Case 1:15-cv-00772-UNA Document 1 Filed 09/02/15 Page 1 of 9 PageiD #: 1
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`OSI PHARMACEUTICALS, LLC and
`GENENTECH, INC. ,
`
`Plaintiffs,
`
`v.
`
`APOTEX INC. and APOTEX CORP.,
`
`Defendants.
`
`)
`)
`)
`)
`)
`) C.A. No. ________ _
`)
`)
`)
`)
`
`COMPLAINT FOR PATENT INFRINGEMENT
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`Plaintiffs OSI Pharmaceuticals, LLC ("OSI"), and Genentech, Inc. ("Genentech")
`
`(collectively, Plaintiffs), by their undersigned attorneys, bring this action against Defendants
`
`Apotex Inc., and Apotex Corp., (collectively, "Apotex"), for patent infringement and allege as
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`follows:
`
`NATURE OF THE ACTION
`
`1.
`
`This is an action for patent infringement under the patent laws of the United
`
`States, Title 35 of the United States Code, arising from Apotex's filing an Abbreviated New
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`Drug Application ("ANDA'') with the United States Food and Drug Administration ("FDA")
`
`seeking approval to commercially market a generic version of OSI's Tarceva® prior to the
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`expiration ofUnited States Patent No. 6,900,221 ("the '221 patent") that covers that product and
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`its use.
`
`THE PARTIES
`
`2.
`
`Plaintiff OSI is a limited liability company organized and existing under the laws
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`of the State of Delaware, with a principal place of business at 1 Astellas Way, Northbrook, IL
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`60062.
`
`

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`Case 1:15-cv-00772-UNA Document 1 Filed 09/02/15 Page 2 of 9 PageiD #: 2
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`3.
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`Plaintiff Genentech is a corporation organized and existing under the laws of the
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`State of Delaware, with its principal place of business located at 1 DNA Way, South San
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`Francisco, California 94080-4990.
`
`4.
`
`On information and belief, Defendant Apotex Inc. is a corporation existing under
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`the laws of Canada, with its principal place of business at 150 Signet Drive, Toronto, Ontario
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`M9Ll T9, Canada.
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`5.
`
`Upon information and belief, acting in concert with Defendant Apotex Corp.,
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`Apotex Inc.
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`is
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`in
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`the business of developing, manufacturing, and marketing generic
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`pharmaceutical products that are distributed and sold throughout the United States and in the
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`State ofDelaware.
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`6.
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`On information and belief, Apotex Corp. is a corporation existing under the laws
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`of Delaware, with its principal place of business at 2400 North Commerce Parkway, Suite 400,
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`Weston, Florida 33326.
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`7.
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`Upon information and belief, acting m concert with Defendant Apotex Inc.,
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`Apotex Corp.
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`is
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`in the business of developing, manufacturing, and marketing generic
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`pharmaceutical products that are distributed and sold throughout the United States and in the
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`State of Delaware. Upon information and belief, Apotex Corp. is also the United States agent for
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`Apotex Inc. for purposes including, but not limited to, filing ANDA submissions to and
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`corresponding with FDA
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`8.
`
`Upon information and belief, Apotex Corp. is a wholly owned affiliate of Apotex
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`Inc. Upon information and belief, Apotex Corp. acts at the direction of, under the control of, and
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`for the direct benefit of Apotex Inc. and is controlled and/or dominated by Apotex Inc.
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`2
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`

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`Case 1:15-cv-00772-UNA Document 1 Filed 09/02/15 Page 3 of 9 PageiD #: 3
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`JURISDICTION AND VENUE
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`9.
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`This action arises under the Patent Laws of the United States and the Food and
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`Drug Laws of the United States, Titles 35 and 21 , United States Code. This Court has
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`jurisdiction over the subject matter ofthis action under 28 U.S.C. §§ 1331 and 1338(a).
`
`10.
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`Venue is proper in this District under 28 U.S.C. § 1391(b), (c), (d), and 28 U.S.C.
`
`§ 1400(b)
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`Apotex Inc.
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`11.
`
`On information and belief, this Court has personal jurisdiction over Apotex Inc.,
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`which develops, manufactures, seeks regulatory approval for, markets, distributes, and sells
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`generic pharmaceuticals for sale and use throughout the United States, including in the State of
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`Delaware.
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`12.
`
`On
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`information and belief, residents of the State of Delaware purchase
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`pharmaceutical drug products from Apotex Inc. in the State of Delaware.
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`13.
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`On information and belief, Apotex Inc., itself or through one of its wholly-owned
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`subsidiaries, has authorized distributors in the State of Delaware to distribute Apotex's
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`pharmaceutical drug products throughout the State of Delaware.
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`14.
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`On information and belief, Apotex Inc. 's submission of ANDA No. 208396,
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`discussed below, indicates its intention to engage in the commercial manufacture, use, sale
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`and/or importation of products that will compete directly with OSI's T ARCEV A® product,
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`which is currently being sold throughout the United States, including in Delaware.
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`15.
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`This Court has personal general jurisdiction over Apotex Inc. by virtue of, inter
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`alia, its having conducted business in this District, having availed itself of the rights and benefits
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`of Delaware law, and having engaged in substantial and continuing contacts with Delaware.
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`3
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`

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`Case 1:15-cv-00772-UNA Document 1 Filed 09/02/15 Page 4 of 9 PageiD #: 4
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`Upon information and belief, Apotex Inc. has regular and continuous commercial business
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`dealings with representatives, agents, distributors, and customers located in Delaware.
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`16.
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`Over the last ten years, Apotex Inc. has been a party to numerous other ANDA-
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`related patent suits in the District ofDelaware.
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`17.
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`In addition, Apotex Inc. has submitted to the jurisdiction of this Court and has
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`previously availed itself of this Court by filing suit in this jurisdiction and/or by asserting civil
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`actions and counterclaims initiated in this jurisdiction. See, e.g. , Apotex, Inc. et al v. Senju
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`Pharmaceutical Co. , C.A. No. 12-196-SLR (D. Del. Feb. 16, 2012).
`
`18.
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`In the alternative, should Apotex Inc. contest jurisdiction in this forum, this Court
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`has personal jurisdiction over Apotex Inc. under Fed. R. Civ. P 4(k)(2) because, on information
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`and belief, Apotex Inc. "is not subject to jurisdiction in any state 's courts of general jurisdiction,"
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`and because "exercising jurisdiction
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`is nevertheless consistent with
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`the United States
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`Constitution and laws" given that Apotex Inc. has filed the ANDA in the United States for a
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`generic product that it intends to market in the United States.
`
`Apotex Corp.
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`19.
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`This Court has personal jurisdiction over Apotex Corp. by virtue of the fact that,
`
`inter alia, Apotex Corp. is incorporated under the laws of the state of Delaware.
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`20.
`
`Upon information and belief, Apotex Corp. develops, manufactures, seeks
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`regulatory approval for, markets, distributes, and sells generic pharmaceuticals for sale and use
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`throughout the United States, including in the State of Delaware.
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`21 .
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`This Court has personal specific jurisdiction over Apotex Corp. because Apotex
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`Corp. has committed, or aided, abetted, contributed to and/or participated in the commission of,
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`the tortious act of patent infringement, including upon information and belief, by acting as
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`4
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`

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`Case 1:15-cv-00772-UNA Document 1 Filed 09/02/15 Page 5 of 9 PageiD #: 5
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`Apotex Inc.'s agent with respect to ANDA filings, such as ANDA No. 208396. In particular, on
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`information and belief, Apotex Corp. collaborated with Apotex Inc. to develop, manufacture, and
`
`seek approval for erlotinib hydrochloride tablets 25 mg, 100 mg and 150 mg ("Apotex's
`
`Proposed Generic Products"), which will cause tortious injury to Plaintiffs.
`
`THE PATENTS-IN-SUIT
`
`22.
`
`On May 31 , 2005, the USPTO duly and lawfully issued the '221 patent, entitled
`
`"Stable Polymorph on N-(3-Ethynylphenyl)-6, 7-Bis(2MethoxyEthoxy)-4-Quinazolinamine
`
`Hydrochloride, Methods of Production, and Pharmaceutical Uses Thereof to inventors Timothy
`
`Norris, Jeffrey W. Raggon, Richard D. Connell, James D. Moyer, Michael J. Morin, Shama M.
`
`Kajiji, Barbara A. Foster, Karen J. Ferrante, and Sandra L. Silberman. A copy ofthe '221 patent
`
`is attached hereto as Exhibit A.
`
`23.
`
`OSI is the owner of the '221 patent and Genentech is a co-exclusive licensee of
`
`the '221 patent.
`
`THE TARCEVA® DRUG PRODUCT
`
`24.
`
`OSI 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 erlotinib
`
`hydrochloride tablets (NDA No. 021743), which it sells under the trade name Tarceva®. The
`
`claims of the '221 patents cover, inter alia, Tarceva® and its method of use.
`
`25.
`
`Pursuant to 21 U.S.C. § 355(b)(1) and attendant FDA regulations, the '221 patent
`
`IS listed in the FDA publication, "Approved Drug Products with Therapeutic Equivalence
`
`Evaluations" (the "Orange Book"), with respect to Tarceva®.
`
`5
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`

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`Case 1:15-cv-00772-UNA Document 1 Filed 09/02/15 Page 6 of 9 PageiD #: 6
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`ACTS GIVING RISE TO THIS SUIT
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`26.
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`Pursuant to Section 505 of the FFDCA, Apotex filed an ANDA for erlotinib
`
`hydrochloride tablets, seeking approval to engage in the commercial use, manufacture, sale, offer
`
`for sale or importation of erlotinib hydrochloride tablets 25 mg, I 00 mg and 150 mg ("Apotex' s
`
`Proposed Generic Products"), before the patent in suit expires. The Apotex ANDA number is
`
`208396.
`
`27.
`
`On information and belief, in connection with the filing of its ANDA as described
`
`in the preceding paragraph, Apotex has provided written certifications to the FDA, as called for
`
`by Section 505 of the FFDCA, which allege that the claims of the '221 patent are invalid,
`
`unenforceable, and/or will not be infringed by the commercial manufacture, use or sale of
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`Apotex's Proposed Generic Products.
`
`28.
`
`No earlier than July 20, 2015, Apotex sent written notice of its ANDA filing to
`
`OSI. The notice alleged that the '221 patent is invalid, unenforceable, and/or will not be infringed
`
`by Apotex. Apotex's notice also informed OSI that Apotex seeks approval to market erlotinib
`
`hydrochloride tablets 25 mg, 100 mg and 150 mg before the patent in suit expires.
`
`29.
`
`This action is being brought pursuant to 21 U.S.C. § 355(j)(5)(B)(iii) within 45
`
`days ofOSI's receipt of Apotex's notice.
`
`COUNT 1: APOTEX'S FILING OF THE ANDA INFRINGES THE '221 PATENT
`
`30.
`
`Plaintiffs reallege and incorporate by reference the allegations contained m
`
`paragraphs 1-29.
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`31.
`
`Apotex's submission of its ANDA to obtain approval to engage in the commercial
`
`manufacture, use, sale, offer for sale or importation of Apotex's Proposed Generic Products,
`
`6
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`

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`Case 1:15-cv-00772-UNA Document 1 Filed 09/02/15 Page 7 of 9 PageiD #: 7
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`prior to the expiration of the '221 patent, constitutes infringement of one or more of the claims of
`
`that patent under 35 U.S.C. § 271(e)(2)(A).
`
`32.
`
`Unless enjoined by this Court, upon FDA approval of Apotex's ANDA, Apotex
`
`will infringe the '221 patent by making, using, offering to sell, importing, and selling Apotex's
`
`Proposed Generic Products in the United States, and by actively inducing and contributing to
`
`infringement by others.
`
`33.
`
`There is a justiciable controversy between the parties hereto as to infringement of
`
`the '221 patent.
`
`34.
`
`Plaintiffs will be substantially and irreparably damaged and harmed if Apotex's
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`infringement ofthe '221 patent is not enjoined.
`
`35.
`
`Plaintiffs do not have an adequate remedy at law.
`
`36.
`
`This case is an exceptional one, and Plaintiffs are entitled to an award of their
`
`reasonable attorneys' fees under 35 U.S.C. § 285.
`
`PRAYER FOR RELIEF
`
`WHEREFORE, Plaintiffs OSI and Genentech respectfully request that the Court enter
`
`judgment against Apotex and for the following relief
`
`a.
`
`A declaration that, under 35 U.S.C. § 271(e)(2)(A), Apotex infringed the
`
`'221 patent by submitting ANDA No. 208396 to the FDA to obtain approval to commercially
`
`manufacture, use, offer for sale, sell or import into the United States Apotex's Proposed Generic
`
`Products prior to expiration of the '221 patent;
`
`b.
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`A judgment declaring that Apotex's manufacture, sale, offer for sale,
`
`marketing and distribution in, or importation into, the United States of the product described in
`
`7
`
`

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`Case 1:15-cv-00772-UNA Document 1 Filed 09/02/15 Page 8 of 9 PageiD #: 8
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`Apotex's ANDA No. 208396 prior to expiration of the '221 patent will infringe, induce
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`infringement and contribute to the infringement of at least one claim of the '221 patent;
`
`c.
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`A judgment pursuant to 35 U.S. C.§ 27l(e)(4)(B) and/or 35 U.S.C. § 283
`
`for a permanent injunction enjoining the Apotex, its officers, agents, servants, employees, and
`
`those persons acting in active concert or participation with all or any of them from: ( i)
`
`manufacturing, using, offering to sell, or selling the Apotex Proposed Generic Products within
`
`the United States, or importing the Apotex Proposed Generic Products into the United States,
`
`prior to the expiration of the '221 Patent, and ( ii) seeking, obtaining or maintaining approval of
`
`the Apotex Proposed Generic until expiration of the '221 patent or any later expiration of
`
`exclusivity to which Plaintiffs are or become entitled, or such other later time as the Court may
`
`determine;
`
`d.
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`A judgment ordering that pursuant to 35 U.S.C. § 271(e)(4)(A), the
`
`effective date of any approval of ANDA No. 205943 under § 505U) of the Federal Food, Drug
`
`and Cosmetic Act (21 U.S . C. § 355U)) shall not be earlier than the expiration date of the '221
`
`patent or any later expiration of exclusivity to which Plaintiffs are or become entitled;
`
`e.
`
`If Apotex manufactures, uses, offers to sell, or sells the Apotex Proposed
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`Generic Products within the United States, or imports the Apotex Proposed Generic Products
`
`into the United States, prior to the expiration of the '221 patent, including any extensions, a
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`judgment awarding Plaintiffs monetary relief including damages no less than a reasonable
`
`royalty and an accounting together with interest;
`
`f
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`A declaration that this is an exceptional case action within the meaning of
`
`35 U.S.C. § 285 and that Plaintiffs be awarded their attorneys' fees, costs and expenses incurred
`
`in prosecuting this action; and
`
`8
`
`

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`Case 1:15-cv-00772-UNA Document 1 Filed 09/02/15 Page 9 of 9 PageiD #: 9
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`g.
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`Such other and further relief as the Court deems just and appropriate.
`
`MORRJS, NICHOLS, ARSHT & TUNNELL LLP
`
`OF COUNSEL:
`
`Leora Ben-Ami
`Peter B. Silverman
`KIRKLAND & ELLIS LLP
`60 1 Lexinton A venue
`New York, NY 10022
`(212) 446-4000
`
`Amanda Hollis
`KIRKLAND & ELLIS LLP
`300 N . LaSalle
`Chicago, IL 60654
`(312) 862-2011
`
`September 2, 2015
`
`/s/ Jac{ (]3. (]J{umenjefd
`
`Jack B. Blumenfeld (#1014)
`Maryellen Noreika (#3208)
`1201 North Market Street
`P.O. Box 1347
`Wilmington, DE 19899-1347
`(302) 658-9200
`jblumenfeld@mnat. com
`mnoreika@mnat. com
`
`Attorneys for Plaintiffs
`
`9
`
`

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`Case 1:15-cv-00772-UNA Document 1-1 Filed 09/02/15 Page 1 of 28 PageiD #: 10
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`EXHIBIT A
`
`

`
`Case 1:15-cv-00772-UNA Document 1-~
`
`(12) United States Patent
`Norris et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 6,900,221 Bl
`May 31,2005
`
`(54) STABLE POLYMORPH ON
`N-(3-ETHYNYLPHENYL)-6, 7-BIS
`(2METHOXYETHOXY)
`-4-QUINAZOLINAMINE HYDROCHLORIDE,
`METHODS OF PRODUCTION, AND
`PHARMACEUTICAL USES THEREOF
`
`(75)
`
`Inventors: Timothy Norris, Gales Ferry, CT (US);
`Jeffrey W. Raggon, North Stonington,
`CT (US); Richard D. Connell, East
`Lyme, CT (US); James D. Moyer, East
`Lyme, CT (US); Michael J, Morin,
`Waterford, CT (US); Shama M. Kajiji,
`Mystic, CT (US); Barbara A. Foster,
`Mystic, CT (US); Karen J. Ferrante,
`East Greenwich, RI (US); Sandra L.
`Silbennan, Randolph, NJ (US)
`
`(73) Assignee: OSJ Phannaceuticals, Inc., Melville,
`NY (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 09!711,272
`
`(22) Filed:
`
`Nov. 9, 2000
`
`Related U.S. Application Data
`( 60) Provisional application No. 60/206,420, filed on May 23,
`2000, provisional application No. 60/193,191, filed on Mar.
`30, 2000, and proviSional application No. 60/164,907, filed
`on Nov. 11, 1999.
`
`(51)
`
`(52)
`(58)
`
`(56)
`
`Int. Cl.7
`
`...... . .. . . ....... .. C07D 239/94; A61K 31/517;
`A61P 35/00
`. ................ ................... 514/266.4; 544/293
`U.S. Cl.
`Field of Search .......... .............. 544/293; 514/266.4
`
`References Cited
`
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`............ 514/266.4
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`
`FOREIGN PATENT DOCUMENTS
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`JP
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`0667165
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`
`(Continued)
`
`OTHER PUBLICATIONS
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`
`(Continued)
`
`Primary Examiner-Thomas C. McKenzie
`(74) Attorney, Agent, or Firm-John P. White; Cooper &
`Dunham LLP
`
`(57)
`
`ABSTRACT
`
`The present invention relates to a stable crystalline form of
`N -(3 -e thy n yip hen y I) -6,7 -b is(2-me tho x ye tho x y) -4 -
`quinazol inarnine hydrochloride designated the B
`polymorph, its production in essentially pure form, and its
`use. The invention also relates to the pharmaceutical com(cid:173)
`positions containing the stable polymorph B form of N-(3-
`e thy n y l p hen y I)- 6, 7 - b is(2- me tho x ye tho x y) -4-
`quinazolinamine as hydrochloride, as well other forms of the
`compound, and to methods of treating hyperproliferative
`disorders, such as cancer, by administering the compound.
`
`79 Claims, 4 Drawing Sheets
`
`

`
`Case 1:15-cv-00772-UNA Document 1-1 Filed 09/02/15 Page 3 of 28 PageiD #: 12
`
`US 6,900,221 Bl
`Page 2
`
`FOREIGN PATENT DOCUMENTS
`
`JP
`JP
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`W09615118
`W09625422
`9628430
`W09630347
`W09640210
`W09703069
`W09730035
`W09732856
`W09738983
`W09741896
`W09813354
`W09903803
`W09955683
`W09960023
`W00031048
`W0134574
`W00170255
`
`1/1994
`3/1994
`9/1994
`11/1994
`7/1995
`8/1995
`2/1997
`2/1998
`2/1998
`1/ 1993
`1/1993
`11/1992
`2/1995
`6/1995
`3/1996
`5/1996
`8/1996
`9/1996
`10/1996
`12/1996
`1/1997
`8/1997
`9/1997
`10/1997
`11/1997
`4/1998
`1/1999
`11/1999
`11/1999
`2/2000
`5/2001
`9/2001
`
`OTIIER PUBLICATIONS
`
`Bleicher, L., et a!., "Aryl- and Hetero-Alkyne Coupling
`Reactions Catalyzed by Palladium on Carbon and Cui inan
`Aqueous Medium," Synlett 1995, Nov., p.p. 1115-1116
`(Exhibit 75).
`Bleicher, L., eta!., "A Practical and Efficient Synthesis of the
`Selective Neuronal Acetylcholine-Gated
`Ion Agonist
`(S)-(- }-5-Ethynyl-3-(1- methyl-2-pyrrolidinyl)pyridine
`Maleate (SIB-1508Y)," Journal of Organic Chemistry
`1998, vol. 63, No. 4, p.p. 1109-1118 (Exhibit 76).
`Botros, S., et a!., "Synthesis of Certain Nitro-quinazoline
`Derivatives Structurally Related to Some Chemotherapeutic
`Agents," Egypt . .1. Pharm. Sci. 1972, vol. 13, No. 1, p.p.
`11-21 (Exhibit 77).
`Cerny, A, "Solvolysis of Some 1-(8a-ergolyinyl}-3,3-Di(cid:173)
`ethylureas and Their Salts," Collection-Czechoslovak
`Chern. Commun.1987, vol. 52, p.p. 1331-1339 (Exhibit78).
`Smaill, J., eta!., "Tyrosine Kinase Inhibitors. 17. Irreversible
`Inhibitors of the Epidermal Growth Factor Receptor:
`4-(Phenylamino)quinazoline- and 4-(Phenylamino)pyrido
`[3,2-d]pyrimidine-6-acrylamides Bearing Additional Solu(cid:173)
`bilizing Functions," 1. Med. Chern. 2000, vol. 43, p.p.
`1380-1397 (Exhibit 85) .
`Spurlock, C., "Increasing Solubility of Enoxacin and Nor(cid:173)
`floxacin by Means Salt Formation," Journal of Parenteral
`Science and Technology 1986, vol. 40, No. 2, p.p . 70-72
`(Exhibit 86).
`Takalo, H., et a!., "Synthesis of Some Substituted Dimethyl
`and Diethyl 4-(Phenylethynyl}-2,6-pyridine- dicarboxy(cid:173)
`lates," Acta Chemica Scandinavica, vol. B42, p.p. 448-454
`(Exhibit 87).
`
`Pollack, V., et a!., "Inhibition of Epidermal Growth Factor
`Receptor-Associated Tyrosine Phosphorylation in Human
`Carcinomas with CP-358,774: Dynamics of Receptor Inhi(cid:173)
`bition In Situ and Antitumor Effects in Athymic Mice,"
`Journal of Pharmacology and Experimental Therapeutics,
`1999, vol. 291, No. 2, p.p. 739-748 (Exhibit 83).
`
`Rosenberg, S., et a!., "Studies Directed toward the Design of
`Orally Active Renin Inhibitors. 2. Development of the
`Efficacious, Bioavailable Renin Inhibitor (2S)-2-Benzyl-3-
`[[ (1-methylpiperazin-4-yl)sulfon y l]propion y I]
`3-thiazol-4-yl-L-alanine
`Amide
`of
`4S)-2-Amino- 1--cyclohexy 1-3,
`4-dihydorxy-6-methylheptane (A-72517)," J. Med. Chern.
`1993, vol. 36, p.p. 460-467 (Exhibit 84).
`
`(2S,
`
`3R,
`
`Hussain, M., et a!., " Parenteral Formulation of the Kappa
`Agonist Analgesic, DuP 747, via Micellar Solubilization,"
`Pharmaceutical Research 1992, vol. 9, No.6, p.p. 750-752
`(Exhibit 79).
`
`Moyer, J., et a!., "Induction of Apoptosis and Cell Cycle
`Arrest by CP-358,774, an Inhibitor of Epidermal Growth
`Factor Receptor Tyrosine Kinase," Cancer Research 1997,
`vol. 57, p.p. 4838-4848 (Exhibit 80).
`
`Norris, T., et a!., "Discovery of a New Stable Polymorph of
`4-(3-ethynylphenylamino}-6,
`7-bis(2-methoxy-ethoxy)quinazolinium Methanesulfonate
`Using Near-Infrared Spectroscopy to Monitor Form Change
`Kinetics," J. Chern. Soc., Perkin Trans. 2000, vol. 2, p.p.
`1233-1236 (Exhibit 81).
`
`Onopchenko, et a!., "Selective Catalytic Hydrogenation of
`Aromatic Nitro Groups in the Presence of Acetylenes.
`Synthesis of (3-Aminophenyl)acetylene via Hydrogenation
`of Dimethylcarbinol Substituted (3-Nitrophenyl) acetylene
`over Heterogeneous Metallic Ruthenium Catallyst," Journal
`of Organic Chemistry 1979, vol. 44, No. 8, p.p. 1233-1236
`(Exhibit 82).
`
`Melissaris, A.P. et a!., " A Simple and Economical Synthetic
`Route to p-Ethynylaniline and Ethynyl-Terminated Sub(cid:173)
`strates" (1994) J. Org. Chern. 59:5818-5821 (Exhibit 16).
`
`Montalbetti, C. et a!., "A Convergent Synthesis of Function(cid:173)
`alized B-seco Taxane Skeletons" (1995) Tetrahedron Ler(cid:173)
`ters 36(33):5891-5894 (Exhibit 17).
`
`Trillo et al., (1993) Tratado de Farmacia Galencia, Prim(cid:173)
`eria Edicion, pp. 81, 83, 84 (Exhibit 18); and.
`
`Sun Cunji et al., (1981) YaoxueXuebao 16(8):564-570 C.A.
`96 122727 (Exhibit 19).
`
`Driscoll D. et al., "Effect of Epidermal Growth Factor
`Receptor Tyrosine Kinase Inhibitor PD183805 on Vascular
`Endothelial Growth Factor Secretion from Several Tumor
`Models" (1999) XP-001014746 (Abstract only) (Exhibit 4).
`
`Ishiwara T. et a!., "Characterization of Keratinocyte Growth
`Factor and Receptor Expression in Human Pancreatic Can(cid:173)
`cer" (1998)American Journal of Pathology 153(1):213-222
`(Exhibit 5).
`
`Liu N. et a!., "Comparative Phenotypic Studies of Duct
`Epithelial Cell Lines Derived from Normal Human Pancreas
`and Pancreatic Carcinoma" (1998) American Journal of
`Parhology 153(1) 263-269 (Exhibit 6).
`
`

`
`Case 1:15-cv-00772-UNA Document 1-1 Filed 09/02/15 Page 4 of 28 PageiD #: 13
`
`US 6,900,221 Bl
`Page 3
`
`Watanabe M. et al., Overexpression of Keratinocyte Growth
`Factor in Cancer Cells and Enterochromaffin Cells in
`Human Colorectal Cancer: (2000) Pathology International
`50:363-372 (Exhibit 7) and.
`Woodburn J.R. et al., "ZD1839, An Epidermal Growth
`Factor Tyrosine Kinase Inhibitor Selected for Clinical
`Development" (1997) XP--001009911
`(Abstract only)
`(Exhibit 8).
`Norris T., et al. "Discovery of a new stable polymorph of
`4-(3-ethynylphenylamino}-6,
`7-bis(2-methoxyethoxy)quinazolinium methanesulfonate
`using near-infrared spectroscopy to monitor form change
`kinetics" J. Chem. Soc., Perkins Trans. 2
`(2000)
`12:2498-2502 (Exhibit 2).
`
`SMR Committee:"Protein Kinases: Therapeutic Opportuni(cid:173)
`ties" The Newsletter for the Society for Medicines Research
`(1999) 5(2):1-8 (Exhibit 3); and.
`
`Pollack et al., "Therapy of human Carcinomas in athymic
`mice by inhibition of EGF receptor-mediated signal trans(cid:173)
`duction with CP-358774: Dynamics of receptor inhibition
`and anti-tumor effects" Proceedings of the Annual Meeting
`of the American Association for Cancer Research (1999)
`291(2):739-748 (Abstract only) (Exhibit 4).
`
`* cited by examiner
`
`

`
`FIGURE 1
`
`4500
`44110
`4300
`41fl0
`4100
`4UOU
`3'!00
`3800 .
`3100
`3GOO
`35110
`3o00
`
`33110 ~-
`
`3200
`3100
`300(1
`2900
`1800
`2700
`2600
`~ 2~0!.!
`;
`l4111l
`
`~ i~~~
`.!:
`11011
`..J
`lUOO
`191HI
`IMIHI
`17011
`1600
`ISOO .
`1400
`1300
`12011
`1100
`11100
`~00
`~00
`700
`C.OIJ
`sou
`400
`3011
`
`i~~1~ .-;:=-;~~·tl-< j ,';~t~f~l j-l~j I j
`
`I
`
`II
`
`3.5 4
`
`5
`
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`
`7
`
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`
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`
`10
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`
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`
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`
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`17
`
`IR
`
`I?
`
`I
`•
`I
`ll 24
`
`I
`
`i
`
`l O 2 1 l2
`2-Theta • Scale
`QJCP-358774·1 35076-18:1-1 . File: Pf746.raw. Type: 2ThfTh loclced . Starl3.000 ··End: 40.040 • ·Step: 0.040 ··Step time: 1.0 s ·Temp : 27 .0 ·c ·Time Started : 16 s - 2·Th eta: 3.000 • -Theta:
`Operations: Import
`·
`
`.
`
`Lj
`()
`s:u
`(J)
`rJ).
`CD
`•
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`< = I
`~
`......
`
`0
`0
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`-...J
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`I c
`z
`)>
`
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`=
`'-<
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`\) c =
`N
`= Ul
`
`0
`0
`
`3
`CD
`::::l
`.......
`.......
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`
`Tl
`CD
`a.
`0
`
`0
`
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`
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`N --.......
`"'U
`s:u co
`CD
`(J1
`
`0 -
`
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`co
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`0
`;!=!:
`.......
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`="'
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`d
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`0\
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`
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`Q
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`1-0
`t:d
`1-0
`
`38 39
`
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`
`23
`
`lG
`
`27 28 B
`
`JU
`
`Jl
`
`Jl 33
`
`J4
`
`35
`
`36
`
`37
`
`

`
`FlGURE 2
`
`IOOU
`
`900
`
`800
`
`700 .
`
`o;c.oul
`""
`5 s
`~suo
`:J
`
`]
`
`400
`
`100
`
`2()0
`
`.100
`
`(')
`
`35 4
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`;
`
`G r;·· , 8, -,;
`
`10
`
`II
`
`ll
`
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`
`14
`
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`
`lb
`
`17~ 18
`
`19
`
`23
`
`14
`
`25
`
`26
`
`17
`
`18
`
`2~ Ju
`
`J l
`
`Jl
`
`JJ
`
`J4
`
`22
`21
`111
`2-Theta- Scale
`iiJCP-358774-1 35076-183-1 -Fie: Pl746.raw- Typo: 2Th/Th loc~od- Slart: 3.000- - End: 40.040 • - Step: 0.040-- Slep lime: 1.0 s- Tenip · 27 .0 ' C - Time SI<Jned: 16 s - 2-Thela : 3.000 '- Tneta: 1.500'-
`0peralor15: Import
`
`d •
`00.
`•
`~
`~
`~
`
`~ = ~
`
`~
`~
`~
`(.;.)
`~
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`0
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`rJ1 ::r
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`N
`0 ......
`""
`
`e
`00
`9'
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`~
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`N
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`
`()
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`Cfl
`(!)
`t->
`t->
`(J1
`I
`
`("') < I
`0
`0
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`----.1
`N
`
`I c z
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`)>
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`0
`0
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`3
`(!)
`:::l
`.......
`t->
`t->
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`I
`
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`0
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`0
`3=t:
`t->
`(J1
`
`J ~
`
`J'6' j, • Ji'39
`
`~
`
`

`
`FIGURE 3
`
`10000
`
`9000
`
`8000
`
`7000
`
`_-j
`
`"" ~ 5000
`;
`:l
`~
`.:
`6000
`..l
`
`4000
`
`3000
`
`2000
`
`b/iJCP-358774-1 35076-07&-1 ·File: L992.raw- Type: 2Th/Th locked· Sla rt: 3.000 • - End: 40.000 · - Slep: 0.040 •- Slep lime: 1.0 s · Temp.: 27.0 'C- Time Slarted : 16 s- 2-Thela: 3.000 •. Thela: 1.500 • . ·Phi:
`Operalions: Import
`
`25
`
`26
`
`27
`
`28
`
`29 30
`
`31
`
`31
`
`JJ
`
`34
`
`35
`
`J(j
`
`37
`
`J8
`
`J9
`
`Cj .
`
`00
`•
`~
`~ ......
`~ = ......
`
`~
`~
`'-<
`~
`!'"'
`
`N = = Ul
`
`fJJ ::r
`
`('!>
`
`('!> -~
`
`0 ......,
`"'"'
`
`e
`
`00
`0\
`
`'to c
`c
`'N
`N
`"""""
`t::d
`"""""
`
`()
`~
`([)
`I-'
`I-'
`U1
`I
`(") < I
`0
`0
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`--..1
`N
`I c
`z
`)>
`
`0
`0
`(") c
`3
`([)
`::::l
`......
`I-'
`I
`I-'
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`0
`
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`
`U1
`
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`
`0 -N
`
`00
`"U
`~
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`0
`~
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`0')
`
`

`
`FIGURE 4
`
`•
`00
`
`c
`.
`"""" ~ = """"
`
`~
`~
`
`~
`~ «
`(.;l
`I-"
`N
`0
`0
`01
`
`~
`
`'J'1 =(cid:173)(C
`
`(C
`.......
`J:;..
`
`0 -J:;..
`
`()
`Pl
`~
`I-'
`I-'
`(.11
`I
`
`("") < I
`0
`0
`-..]
`-..]
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`
`I c z
`
`)>
`
`0
`0
`("") c
`3
`('J)
`:::l
`.......
`I-'
`I
`I-'
`
`11
`('J)
`0..
`0
`
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`N --1-'
`
`(.11
`
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`19 20
`2-Theta ·Scale
`RJCP-358774-1 35076-Ql6-1 -File: L992.r1lw - Typo: 2ThfTh locked· Stan: 3.000" ·End: 40.000" · Step: 0.040 "·Step lima: 1.0 s ·Temp : 27 0 "C ·Time Started: 16 s- 2-Theta: 3.000' • Thela : 1.500 • • -
`
`38
`
`39
`
`"'0
`~
`('J)
`00
`0 _,
`N
`00
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`0
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`37
`
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`
`5
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`6
`
`10
`
`II
`
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`
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`
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`
`17
`
`18
`
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`
`Operations: Import
`
`1500
`
`\400
`
`1300
`
`1200 -
`
`I 100
`
`1000"
`
`'iii' 900
`
`... c
`::1
`0 suo
`~
`~ iOO
`
`600
`
`500
`
`400
`
`300
`
`200
`
`100
`
`0
`
`

`
`Case 1:15-cv-00772-UNA Document 1-1 Filed 09/02/15 Page 9 of 28 PageiD #: 18
`
`US 6,900,221 Bl
`
`1
`STABLE POLYMORPH ON
`N-(3-ETHYNYLPHENYL)-6, 7-BIS
`(2METHOXYETHOXY)
`-4-QUINAZOLINAMINE HYDROCHWRIDE,
`METHODS OF PRODUCTION, AND
`PHARMACEUTICAL USES THEREOF
`
`2
`quinazolinamine hydrochloride, particularly in the stable
`polymorph form.
`The present invention also relates to novel uses of N-(3-
`e th yny lp hen yl) -6,7- bis(2-me th oxye thoxy) -4-
`5 quinazolinamine, in either its hydrochloride or mesylate
`forms, in an anhydrous or hydrous form, as well as in its
`various polymorph forms, in the treatment of hyperprolif(cid:173)
`erative disorders, such as cancers, in mammals.
`
`DESCRIPTION OF THE FIGURES
`
`This application claims the benefit of U.S. Provisional
`Application No. 60/206,420, filed May 23, 2000, U.S.
`Provisional Application No. 60/193,191, filed Mar. 30, 10
`2000, and U.S. Provisional Application No. 60/164,907,
`filed Nov. 11, 1999, the contents of which are hereby
`incorporated by reference.
`Throughout this application various publications are ref(cid:173)
`erenced. The disclosures of these publications in their entire- 15
`ties are hereby incorporated by reference into this applica(cid:173)
`tion in order to more fully describe the state of the art to
`which this invention pertains.
`
`FIG. 1 The X-ray powder diffraction patterns for the
`hydrochloride polymorph A, the thermodynamically less
`stable form, over a larger range to show the first peaks.
`FIG. 2 The X-ray powder diffraction patterns for the
`hydrochloride polymorph A, the thermodynamically less
`stable form, are over a shorter range to show more detail.
`FIG. 3 The X-ray powder diffraction patterns for the
`hydrochloride polymorph B, the thermodynamically more
`20 stable form, over a larger range to show the first peaks.
`FIG. 4 The X-ray powder diffraction patterns for the
`hydrochloride polymorph B, the thermodynamically more
`stable form, over a shorter range to show more detail.
`
`BACKGROUND OF THE INVENTION
`
`25
`
`N -(3-e thynylphenyl)-6, 7 -bis(2-methoxyethoxy)-4-
`quinazolinamine, in either its hydrochloride or mesylate
`forms, or in an anhydrous and hydrous form, is useful in