid and enforceable;
`
`A judgment that Amneal has infringed the ’060 Patent, and a declaration that
`
`Amneal’s commercial manufacture, distribution, use, and sale of its ANDA Products would
`
`infringe the ’060 Patent;
`
`-12-
`
`

`
`’722, ’ 122, and ’06O Patents, including any extensions;
`
`Case 1:12-cv-08115-TPG-GWG Document 3 Filed 11/14/12 Page 13 of 106
`J.
`A permanent injunction, pursuant to 35 U.S.C. § 27l(e)(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, ’722, ’ 122, and ’060
`
`Patents for the full terms thereof, including any extensions;
`
`K.
`
`An order that damages or other monetary relief be awarded to Endo and
`
`Griinenthal if Arnneal 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 ofthe ’482, ’722, ’l22, and ’060 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 and Griinenthal with prejudgment interest;
`
`L.
`
`A declaration that this an exceptional case and an award of reasonable attorneys’
`
`fees pursuant to 35 U.S.C. § 285;
`
`M.
`
`Reasonable attorneys’ fees, filing fees, and reasonable costs of suit incurred by
`
`Endo and Grtinenthal in thisaction; and
`
`N.
`
`Such other and further relief as the Court may deem just and proper.
`
`-13-.
`
`

`
`ENDO PHARMACEUTICALS INC.
`Case 1:12-cv-08115-TPG-GWG Document 3 Filed 11/14/12 Page 14 of 106
`3/éflg/yggg
`Stephen D. Hoffman (SH 6089)
`WILK AUSLANDER LLP
`
`_ Of Counsel:
`
`Basil J. Lewris
`
`Joann M. Neth
`
`Jennifer H. Roscetti
`
`FINNEGAN, HENDERSON, FARRABOW,
`GARRETT & DUNNER LLP
`
`901 New York Avenue, N.W.
`
`--
`
`Washington, DC 20001
`(202) 408-4000
`bi11.1ewris@finnegan.com
`joann.neth@finnegan.corn
`jennifer.r0scetti@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
`
`14706803
`
`1515 Broadway, 43rd Floor
`New York, NY 10036
`
`(212) 981-2300
`shoffman@wi1kaus1ander.com
`
`ATTORNEYS FOR PLAINTIFF
`
`GRUNENTHAL GMBH
`
`Martin J. B1ack
`
`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.
`
`-14-
`
`

`
`Case 1:12-cv-08115-TPG-GWG Document 3 Filed 11/14/12 Page 15 of 106
`Case1:12-cv-08115—TPG-GWG Document3 Fi|ed11/14/12 Page15of106
`
`EXHIBIT A
`
`EXHIBIT A
`
`

`
`Case 1:12-cv-08115-TPG-GWG Document 3 Filed 11/14/12 Page 16 of 106
`“’°°1"||||fM||fl||||||1'|ll1I|||H||111|||||1|lIF|1|1|M|fi||1|l||1||
`
`US00785l482B2
`
`(12) United States Patent
`Dung et al.
`
`(10) Patent No.:
`
`(45) Date of Patent:
`
`US 7,851,482 B2
`Dec. 14, 2010
`
`(54) METHOD FOR MAKING ANALGESICS
`
`(75)
`
`Inventors: Jen-Sen Dung, Boothwyn, PA (US);
`Erno 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, the term of this
`patent is extended or adjusted under 35
`U.S.C. l54(b) by 646 days.
`
`(21) Appl.No.: 11/866,840
`
`(22)
`
`Filed:
`
`Oct. 3, 2007
`
`(65)
`
`(30)
`
`Prior Publication Data
`
`US 2008/0146601A1
`
`Jun. 19, 2008
`
`Foreign Application Priority Data
`
`Dec. 14, 2006
`
`(GB)
`
`............................... .. 0624880.1
`
`(51)
`
`Int. Cl.
`(2006.01)
`A61K 31/485
`(2006.01)
`C07D 489/04
`(52) U.S. Cl.
`.......................... .. 514/282; 546/45; 546/44
`(58) Field of Classification Search ............... .. 514/282;
`546/45, 44
`See application file for complete search history.
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`3,332,950 A
`3,433,791 A
`3,812,132 A
`3,845,770 A
`3,916,899 A
`4,063,064 A
`4,088,864 A
`4,200,098 A
`4,285,987 A
`4,861,598 A
`4,957,681 A
`5,071,985 A
`5,215,758 A
`5,273,760 A
`5,286,493 A
`5,324,351 A
`5,356,467 A
`5,472,712 A
`5,869,669 A
`5,922,876 A
`5,948,788 A
`5,952,495 A
`5,981,751 A
`6,008,354 A
`6,008,355 A
`6,013,796 A
`6,177,567 B1
`6,262,266 B1
`6,291,675 B1
`6,365,742 B1
`6,395,900 B1
`
`7/1967 Blumberg et al.
`3/1969 Bentley
`5/1974 Grewet al.
`11/1974 Theeuwes et al.
`11/1975 Theeuwes et al.
`12/1977 Saunders et al.
`5/1978 Theeuwes et al.
`4/1980 Ayer et al.
`8/1981 Ayer etal.
`8/1989 Oshlack
`9/1990 Klimesch etal.
`12/1991 Andre et al.
`6/1993 Krishnamurthy
`12/1993 Oshlack et al.
`2/1994 Oshlack et al.
`6/1994 Oshlacket al.
`10/1994 Oshlack et al.
`12/1995 Oshlack et al.
`2/1999 Huang et al.
`7/1999 Huang et al.
`9/1999 Huang et al.
`9/1999 Huang et al.
`11/1999 Mudryket al.
`12/1999 Huang et al.
`12/1999 Huang etal.
`1/2000 Huang et al.
`1/2001 Chiu etal.
`7/2001 Chiu etal.
`9/2001 Coopet al.
`4/2002 Mudryk et al.
`5/2002 Coop et al.
`
`6,403,798 B2
`6,723,894 B2
`6,864,370 B1
`6,949,645 B1
`7,071,336 B2
`7,129,248 B2
`7,153,966 B2
`2002/0045755 A1
`2003/0129230 A1
`2003/0129234 A1
`2003/0157167 A1
`2006/0009479 A1
`2006/0173029 A1
`2008/0045716 A1
`2008/0125592 A1
`2008/0312442 A1
`
`6/2002 Chiu et al.
`4/2004 Fist et al.
`3/2005 Lin et al.
`9/2005 Francis
`7/2006 Francis et al.
`10/2006 Chapman et al.
`12/2006 Casner et al.
`4/2002 Coop et al.
`7/2003 Baichwal et al.
`7/2003 Baichwal et al.
`8/2003 Kao et al.
`1/2006 Bailey et al.
`8/2006 Chapman et al.
`2/2008 Smith et al.
`5/2008 Huang
`12/2008 Buehler et al.
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`W0
`W0
`W0
`W0
`
`0 359 647
`WO 99/02529
`WO 01/29048
`WO 2005/028483
`WO 2007/103105 A2 *
`
`3/1990
`1/1999
`4/2001
`3/2005
`9/2007
`
`OTHER PUBLICATIONS
`
`Andrew Coop et al., “L-Selectride as a General Reagent for the
`O-Demethylation and N-Decarbomethoxylation of Opium Alkaloids
`and Derivatives,” J'. Org. Chem., 1998, 63 (13), pp. 4392-4396.
`Ulrich Weiss, Derivatives of Morphine.
`II. Demethylation of
`14-hydroxycodeinone.
`14-Hydroxymorphinone
`and
`8, 14-
`Dihydroxydihydromorphinone, J'. Org. Chem., 1957, 22 (11), pp.
`1505-1508.
`U.S. Appl. No. 12/446,171 which is a National Stage of PCT/US07/
`68009 to Bao-Shan Huang, filed May 2, 2007 and entitled “Process
`for Preparing Oxymorphone”.
`U.S . Appl. No. 12/446,172 which is the National Stage ofPCT/US07/
`81513 to Bao-Shan Huang, filed Oct. 16, 2007 and entitled “Process
`for Preparing Oxymorphone, Naltrexone, and Buprenorphine”.
`Andre et al., “O-Demethylation of Opioid Derivatives with Methane
`Sulfonic Acid / Methionine: Application to the Synthesis of
`Naloxone and Analogues,” Synthetic Communications, vol. 22, No.
`16, pp. 2313-2327 (1992).
`Hosztafi et al., “Reactions of Azodicarboxylic Esters with Amines,”
`Scientia Pharmaceutica, vol. 55, pp. 61-75 (1987).
`Marton et al., “Herstellung von 6, 14-Ethenomorphinan-Derivaten,”
`Monatshefteftir Chemie, vol. 125, pp. 1229-1239 (1994).
`
`* cited by examiner
`
`Primary Examiner—Charanjit S Aulakh
`(74) Attorney, Agent, or Firm—RatnerPrestia
`
`(57)
`
`ABSTRACT
`
`Improved analgesic oxymorphone hydrochloride contains
`less than 10 ppm of alpha, beta unsaturated ketones and
`pharmaceutical preparations comprising such oxymorphone
`hydrochloride. The oxymorphone hydrochloride is produced
`by reducing a starting material oxymorphone hydrochloride
`using gaseous hydrogen and under specified acidity, solvent
`system and temperature conditions. A specific polymorph of
`oxymorphone hydrochloride may be obtained by hydration.
`
`21 Claims, 1 Drawing Sheet
`
`

`
`Case 1:12-cv-08115-TPG-GWG Document 3 Filed 11/14/12 Page 17 of 106
`Case 1:12—cv—08115-TPG-GWG Document 3
`Filed 11/14/12 Page 17 of 106
`
`U.S. Patent
`
`Dec. 14, 2010
`
`US 7,851,482 B2
`
`LO
`<3’
`
`40
`
`35
`
`30
`
`25
`
`°2Theta
`
`20
`
`15
`
`10
`
`l‘||
`
`I
`
`||I[llIl[
`500
`
`|_‘
`
`CQQ‘
`
`-
`
`3000
`
`2500
`
`2000
`
`FTT‘|‘|l‘1-ll
`
`1500-
`
`Counts/s
`
`

`
`Case 1:12-cv-08115-TPG-GWG Document 3 Filed 11/14/12 Page 18 of 106
`Case 1:12-CV-08115-TPG-GWG Document 3
`Filed 11/14/12 Page 18 of 106
`
`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 of oxymor-
`phone and a method for its synthesis.
`Several methods for synthesising oxymorphone from com-
`pounds isolated from the opium poppy or compounds derived
`therefrom are known, for example, starting from morphine,
`thebaine, or from oxycodone. There remains the need 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.
`U.S. Pat. No. 7,129,248 claims a process for producing
`oxycodone hydrochloride with less than 25 ppm of 14-hy-
`droxycodeinone, by hydrogenating oxycodone having
`greater than 100 ppm 14-hydroxycodeinone. The synthetic
`route to oxycodone taught in US’248 starts from thebaine and
`produces 14-hydroxycodeinone as an intermediate product
`and 8,14-dihydroxy-7,8-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 14-hydroxycodeinone. Thus the final oxyc-
`odone hydrogen chloride salt contains unreacted 14-hydroxy-
`codeinone as well as 14-hydroxycodeinone derived from the
`by-product 8,14-dihydroxy-7,8-dihydrocodeinone. A hydro-
`genation step is claimed to reduce contents of 14-hydroxyco-
`deinone from at least 100 ppm to less than 25 ppm.
`SUMMARY OF THE INVENTION
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`The present invention provides an oxymorphone hydro-
`chloride product containing less than 10 ppm of alpha, beta
`unsaturated ketones.
`
`45
`
`The invention also provides a method ofpurifying oxymor-
`phone hydrochloride to yield an oxymorphone hydrochloride
`product containing less than 10 ppm of alpha, beta unsatur-
`ated ketones, which method comprises reducing a starting
`material oxymorphone hydrochloride in a strongly acid water
`and alcohol solvent, using gaseous hydrogen at a temperature
`in the 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.
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`The invention will be described below with reference to 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
`
`55
`
`60
`
`65
`
`Preferably, the solvent is ethanol/water, although other
`water miscible alcohols, such as isopropanol and n-propanol,
`
`2
`
`may be used. The reaction medium is very acidic, preferably
`by incorporating at least two equivalents ofhydrochloric acid.
`A pH ofless than 1 is desirable.
`The reaction temperature is mo st preferably maintained at
`about 65° C. Hydrogen is conveniently supplied to the reac-
`tion vessel at 2.41 bar pressure.
`The method of the invention has been able to reduce start-
`
`ing material oxymorphone hydrochloride having very high
`(ofthe order of0.3 to 0.5%, or 3,000 to 5,000 ppm) content of
`alpha, beta unsaturated ketones to less than 10 ppm, and in
`many cases to undetectable levels (by HPLC).
`The starting material oxymorphone 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-
`ric acid and an alcohol/water reaction medium. Suitable tem-
`
`peratures are 60-70° C. It can be seen that the reaction
`medium is ideal for the reduction of the method of the inven-
`
`tion, so that it is generally not necessary to isolate the oxy-
`morphone hydrochloride. However, the starting material oxy-
`morphone hydrochloride may be isolated from the reaction
`medium or may be from another source.
`The oxymorphone free base is itselfpreferably prepared by
`a reduction of 14-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 temperatures are of
`the order of30° C. The base is precipitated by adding aqueous
`ammonia (NH4OH).
`This reduction may be in the presence of the reaction
`medium to which is added dichloromethane in methanol,
`Florasil and n-propanol.
`The 14-hydroxymorphinone itself is most suitably pre-
`pared by hydroxylation of oripavine, using hydrogen perox-
`ide in the presence of formic acid.
`Oripavine is a known compound, which is extractable from
`poppy straw. The strain developed in Tasmania to be a high-
`Thebaine-yielding 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
`of 50%) overall yields from oripavine, as well as remarkably
`high purity. Under favourable conditions, the presence of
`alpha, beta unsaturated ketones is undetectable by conven-
`tional means such as HPLC, but the 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 unsaturated ketones can be incorporated into
`pharmaceutical dosage forms, e.g., by admixtures of the oxy-
`morphone hydrochloride having less than 10 ppm of alpha,
`beta unsaturated ketones with conventional excipients, i.e.,
`pharmaceutically acceptable organic or inorganic carrier sub-
`stances. For oral formulations, 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 arabic, vegetable oils, benzyl alcohols,
`polyethylene glycols, gelate, carbohydrates such as lactose,
`amylose or starch, magnesium stearate, talc, silicic acid, vis-
`cous paraffin, perfume oil, fatty acid monoglycerides and
`diglycerides, pentaerythritol fatty acid esters, hydroxy-meth-
`ylcellulose, polyvinylpyrrolidone, etc. The pharmaceutical
`preparations can be sterilized and if desired mixed with aux-
`iliary agents, e.g., lubricants, disintegrants, preservatives, sta-
`bilizers, wetting agents, emulsifiers, salts for influencing
`osmotic pressure buffers, colouring, flavouring and/or aro-
`
`

`
`Case 1:12-cv-08115-TPG-GWG Document 3 Filed 11/14/12 Page 19 of 106
`Case 1:12-CV-08115-TPG-GWG Document 3
`Filed 11/14/12 Page 19 of 106
`
`US 7,851,482 B2
`
`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 or more agents
`selected from the group consisting of inert, non-toxic phar-
`maceutically acceptable excipients that are suitable for the
`manufacture of tablets. Such excipients include, for example
`an inert diluent suc