Case 2:07-cv-04050-SDW-MCA Document 1 Filed 08/23/07 Page 1 of 21 PageID: 4
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`
`Charles M. Lizza
`
`William C. Baton
`
`SAUL EWING LLP
`
`One Riverfront Plaza
`
`Newark, New Jersey 07102-5490
`(973) 286—6700
`clizza@saul.com
`
`Attorneys for Plaintifl
`Celgene Corporation
`
`UNITED STATES DISTRICT COURT
`
`DISTRICT OF NEW JERSEY
`
`Civil Action No.
`
`COMPLAINT FOR PATENT
`INFRINGEMENT
`(Filed Electronically)
`
`)
`)
`)
`
`))
`
`)
`;
`)
`;
`
`CELGENE CORPORATION,
`~
`Plaintiff,
`
`v.
`BARR LABORATORIES, INC., and
`BARR PHARMACEUTICALS, INC.,
`Defendants.
`
`Plaintiff Celgene Corporation (“Celgene”), by its undersigned attorneys, brings this
`
`action against defendants, Barr Laboratories, Inc. and Barr Pharmaceuticals, Inc., for patent
`
`infringement and alleges as follows:
`
`Nature of the Action
`
`1.
`
`This is an action for patent infringement under the patent laws of the United
`
`States, 35 United States Code, arising from Barr Laboratories, Inc’s filing of an Abbreviated
`
`New Drug Application (“ANDA”) with the United States Food and Drug Administration
`
`(“FDA”) seeking approval to commercially market a generic Version of Celgene’s THALOMID
`
`®
`
`brand drug prior to the expiration of United States Patent No. 7,230,012 (“the ’012 patent”).
`
`NYl—4010511v1
`
`
`
`

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`The Parties
`
`2.
`
`Plaintiff Celgene is a corporation organized and existing under the laws of the
`
`State of Delaware, having a principal place of business at 86 Morris Avenue, Summit, New
`
`Jersey 07901.
`
`3.
`
`On information and belief, defendant Barr Laboratories, Inc. (“Barr”) is a
`
`corporation having its principal place of business at 223 Quaker Road, Pomona, New York
`
`10970.
`
`4.
`
`On information and belief, defendant Barr Pharmaceuticals, Inc. is a corporation
`
`organized and existing under the laws of the State of Delaware, having a place of business at 400
`
`Chestnut Ridge Road, Woodcliff Lake, NJ 07677.
`
`5.
`
`On information and belief, defendant Barr Laboratories, Inc. is a subsidiary of
`
`defendant Barr Pharmaceuticals, Inc.
`
`6.
`
`On information and belief, Barr Laboratories, Inc. and Barr Pharmaceuticals, Inc.
`
`are registered to do business in New Jersey. Further, on information and belief, Barr
`
`Laboratories, Inc. and Barr Pharmaceuticals, Inc. maintain executive offices and a manufacturing
`
`facility and otherwise transact business within this District.
`
`7.
`
`On information and belief, the acts of Barr Laboratories, Inc. complained of
`
`herein were done at the direction of, with the authorization of, or with the cooperation,
`
`participation, or assistance of, or at least in part for the benefit of, Barr Pharmaceuticals, Inc.
`
`8.
`
`Barr Laboratories, Inc. and Barr Pharmaceuticals, Inc. are referred to hereinafter,
`
`collectively, as “Barr.”
`
`NYl-4010511vl
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`Jurisdiction and Venue
`
`9.
`
`This Court has jurisdiction over the subject matter of this action pursuant to 28
`
`U.S.C. §§ 1331 and 1338(a) and 2201 and 2202.
`
`10.
`
`This Court has personal jurisdiction over Barr by virtue of the fact that Barr has
`
`availed itself of the laws of New Jersey and conducts business in New Jersey.
`
`11.
`
`Venue is proper in this District pursuant to 28 U.S.C. §§ 1391 and 1400(b).
`
`The ’012 Patent
`
`12.
`
`On June 12, 2007, the United States Patent and Trademark Office (“USPTO”)
`
`duly and lawfully issued the ’012 patent, entitled “Pharmaceutical Compositions And Dosage
`
`Forms of Thalidomide” to Celgene as assignee of the inventors Paul D’Angio and John McCarty.
`
`A copy of the ’012 patent is attached hereto as Exhibit A.
`
`The THALOMID® Drug Product
`
`13.
`
`Celgene holds an approved New Drug Application (“NDA”) under Section 505(a)
`
`of the Federal Food Drug and Cosmetic Act (“FFDCA”), 21 U.S.C. § 355(a) for thalidomide
`
`capsules (NDA No. 20-785), which it sells as THALOMID® brand drug. The claims of the ’012
`
`patent cover pharmaceutical compositions containing the drug thalidomide.
`
`14.
`
`Pursuant to 21 U.S.C. § 355(b)(1) and attendant FDA regulations, the ’012 patent
`
`is listed in the FDA publication, “Approved Drug Products with Therapeutic Equivalence
`
`Evaluations” (the “Orange Book”), with respect to THALOMID® brand drug.
`
`Civil Action No. 07-0286
`
`15.
`
`Pursuant to Section 505 of the FFDCA, Barr filed ANDA No. 78-505 for
`
`thalidomide capsules. That ANDA seeks approval to engage in the commercial use,
`
`NYl-4010511vl
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`

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`manufacture, sale, offer for sale or importation into the United States of thalidomide capsules 50
`
`mg, 100 mg, and 200 mg (“Barr’s Proposed Products”), before the ’012 patent expires.
`
`16.
`
`In connection with the filing of ANDA No. 78-505, Barr provided written
`
`certification to the FDA, as called for by Section 505 of the FFDCA, which alleged that the
`
`claims of several US. Patents owned by Celgene are invalid, unenforceable, and/or not infringed
`
`by the activities described in Barr’s ANDA. Those patents are United States Patent Nos.
`
`6,045,501 (the ’501 patent”), 6,315,720 (“the ’720 patent”), 6,561,976 (“the ’976 patent”),
`
`6,561,977 (“the ’977 patent”), 6,755,784 (“the ’784 patent”), 6,869,399 (“the ’399 patent”), and
`
`7,141,018 (“the ’018 patent”).
`
`17.
`
`No earlier than December 6, 2006, Barr sent written notice of its initial ANDA
`
`filing to Celgene (“Barr’s Initial Notice Letter”). Barr’s Initial Notice Letter alleged that the
`
`claims of the ’501, ’720, ’976, ’977, ’784, ’399, and ’018 patents are invalid, unenforceable,
`
`and/or will not be infringed by Barr. Barr’s notice also informed Celgene that Barr seeks
`
`approval to market Barr’s Proposed Products before those patents expire.
`
`18.
`
`In response to Barr’s Initial Notice Letter, Celgene filed suit pursuant to 21
`
`I U.S.C. § 355G)(5)(B)(iii) within 45 days of Celgene’s receipt of Barr’s notice. See Celgene
`
`Corp. v. Barr Labs, Inc, el‘ al, No. 07-0286 (SDW) (D.N.J.).
`
`Acts Giving Rise to this Suit
`
`19.
`
`After the ’012 patent issued and Celgene listed it in the Orange Book with respect
`
`to Thalomid® brand drug, Barr amended its ANDA to certify against the ’012 patent and was
`
`thus required to send Celgene a supplemental notification pursuant to 21 U.S.C.
`
`§ 505G)(2)(B)(ii)-
`
`NYI-4010511vl
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`

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`
`20.
`
`In connection with the filing and amendment of its ANDA as described in the
`
`proceeding paragraphs, Barr has provided written certification to the FDA, as called for by
`
`Section 505 of the FFDCA, which alleges that the claims of the ’012 patent are invalid.
`
`21.
`
`No earlier than July 11, 2007, Barr sent written notice of its ANDA amendment to
`
`Celgene (“Barr’s Supplemental Notice Letter”). Barr’s Supplemental Notice Letter alleged that
`
`the claims of the ’012 patent are invalid. Barr’s Supplemental Notice letter also informed
`
`Celgene that Barr seeks approval to market Barr’s Proposed Products before the ”012 patent
`
`expires.
`
`22.
`
`This action is being brought pursuant to 21 U.S.C. § 3550)(5)(B)(iii) within 45
`
`days of Celgene’s receipt of Barr’s Supplemental Notice Letter.
`
`Count I: Barr’s Filing of the ANDA Infringes the ’012 Patent
`
`23.
`
`Plaintiffs repeat and reallege the allegations of paragraphs 1—22 as though fully set
`
`forth herein.
`
`24.
`
`Barr’s submission and amendment of its ANDA to obtain approval to engage in
`
`the commercial use, manufacture, sale, offer for sale, or importation of thalidomide capsules,
`
`prior to the expiration of the ’012 patent, constitutes infringement of one or more of the claims of
`
`that patent under 35 U.S.C. § 271(e)(2)(A).
`
`25.
`
`There is a justiciable controversy between the parties hereto as to infringement of
`
`the ’012 patent.
`
`26.
`
`Unless enjoined by this Court, Barr, upon FDA approval of Barr’s ANDA, will
`
`.
`
`infringe the ’012 patent by making, using, offering to sell, importing, and selling Barr’s Proposed
`
`Products in the United States.
`
`NYl—4010511vl
`
`

`

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`
`27.
`
`Celgene will be substantially and irreparably damaged and harmed if Barr’s
`
`infringement of the ’012 patent is not enjoined.
`
`28.
`
`29.
`
`Celgene does not have an adequate remedy at law.
`
`This case is an exceptional one, and Celgene is entitled to an award of its
`
`reasonable attorney’s fees under 35 U.S.C. § 285.
`
`Count II: Inducing Infringement
`
`30.
`
`Plaintiffs repeat and reallege the allegations of paragraphs 1—29 as though fully set
`
`forth herein.
`
`31.
`
`Upon information and belief, Barr Pharmaceuticals, Inc. has infringed the ’012,
`
`patent under 35 U.S.C. § 271(b) by actively inducing Barr Laboratories, Inc. to infringe the ’012
`
`patent.
`
`PRAYER FOR RELIEF
`
`WHEREFORE, Plaintiff Celgene Corporation respectfully requests the following relief:
`
`(A)
`
`A judgment be entered that Defendants have infringed the ’0 12 patent by
`
`submitting and amending the aforementioned ANDA;
`
`(B)
`
`A judgment be entered that Defendants have infringed, and that Defendants’
`
`making, using, selling, offering to sell, or importing Barr’s Proposed Products will infringe one
`
`or more claims of the ’012 patent;
`
`(C)
`
`An Order that the effective date of FDA approval of ANDA No. 78—505 be a date
`
`which is not earlier than the later of the expiration of the ’012 patent, or any later expiration of
`
`exclusivity to which Plaintiff is or becomes entitled;
`
`(D)
`
`Preliminary and permanent injunctions enjoining Defendants and their officers,
`
`agents, attorneys, and employees, and those acting in privity or concert with them, from making,
`
`NYl-4010511v1
`
`

`

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`
`using, selling, offering to sell, or importing Barr’s Proposed Products until after the expiration of
`
`the ’012 patent, or any later expiration of exclusivity to which Plaintiff is or becomes entitled;
`
`(E)
`
`A permanent injunction be issued, pursuant to 35 U.S.C. § 271(c)(4)(B),
`
`restraining and enjoining Defendants, their officers, agents, attorneys, and employees, and those
`
`acting in privity or concert with them, from practicing the invention as claimed in the ’012
`
`patent, or from actively inducing or contributing to the infringement of the ’012 patent until after
`
`that patent expires, or any later expiration of exclusivity to which Plaintiff is or becomes entitled;
`
`(F)
`
`A declaration that the commercial manufacture, use, importation into the United
`
`States, sale, or offer for sale of Barr’s Proposed Products will directly infringe or induce and/or
`
`contribute to infringement of the ’012 patent until after that patent expires, or any later expiration
`
`of exclusivity to which Plaintiff is or becomes entitled;
`
`(G)
`
`To the extent that Defendants have committed any acts with respect to the
`
`compositions claimed in the ’012 patent, other than those acts expressly exempted by 35 U.S.C.
`
`§ 271(e)(1), Plaintiff be awarded damages for such acts;
`
`(H)
`
`If Defendants engage in the commercial manufacture, use, importation into the
`
`United States, sale, or offer for sale of Barr’s Proposed Products prior to the expiration of the
`
`”012 patent, a judgment awarding damages to Plaintiff resulting from such infringement together
`
`with interest;
`
`(I)
`
`(J)
`
`Attorney’s fees in this action as an exceptional case pursuant to 35 U.S.C. § 285;
`
`Costs and expenses in this action; and
`
`(K)
`
`Such further and other relief as this Court may deem just and proper.
`
`NYI-4010511vl
`
`

`

`Case 2:07-cv-04050-SDW-MCA Document 1 Filed 08/23/07 Page 8 of 21 PageID: 11
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`Case 2:33-av-00001 Document 1772 Filed 08/23/2007 Page 8 of 21
`
`Dated: August 23, 2007
`
`Respectfully submitted,
`
`8/ Charles M Lizza
`
`Charles M. Lizza
`William C. Baton
`
`SAUL EWING LLP
`
`One Riverfront Plaza
`
`Newark, New Jersey 07102—5490
`(973) 286—6700
`clizza@saul.com
`
`Attorneys for Plaintifl
`Celgene Corporation
`
`OF COUNSEL:
`
`F. Dominic Cerrito
`
`Daniel L. Malone
`
`JONES DAY
`
`222 East 41St Street
`
`New York, New York 10017—6702
`Telephone:
`(212) 326-3939
`Facsimile:
`(212) 755-7306
`
`Daniel E. Reidy
`JONES DAY
`
`77 West Wacker
`
`Chicago, Illinois 60601-1692
`Telephone:
`(312) 269—4140
`Facsimile:
`(312) 782—8585
`
`Richard G. Greco
`
`Benjamin C. Hsing
`KAYE SCHOLER LLP
`
`425 Park Avenue
`
`New York, New York 10022-3598
`Telephone:
`(212) 836-8500
`Facsimile:
`(212) 836-8689
`
`NYI-4010511v1
`
`

`

`Case 2:07-cv-04050-SDW-MCA Document 1 Filed 08/23/07 Page 9 of 21 PageID: 12
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`Case 2:33-av-00001 Document 1772 Filed 08/23/2007 Page 9 of 21
`
`LOCAL CIVIL RULE 11.2 CERTIFICATION
`
`I hereby certify that Civil Action No. 07—286 (SDW), Celgene Corporation, v. Barr
`
`Laboratories, Inc, et al., is a related action pending in this District. The parties in the related
`
`action are identical to this action. The plaintiff is Celgene Corporation (“Celgene”) and the
`
`defendants are Barr Laboratories, Inc. and Barr Pharmaceuticals, Inc. (collectively, “Barr”).
`
`Both actions arise out of Barr’s filing of ANDA No. 78~505 which seeks approval to market a
`
`generic version of Celgene’s Thalomid® brand drug.
`
`I further certify that, to the best of my
`
`knowledge, the matter in controversy is not the subject of any other action pending in any court,
`
`or of any pending arbitration or administrative proceeding.
`
`Dated: August 23, 2007
`
`By: s/ Charles M. Lizza
`Charles M. Lizza
`
`William C. Baton
`
`SAUL EWING LLP
`
`One Riverfront Plaza
`
`Newark, New Jersey 07102-5490
`(973) 286-6700
`clizza@saul.com
`
`Attorneysfor Plaintifl
`Celgene Corporation
`
`OF COUNSEL:
`
`F. Dominic Cerrito
`
`Daniel L. Malone
`
`JONES DAY
`
`222 East 41St Street
`
`New York, New York 10017-6702
`Telephone:
`(212) 326—3939
`Facsimile:
`(212) 755-7306
`
`NYI-4017586v1
`
`

`

`Case 2:07-cv-04050-SDW-MCA Document 1 Filed 08/23/07 Page 10 of 21 PageID: 13
`Case 23%19219305A911‘fdbw-MQ3‘00WW72 FilaréafifQQ/Qflzoé’fige F199?! 1% MID: 13
`Case 2:33-av-00001 Document 1772 Filed 08/23/2007 Page 10 of 21
`
`Daniel E. Reidy
`JONES DAY
`
`77 West Wacker
`
`Chicago, Illinois 60601-1692
`Telephone:
`(312) 269-4140
`Facsimile:
`(312) 782—8585
`
`Richard G. Greco
`
`Benjamin C. Hsing
`KAYE SCHOLER LLP
`
`425 Park Avenue
`
`New York, New York 10022—3598
`Telephone:
`(212) 836-8500
`Facsimile:
`(212) 836—8689
`
`NYl—40l7586vl
`
`

`

`Case 2:07-cv-04050-SDW-MCA Document 1 Filed 08/23/07 Page 11 of 21 PageID: 14
`Case ZEQEéEQQWfiQW'MQZ‘OCWWVZ Fimwwgflaomenaw 21 smelt): 14
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`
`
`
`EXHIBIT A
`
`

`

`Case 2:07-cv-04050-SDW-MCA Document 1 Filed 08/23/07 Page 12 of 21 PageID: 15
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`Case 2:33-av-00001 Document 1772 Filed 08/23/2007 Page 12 of 21
`llllllililllllllllllllllllilllillllll|||l|llillllllilllilllllllllilllllllll
`USOO7230012B2
`
`(12) United States Patent
`US 7,230,012 B2
`(10) Patent No.:
`
`Jun. 12, 2007(45) Date of Patent:
`D’Angio et a].
`
`(54) PHARMACEUTICAL COMPOSITIONS AND
`DOSAGE FORMS OF THALIDOMIDE
`
`(75)
`
`Inventors: Paul D’Angio, Basking Ridge, NJ
`(US); John McCarty, Miami Springs,
`FL (US)
`.
`
`(73) Assignee: Celgene Corporation, Summit, NJ
`(US)
`
`( "‘ ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 162 days.
`
`(21) App1.No.: 10/608,077
`
`(22) Filed:
`
`Jun. 30, 2003
`
`(65)
`
`Prior Publication Data
`US 2004/0138263 A1
`Jul. 15, 2004
`
`Related US. Application Data
`
`(60) Provisional application No. 60/426,016, filed on Nov.
`14, 2002.
`
`(51)
`
`Int. Cl.
`(2006.01)
`A61K 31/445
`(2006.01)
`A61K 9/48
`(52) US. Cl.
`....................... 514/323; 514/323; 424/451
`(58) Field of Classification Search ..................... None
`See application file for complete search history.
`
`(56)
`
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`
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`5,405,855 A
`5,434,170 A
`5,593,990 A
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`5,643,915 A "‘
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`5,712,291 A
`5,731,325 A
`6,001,828 A
`6,071,948 A
`6,114,355 A
`6,140,346 A
`6,228,879 B1
`6,235,756 B1
`6,469,045 Bl
`6,914,067 B2 "‘
`2003/0191098 A1
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`........... 514/231.5
`1/1995 Kaplan et a1.
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`514/323
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`1/1997 D’Amato .............. 514/235.2
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`..
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`.
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`
`1/1998 D'Amato ..........
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`
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`.
`514/323
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`
`6/2000 D'Amato .......
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`
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`.
`.. 514/323
`......
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`514/416
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`514/323
`
`10/2002 D’Amato
`514/416
`7/2005 Govindarajan et al.
`..... 514/283
`10/2003 D’Arnato .................... 514/171
`
`OTHER PUBLICATIONS
`
`Baker et al., Eflicacy of Thalidomide in the Treatment of Relapsed
`and Refractory Myeloma, Haematology Society of Australia and
`New Zealand, Abstracts Jul. 25-28, 2000, 54.‘
`
`Gennaro, Remington: The Science and Practice of Pharmacy, Mack
`Publishing Co. 19‘”, 1618, 1642-1644."'
`Schefiler et. al., 1999, Clin Pharmacol Ther, 65, 483—4903”
`Teo et. a1, 1999, Journal of Clinical Pharmacology, 39, 1162-11683“
`Teo et a1., 2000, Biopharmaceutics and Drug Disposition, 21,
`33—403“
`“Thalomid,” Physician 's Desk Reference, 53th Ed., pp. 3457—3462
`(1999).
`'
`“Thalomid,” Physician 's Desk Reference, 54th Ed., pp. 911-916
`(2000).
`“Thalomid,” Physician 's Desk Reference, 55th Ed., pp. 1081-1085
`(2001).
`“Thalomid,” Physician's Desk Reference, 56th Ed., pp. 1154-1158
`(2002).
`“Thalomid,” Physician ’s Desk Reference, 57th Ed., pp. 1153-1157
`(2003).
`“Thalomid,” Physician ’s Desk Reference, 58th Ed., pp. 1122-1127
`(2004).
`“Thalomid,” Physician ’s Desk Reference, 59th Ed., pp. 1095-1099
`(2005).
`“'I'haildomide,” Printout
`html/cw en en aboutus.
`jhtml?CatId=cw_en_en_aboutus_e_0l (date unknown).
`“Getting Thalidomide,” Printout
`from http://www.4imago.com/
`mpd/mexico.htm (May 12, 2004).
`“Talizer,” Printout from http://216.239.37.lO4/translate_c?h1=en
`&sl=es&u=http://wwww.facmed.unammx/bmnd/pl
`(date
`unknown).
`from
`Printout
`“Sauramide,”
`suaramide_photo.htm (date unknown).
`“Notice Destinee Au Patient,” Notice to Patients
`Thalidomide Laphal (Date unknown).
`“Historical Timeline," Printout
`from http://www.p11armion.com/
`corporateweb/home.nsf/Content/Historical
`Timeline
`(date
`unknown).
`“Thalidomide 100 mg Tablets (EntreMed Formulation),” Celgene
`internal document (date unknown).
`“Products,” Printout
`from http://wwwd'tburphm’macom/htrnls/
`prod_form.ht_rnl (date unknown).
`
`from www.grunentha.i.com/cw/en_EN/
`
`http://www.kodc .or.kr/j aga/
`
`regarding
`
`(Continued)
`
`Primary Examiner—Frederick Krass
`Assistant Examiner—Lezah Roberts
`(74) Attorney, Agent, or Firm—Jones Day
`
`(57)
`
`ABSTRACT
`
`Pharmaceutical compositions and single unit dosage forms
`of thalidomide and pharmaceutically acceptable prodrugs,
`salts, solvates, hydrates, or clathrates are disclosed. Also
`disclosed are methods of treating and preventing diseases
`and conditions such as, but not limited to, leprosy, chronic
`graft-vs-host disease, rheumatoid arthritis, sarcoidosis, an
`inflammatory condition, inflammatory bowel disease, and
`cancer using the novel dosage fon'ns disclosed herein.
`
`10 Claims, No Drawings
`
`

`

`Case 2:07-cv-04050-SDW-MCA Document 1 Filed 08/23/07 Page 13 of 21 PageID: 16
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`US 7,230,012 B2
`Page 2
`
`OTHER PUBLICATIONS
`
`from http://www.lipomed.com/
`“Myrin (Thaidomide)," Printout
`Pharma/myrin/overview/ (date unknown).
`“Thalidomide,” The Merck Index, 11‘h Ed., p. 9182 (1989).
`“Thalidomide,” The Merck Index. 12m Ed., p. 9389 (1996).
`“Thalidomide,” The Merck Index. 13'h Ed., p. 9323 (2001).
`Guo et a1., “A prototype intelligent hybrid system for hard gelatin
`capsule formulation developmen .” Pharmaceutical Technology,
`pp. 44-60 (Sep. 2002).
`
`Rouhi, “Thalidomide," Chemical & Engineering News, pp. 122-123
`(Jun. 20, 2005).
`“Thalidomide,” Drugs of the Future, Entry # 91361 (2005).
`Abdel-Razeq et 31., Drugs oft/1e Future, 29(10): 1059-1063(2004).
`Sommer, Drugs oft/Ia Future, 24(1):67-75 (1999).
`“Thalidomide,” Drug Data Report, 17(5):468 (1995).
`“Thalidomide,” Drug Data Report, l7(5):482 (1995).
`“Thalidomide,” Drug Data Report, 20(11):962 (1998).
`
`* cited by examiner
`
`

`

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`Case 2:33-av-00001 Document 1772 Filed 08/23/2007 Page 14 of 21
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`
`
`US 7,230,012 B2
`
`1
`PHARMACEUTICAL COMPOSITIONS AND
`DOSAGE FORMS OF THALIDOMIDE
`
`This application claims priority to provisional application
`No. 60/426,016, filed Nov. 14, 2002, the entirety of which is
`incorporated herein by reference.
`
`5
`
`1. FIELD OF THE INVENTION
`
`The present invention relates, in part, to pharmaceutical
`compositions and dosage forms comprising thalidomide and
`phannaceutically acceptable prodrugs,
`salts,
`solvates,
`hydrates, and clathrates thereof.
`
`2. BACKGROUND OF THE INVENTION
`
`Thalidomide is a racemic compound sold under the trade-
`name TI-IALOMID® and chemically named OL-(N-phthal-
`imido)glutarimide or 2-(2,6-dioxo-3-piperidinyl)-1H—isoin-
`dole—l,3(2H)-dione. Thalidomide was originally developed
`to treat morning sickness, but due to tetragenic eflects it was
`withdrawn from use. Thalidomide is currently approved in
`the United States for the treatment of erythema nodosum
`leprosum in humans. Physician ‘5 Desk Reference®, 1081-
`l085 (55th ed., 200l).
`Thalidomide has reportedly been used on patients with
`leprosy, chronic graft-vs-host disease, rheumatoid arthritis,
`sarcoidosis, several inflammatory skin diseases, and inflam-
`matory bowel disease. See generally, Koch, H. R, 22 Prog.
`Med. Chem. 165-242 (1985). See also, Moller, D. R., et al.,
`159 J. Innnunol. 5157-5161 (1997); Vasiliauskas, E. A., et
`al., 117 Gastroenterology 1278-1287 (1999); and Ehren-
`preis, E. D., et al., 117 Gaslroenterology 1271-1277 (1999).
`It has further been alleged that thalidomide can be combined
`with other drugs to treat iscehernia/reperfusion associated
`with coronary and cerebral occlusion. US. Pat. No. 5,643,
`915.
`More recently, thalidomide has been used in the treatment
`of specific types of cancers. These include refractory mul-
`tiple myeloma, brain, melanoma, breast, colon, mesothe-
`lioma, and renal cell carcinoma. See, e.g., Singhal, S., et al.,
`341(21) New England J. Med, 1565-1571 (1999); and
`Marx, G. M., et al., 18 Proc. Am. Soc. Clin. Oncology, 454a
`(1999). It has further been reported that thalidomide has
`been used to prevent the development of chronic cardiomy-
`opathy in rats caused by doxorubicin. Costa, P. T., et al.,
`92(10:suppl. 1) Blood, 235b (1998). Other reports concern-
`ing the use of thalidomide in the treatment of specific
`cancers include combination with carboplatin in the treat-
`ment of glioblastoma multiforme. McCann, J., Drug Topics
`41 -42 (Jun. 21, 1999). Thalidomide has reportedly also been
`used as an antiemetic during the treatment of astrocytoma.
`Zwart, D., 16(12) Arzneim.-Forsclz., 1688-1689 (1966). A
`method of inhibiting of angiogenesis is disclosed by US.
`Pat. No. 6,235,756 B1, which is incorporated herein by
`reference.
`Thalidomide is administered to patients orally. Presently,
`thalidomide is orally administered in a size 110 capsule shell
`containing 12.5 percent weight by total weight of the com—
`position. The capsule fill weight is 400 mg, so only 50 mg
`of thalidomide are included per capsule. For use in the
`treatment of diseases such as cancer, however, 200 mg to
`800 mg dosages are commonly required. Therefore, patients
`may have to ingest 4 to 16 capsules ol'thalidoniide to receive
`a therapeutically eifective amount of the drug. Because of
`the large size of the #0 capsule and the large amount of
`thalidomide required to treat certain diseases and conditions,
`
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`patient compliance may be problematic. To be specific, some
`patients may not take thalidomide in its currently available
`oral dosage form as often or in the large amounts necessary
`to effectively treat their disease. Therefore, a need exists for
`new phannaceutical dosage forms of thalidomide.
`
`3. SUMMARY OF THE INVENTION
`
`This invention encompasses novel pharmaceutical dosage
`forms of thalidomide and pharmaceutically acceptable pro-
`drugs, salts, solvates, hydrates, and clathrates thereof. The
`invention further encompasses methods of treating or pre-
`venting diseases and conditions such as, but not limited to,
`leprosy, chronic graft-vs-host disease, rheumatoid arthritis,
`sarcoidosis, an inflammatory condition, inflammatory bowel
`disease, and cancer, using thalidomide and pharmaceutically
`acceptable prodrugs, salts, solvates, hydrates, and clathrates
`thereof in the novel dosage forms described herein,
`
`3.1. Definitions
`
`As used herein and unless otherwise indicated, a compo-
`sition that is “substantially free” of a compound means that
`the composition contains less than about 20 percent by
`weight, more preferably less than about 10 percent by
`weight, even more preferably less than about 5 percent by
`weight, and most preferably less than about 3 percent by
`weight of the compound.
`As used herein and unless otherwise indicated, the term
`“stereomerically pure” means a composition that comprises
`one stereoisomer of a compound and is substantially free of
`other stereoisomers of that compound. For example, a
`stereomerically pure composition of a compound having one
`chiral center will be substantially free of the opposite
`enantiomer of the compound. A stereomerically pure com-
`position of a compound having two chiral centers will be
`substantially free of other diastereomers of the compound. A
`typical stereomerically pure compound comprises greater
`than about 80 percent by weight of one stereoisomer of the
`compound and less than about 20 percent by weight of other
`stereoisomers of the compound, more preferably greater
`than about 90 percent by weight of one stereoisomer of the
`compound and less than about 10 percent by weight of the
`other stereoisomers of the compound, even more preferably
`greater than about 95 percent by weight of one stereoisomer
`of the compound and less than about 5 percent by weight of
`the other stereoisomers of the compound, and most prefer-
`ably greater than about 97 percent by weight of one stere-
`oisomer of the compound and less than about 3 percent by
`weight of the other stereoisomers of the compound.
`As used herein and tuiless otherwise indicated, the term
`“enantiomerically pure” means a stereomerically pure com-
`position of a compound having one chiral center.
`the term
`As used herein, unless otherwise specified,
`“pharmaceutically acceptable salt(s),”
`as used herein
`includes, but
`is not
`limited to, salts of acidic or basic
`moieties of thalidomide. Basic moieties are capable of
`forming a wide variety of salts with various inorganic and
`organic acids. The acids that can be used to prepare phar-
`maceutically acceptable acid addition salts of such basic
`compounds are those that form non-toxic acid addition salts,
`i.e., salts containing phannacologically acceptable anions.
`Suitable organic acids include, but are not limited to, maleic,
`fumaric, benzoic, ascorbic, succinic, acetic, formic, oxalic,
`propionic, tartaric, salicylic, citric, gluconic,
`lactic, man-
`delic, cinnamic, oleic,
`tannic, aspartic, stearic, palmitic,
`glycolic, glutamic, gluconic, glucaronic, saccharic, isonico-
`
`

`

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`US 7,230,012 B2
`
`3
`tinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic,
`benzenesulfonic acids, or pamoic (i.e., l,l'-methylene—bis-
`(2-hydroxy-3-naphthoate) acids. Suitable inorganic acids
`include, but are not limited to, hydrochloric, hydrobromic,
`hydroiodic, sulfuric, phosphoric, or nitric acids. Compounds
`that include an amine moiety can form phannaceutically
`acceptable salts with various amino acids, in addition to the
`acids mentioned above. Chemical moieties that are acidic in
`nature are capable of forming base salts with various phar-
`macologically acceptable cations. Examples of such salts are
`alkali metal or alkaline earth metal salts and, particularly,
`calcium, magnesium, sodium, lithium, Zinc, potassium, or
`iron salts.
`As used herein to describe a compound or chemical
`moiety, the term “derivative” means a compound or chemi-
`cal moiety wherein the degree of saturation of at least one
`bond has been changed (e.g., a single bond has been changed
`to a double or triple bond) or wherein at least one hydrogen
`atom is replaced with a different atom or a chemical moiety.
`Examples of different atoms and chemical moieties include,
`but are not limited to, halogen, oxygen, nitrogen, sulfur,
`hydroxy, methoxy, alkyl, amine, amide, ketone, and alde-
`hyde.
`As used herein and unless otherwise indicated, the term
`“prodrug” means a derivative of a compound that can
`hydrolyze, oxidize, or otherwise react under biological con—
`ditions (in vitro or in vivo) to provide the compound.
`Examples of prodrugs include, but are not limited to, deriva-
`tives of thalidomide that include biohydrolyzable moieties
`such as biohydrolyzable amides, biohydrolyzable esters,
`biohydrolyzable carbamates, biohydrolyzable carbonates,
`biohydrolyzable ureides, and biohydrolyzable phosphate
`analogues. Other examples of prodrugs include derivatives
`of thalidomide that
`include —NO, ——NOZ, —ONO, or
`——ONO2 moieties.
`As used herein and unless otherwise indicated, the terms
`“biohydrolyzable carbamate," “biohydrolyzable carbonate,”
`“biohydrolyzable ureide,” “biohydrolyzable phosphate”
`mean a carbamate, carbonate, ureide, or phosphate, respec—
`tively, of a compound that either: 1) does not interfere with
`the biological activity of the compound but can confer upon
`that compound advantageous properties in vivo, such as
`uptake, duration of action, or onset of action; or 2) is
`biologically inactive but is converted in vivo to the biologi-
`cally active compound. Examples of biohydrolyzab‘le car-
`bamates include, but are not limited to, lower alkylamines,
`substituted ethylenediamines, aminoacids, hydroxyalky-
`lamines, heterocyclic and heteroaromatic amines, and poly-
`ether amines.
`As used herein and unless otherwise indicated, the term
`“biohydrolyzable ester” means an ester of a compound that
`either: 1) does not interfere with the biological activity of the
`compound but can confer upon that compound advantageous
`properties in vivo, such as uptake, duration of action, or
`onset ofaction; or 2) is biologically inactive but is converted
`in vivo to the biologically active compound. Examples of
`biohydrolyzable esters include, but are not limited to, lower
`alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl
`esters, and choline esters.
`As used herein and unless otherwise indicated, the term
`“biohydrolyzable amide” means an amide of a compound
`that either: 1) does not interfere with the biological activity
`of the compound but can confer upon that compound
`advantageous properties in vivo, such as uptake, duration of
`action, or onset of action; or 2) is biologically inactive but
`is converted in vivo to the biologically active compound.
`Examples of biohydrolyzable amides include, but are not
`
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`lower alkyl amides, a-amino acid amides,
`limited to,
`alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.
`
`4. DETAILED DESCRIPTION OF THE
`INVENTION
`
`This invention encompasses novel pharmaceuti