Case 1:15-cv-00697-RGA Document 99-1 Filed 08/14/17 Page 1 of 73 PageID #: 1279
`Case 1:15-cv-00697-RGA Document 99-1 Filed 08/14/17 Page 1 of 73 PageID #: 1279
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`EXHIBITS A - F
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`REDACTED PUBLIC VERSION
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`Case 1:15-cv-00697-RGA Document 99-1 Filed 08/14/17 Page 1 of 73 PageID #: 1279
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`EXHIBITS A - F
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`REDACTED PUBLIC VERSION
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`EXHIBIT A
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`Parties’ Statement of Undisputed Facts
`
`Pursuant to Local Rule 163(c)(3), the parties submit this statement of undisputed facts
`
`that require no proof at trial.
`
`I.
`
`PARTIES
`
`1.
`
`Plaintiff Hospira is a Delaware corporation with its principal place of business at
`
`275 North Field Drive, Lake Forest, Illinois 60045.
`
`2.
`
`Defendant Amneal is a Delaware corporation with its principal place of business
`
`at 400 Crossing Boulevard, Third Floor, Bridgewater, New Jersey 08807.
`
`II.
`
`JURISDICTION
`
`3.
`
`Subject matterjurisdiction over this action is proper under 28 U.S.C. §§ 1331 and
`
`1338(a). Subject matterjurisdiction over Amneal’s counterclaims is proper under 28 U.S.C. §§
`
`1331, 1338(a), 2201, and 2202, and 35 U.S.C. § 1 et seq.
`
`4.
`
`No party contests venue or personal jurisdiction for the purposes of this litigation
`
`only.
`
`III.
`
`PATENTS-IN-SUIT
`
`5.
`
`US. Patent No. 8,242,158 (“the ‘158 patent”), entitled “Dexmedetomidine
`
`Premix Formulation,” was issued by the United States Patent and Trademark Office (“PTO”) on
`
`August 14, 2012. The ‘158 patent issued from US. Patent Application No. 13/343,672 (“the
`
`‘672 application”), which was filed on January 4, 2012.
`
`6.
`
`U.S. Patent No. 8,338,470 (“the ‘470 patent”), entitled “Dexmedetomidine
`
`Premix Formulation,” was issued by the PTO on December 25, 2012. The ‘470 patent issued
`
`from US. Patent Application No. 13/541,524 (“the ‘524 application”), which was a continuation
`
`ofthe ‘672 application.
`
`
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`7.
`
`U.S. Patent No. 8,455,527 (“the ‘527 patent”), entitled “Methods of Treatment
`
`Using a Dexmedetomidine Premix Formulation,” was issued by the PTO on June 4, 2013. The
`
`‘527 patent issued from U.S. Patent Application No. 13/678,l48 (“the ‘ 148 application”), which
`
`was a continuation of the ‘524 application.
`
`8.
`
`U.S. Patent No. 8,648,106 (“the ‘106 patent”), entitled “Dexmedetomidine
`
`Premix Formulation,” was issued by the PTO on February 11, 2014. The ‘106 patent issued
`
`from U.S. Patent Application No. 13/867,861 (“the ‘861 application”), which was a continuation
`
`of U.S. Patent Application No. 13/678,260 (“the ‘260 application”). The ‘260 application was a
`
`continuation ofthe ‘524 application.
`
`9.
`
`The parties may collectively refer to the ‘158, ‘470, ‘527, and ‘106 patents as the
`
`“Patents-in-Suit” or the “Asserted Patents.”
`
`10.
`
`The inventors assigned their rights in the Patents-in-Suit to Hospira.
`
`11.
`
`Hospira owns all rights, title, and interest to the Patents-in-Suit.
`
`IV.
`
`HOSPIRA’S NEW DRUG APPLICATION
`
`12.
`
`Hospira is the owner of New Drug Application (“NDA”) No. 21-038 for
`
`dexmedetomidine hydrochloride injection, which Hospira sells in the United States under the
`
`trade name Precedex.
`
`13.
`
`NDA No. 21-038 was approved by the Food and Drug Administration (“FDA”)
`
`on December 17, 1999, for a 100 ug/mL dexmedetomidine hydrochloride formulation in a 2 mL
`
`glass vial.
`
`14.
`
`On March 13, 2013, the FDA approved NDA supplement S-020 for 4 pg/mL
`
`ready-to-use formulations of dexmedetomidine hydrochloride injection in 50 mL and 100 mL
`
`glass bottles.
`
`
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`15.
`
`On November 14, 2014,
`
`the FDA approved NDA supplement S-024 for a 4
`
`ug/mL ready-to-use formulation of dexmedetomidine hydrochloride injection in a 20 mL glass
`
`vial.
`
`16.
`
`Precedex is indicated for:
`
`(1) sedation of initially intubated and mechanically
`
`ventilated patients during treatment in an intensive care setting, and (2) sedation of non-intubated
`
`patients prior to and/or during surgical and other procedures.
`
`17.
`
`Pursuant to 21 U.S.C. § 355(b)(1), the Patents-in-Suit are listed in the FDA’s
`
`“Approved Drug Products with Therapeutic Equivalence Evaluations” (“the Orange Book”) as
`
`covering Precedex Premix.
`
`V.
`
`AMNEAL’S ABBREVIATED NEW DRUG APPLICATION
`
`18.
`
`On June 8, 2014, Amneal submitted ANDA No. 207551 (“the Amneal ANDA”)
`
`to the FDA under 21 U.S.C.
`
`§ 3550), seeking approval
`
`to engage in the commercial
`
`manufacture,
`
`importation, use, or sale of ready-to-use dexmedetomidine hydrochloride drug
`
`products in 50 mL and 100 mL glass vials (“the Amneal ANDA Products”) prior to the expiry of
`
`the Patents-in-Suit.
`
`19.
`
`Pursuant to 21 U.S.C. § 3550)(2)(B), Amneal sent to Hospira a notice letter dated
`
`June 26, 2015, and received June 30, 2015, stating that it had submitted the Amneal ANDA with
`
`certifications pursuant to 21 U.S.C. § 3550)(2)(A)(vii)(1V) that the Patents-in-Suit are invalid
`
`and/or will not be infringed by Amneal.
`
`20.
`
`On August 10, 2015, within 45 days of receipt of Amneal’s notice letter, Hospira
`
`filed the present suit, alleging that Amneal’s filing of its ANDA with a Paragraph 1V
`
`Certification, as well as any future manufacture, use, sale, offer for sale, and/or importation of
`
`the Amneal ANDA Products, infringe the Patents—in-Suit.
`
`
`
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`21.
`
`Each Amneal ANDA Product contains dexmedetomidine or a pharmaceutically
`
`acceptable salt thereof at a concentration of about 4 ug/mL.
`
`22.
`
`Each Amneal ANDA Product contains sodium chloride at a concentration of
`
`about 0.9 weight percent.
`
`23.
`
`The 50 mL Amneal ANDA Product is formulated as a total volume of 50 mL.
`
`24.
`
`The 100 mL Amneal ANDA Product is formulated as a total volume of 100 mL.
`
`25.
`
`The proposed Prescribing Information for the Amneal ANDA Products includes
`
`the indication of “sedation of non-intubated patients prior to and/or during surgical and other
`
`procedures.”
`
`26.
`
`The proposed Prescribing Information for the Amneal ANDA Products instructs
`
`users of the product, such as physicians or nurses, to provide sedation to a patient in need thereof
`
`by administering an effective amount of a ready-to-use liquid pharmaceutical composition for
`
`parenteral administration containing dexmedetomidine or a pharmaceutically acceptable salt
`
`thereof at a concentration of about 4 ug/mL disposed within a sealed glass container.
`
`27.
`
`The proposed Prescribing Information for the Amneal ANDA Products instructs
`
`users of the product, such as physicians or nurses, to administer an Amneal ANDA Product by
`
`intravenous infusion.
`
`VI.
`
`DEXMEDETOMIDINE
`
`28.
`
`Dexmedetomidine is the active ingredient in Precedex and the Amneal ANDA
`
`Products.
`
`29.
`
`Dexmedetomidine is an dg-adrenoceptor agonist that is used for, among other
`
`things, sedation.
`
`
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`VII.
`
`PRIOR ART TO THE PATENTS-IN-SUIT
`
`30.
`
`The Precedex Concentrate product and the 2010 Precedex Label were publicly
`
`available before the priority dates ofthe patents in suit (i.e., January 4, 2012).
`
`31.
`
`The Precedex Concentrate product is indicated for parenteral administration to a
`
`subject or patient upon dilution to a dexmedetomidine concentration of 4 mcg/mL.
`
`32.
`
`The Precedex Concentrate product contains sodium chloride at a concentration of
`
`about 0.9 weight percent.
`
`33.
`
`34.
`
`The Precedex Concentrate product is disposed within a sealed glass container.
`
`The 2010 Precedex Label instructed to dilute the 2 mL of Precedex Concentrate
`
`with 48 mL of 0.9 weight percent sodium chloride injection to a total of 50 mL, to achieve the
`
`required concentration of 4 mcg/mL dexmedetomidine.
`
`35.
`
`The resulting 50 mL solution of Precedex Concentrate after dilution, according to
`
`the 2010 Precedex Label, contained sodium chloride at a concentration of about 0.9 weight
`
`percent.
`
`36.
`
`The Precedex Premix product is indicated for:
`
`(1) sedation of initially intubated
`
`and mechanically ventilated patients during treatment
`
`in an intensive care setting, and (2)
`
`sedation of non-intubated patients prior to and/or during surgical and other procedures.
`
`37.
`
`Hospira’s predecessor in interest, Abbott Laboratories, obtained rights to US.
`
`Patent No. 4,910,214 (the “’214 patent”) in 1994.
`
`38.
`
`The ’214 patent discloses dexmedetomidine.
`
`39.
`
`Hospira is co-assignee 0fU.S. Patent No. 6,716,867 (the “’867 patent”).
`
`40.
`
`The ’867 patent discloses “a method of sedating a patient in an intensive care unit,
`
`which comprises administering to the patient an effective amount of dexmedetomidine or a
`
`pharmaceutically acceptable salt thereof, wherein the patient remains arousable and orientated.”
`
`5
`
`
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`41.
`
`Akers, M., Sterile Drug Products - Formulation, Packaging, Manufacturing, and
`
`Quality, ch. 7, Sterile products packaging chemistry, 72—95 (2010) (“Akers”) was publicly
`
`available before the priority dates ofthe patents in suit (i.e., January 4, 2012).
`
`42.
`
`Bauer, E., Pharmaceutical Packaging Handbook,
`
`ch.
`
`6, Pharmaceutical
`
`Packaging Materials, 189-272 (2009) (“Bauer”) was publicly available before the priority dates
`
`of the patents in suit.
`
`43.
`
`Cain,
`
`J ., Dexmedetomidine and Hextend: Their Role
`
`in Trauma Care,
`
`International TraumaCare, Vol 17, No. 1, pg. 5 (2007) (“Cain”) was publicly available before the
`
`priority dates of the patents in suit.
`
`44.
`
`Eichhorn, J ., APSF Hosts Medication Safety Conference, APSF Newsletter, Vol.
`
`25, No. 1, 1—20 (2010) (“Eichom”) was publicly available before the priority dates of the patents
`
`in suit.
`
`45.
`
`Fanikos, J ., Premixed Products Improve Safe Medication Practices, Pharmacy
`
`Practice News, 56-57 (November 2011) (“Fanikos”) was publicly available before the priority
`
`dates of the patents in suit.
`
`46.
`
`Gerlach, A., et al., A new dosing protocol reduces dexmedetomidine-associated
`
`hypotension in critically ill surgical patients, Journal of Critical Care, Vol. 24, No. 4, 568-574
`
`(2009) (“Gerlach”) was publicly available before the priority dates of the patents in suit.
`
`47.
`
`Giorgi,
`
`I., et al., Risk and pharmacoeconomic analyses of the injectable
`
`medication process in the paediatric and neonatal intensive care units, International Journal for
`
`Quality in Health Care, Vol. 22, No. 3, 170-178 (2010) (“Giorgi”) was publicly available before
`
`the priority dates ofthe patents in suit.
`
`
`
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`48.
`
`Jenkins, W., et al., Packaging Drugs and Pharmaceuticals, Technomic Publishing
`
`AG, 259-263 (1993) (“Jenkins”) was publicly available before the priority dates ofthe patents in
`
`suit.
`
`49.
`
`Lavoisier Sodium Chloride 0.9% injectable solution (2009) (“Lavoisier”) was
`
`publicly available before the priority dates ofthe patents in suit.
`
`50.
`
`Linden, P., et al., Ready-to-use Injection Preparations versus Conventional
`
`Reconstituted Admixtures, Pharmacoeconomics, Vol. 20, No. 8, 529-536 (2002) (“Linden”) was
`
`publicly available before the priority dates ofthe patents in suit.
`
`51.
`
`Morrison and Boyd, Organic Chemistry, 6th ed., 136-138 (1992) (“Morrison”)
`
`was publicly available before the priority dates of the patents in suit.
`
`52.
`
`Nema, S., et al. (ed.), Pharmaceutical Dosage Forms: Parenteral Medications,
`
`3rd ed., Vol. 3: Regulations, Validation and the Future, (2010) (“Nema”) was publicly available
`
`before the priority dates of the patents in suit.
`
`53.
`
`Palmgrén, J ., et al., Drug adsorption to plastic containers and retention of drugs
`
`in cultured cells under
`
`in vitro conditions, European Journal of Pharmaceutics
`
`and
`
`Biopharmaceutics, Vol. 64, 369-378 (2006) (“Palmgren”) was publicly available before the
`
`priority dates of the patents in suit.
`
`54.
`
`Sacha, G., et al., Practical fundamentals of glass, rubber, and plastic sterile
`
`packaging systems, Pharmaceutical Development and Technology, Vol. 15, No. 1, 6—34 (2010)
`
`(“Sacha”) was publicly available before the priority dates ofthe patents in suit.
`
`55.
`
`Stanaszek, W., et al., Comparison of Drug Stability in Glass Versus Plastic
`
`Containers: Analysis ofPrefilled Syringe Admixtures, Pro. Okla. Acad. Sci., Vol. 58, 102-105
`
`(1978) (“Stanaszek”) was publicly available before the priority dates ofthe patents in suit.
`
`
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`56.
`
`Trissel, L., et al., Compatibility Screening of Precedex During Simulated Y—Site
`
`Administration with Other Drugs, International Journal of Pharmaceutical Compounding, Vol. 6,
`
`No. 3 230-233 (2002) (“Trissel”) was publicly available before the priority dates ofthe patents in
`
`suit.
`
`57.
`
`Trissel, L., Handbook on Injectable Drugs, 16th ed. (2011) (“Trissel Handbook”)
`
`was publicly available before the priority dates of the patents in suit.
`
`58.
`
`The ’867 patent issued on April 6, 2004, and was publicly available before the
`
`priority dates of the patents in suit.
`
`59.
`
`Wang, Y., et a1., Sterile Pharmaceutical Packaging: Compatibility and Stability,
`
`Parenteral Drug Association,
`
`Inc., Technical Report No. 5 (1984) (“Wang”) was publicly
`
`available before the priority dates of the patents in suit.
`
`60. Webb, P., et a1., The Keys to RTU Parenterals, Pharmaceutical Formulation &
`
`Quality, Vol. 11, N0. 5 (2009) (“Webb 1”) was publicly available before the priority dates of the
`
`patents in suit.
`
`61.
`
`Webb, P., et al., Ensure Safety, Efficacy of Ready—to-Use IV Drug Products -
`
`Stability Considerations are Key, Pharmaceutical Formulation & Quality, Vol. 11, No. 6 (Oct-
`
`Nov, 2009) (“Webb 11”) was publicly available before the priority dates of the patents in suit.
`
`
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`EXHIBIT B
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`Hospira’s Statement of Disputed Issues of Fact
`
`Pursuant to Local Rule l6.3(a)(4), Hospira submits this statement of disputed issues of
`
`fact. The identification of these issues is based in part on Hospira’s current understanding of
`
`Amneal’s defenses and counterclaims. Hospira reserves the right to supplement, amend, or
`
`modify this list, for example, to respond to any new issues, arguments, or evidence from Hospira,
`
`or in the event of any Court ruling that might raise new issues.
`
`To the extent Hospira’s statement of the issues of law that remain to be litigated set forth
`
`in Exhibit D contains issues of fact, those issues are incorporated herein by reference. Should
`
`the Court determine that any issue identified in this statement as a factual
`
`issue is more
`
`appropriately considered a legal issue, Hospira incorporates the issue by reference into Exhibit
`
`D.
`
`I.
`
`PERSON OF ORDINARY SKILL IN THE ART
`
`1.
`
`With respect to the product properties of the Patents-in-Suit, a person of ordinary
`
`skill in the art (“POSA”) would have an advanced degree, such as a Ph.D. or Pharm.D., in
`
`chemistry, pharmacology, biology, pharmaceutical development, or a related science, and would
`
`be familiar with the principles of stereochemistry.
`
`2.
`
`With respect to the method of treatment limitations of the Patents-in-Suit, a POSA
`
`would be an MD. with several years of experience administering pharmaceuticals to patients.
`
`11.
`
`INFRINGEMENT
`
`A.
`
`‘106 Patent
`
`3.
`
`Amneal infringes each Asserted Claim ofthe ‘106 patent.
`
`
`
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`1. Claim 1
`
`a)
`
`“ready-to-use liquid pharmaceutical composition”
`
`4.
`
`A ready-to-use liquid pharmaceutical composition is a composition that
`
`is
`
`“formulated to be suitable for administration to a patient upon manufacture without dilution or
`
`reconstitution.” (See infia § III.A.)
`
`5.
`
`Amneal’s ANDA Products are formulated to be suitable for administration to a
`
`patient upon manufacture without dilution or reconstitution and, therefore, are "ready to use.”
`
`(E. g., DEX00000039, DEX00000044.)
`
`6.
`
`Similarly, Amneal’s ANDA Products require no further dilution or reconstitution
`
`before administration to a patient and, therefore, are “ready to use” under Amneal’s construction
`
`of the term.
`
`1))
`
`“for parenteral administration to a subject”
`
`7.
`
`The Amneal ANDA Products are intended for parenteral administration to a
`
`subject.
`
`(DEX00000039, 41.)
`
`It is undisputed that the Amneal ANDA Products infringe this
`
`limitation.
`
`0)
`
`pharmaceutically
`a
`or
`dexmedetomidine
`“comprising
`acceptable salt
`thereof disposed within a
`sealed glass
`container”
`
`8.
`
`It
`
`is undisputed that
`
`the Amneal ANDA Products contain about 4 ug/mL
`
`dexmedetomidine. (DEX00000039; DEX00000878; DEX00003491).
`
`9.
`
`The Amneal ANDA Products are contained within a sealed glass container.
`
`(DEX00000039; DEX00000041; DEX00000044; DEXOOOOOOSS.)
`
`10.
`
`A POSA as to the product aspects of the claimed subject matter would understand
`
`that a “sealed glass container” is a "glass container closed to maintain sterility by having a seal or
`
`another closure that passes closure integrity testing.”
`
`
`
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`11.
`
`The Amneal ANDA Products feature a stopper closure system designed to ensure
`
`that the Amneal ANDA Products remain sterile during storage. (DEX0000041 1; DEX00000879;
`
`DEX00003289-99.)
`
`12.
`
`The container closure system passed closure integrity testing, demonstrating that
`
`the system is sealed. (DEX00000846-73.)
`
`13.
`
`In addition to the stopper closure, the Amneal ANDA Products are closed with a
`
`seal. (DEX00000411; DEX00000879; DEX00003289-99.)
`
`14.
`
`Thus, the Amneal ANDA Products are disposed within a sealed glass container
`
`because they are closed to maintain sterility by having a seal or another closure that passes
`
`closure integrity testing.
`
`15.
`
`Similarly, the Amneal ANDA Product are closed tightly to prevent unwanted
`
`materials entering or exiting the glass container, and so are “sealed glass containers” under
`
`Amneal’s construction of the term as well.
`
`d)
`
`“wherein the liquid pharmaceutical composition when stored
`in the glass container for at least five months exhibits no
`more than about 2% decrease in the concentration of
`dexmedetomidine”
`
`16.
`
`On May 6, 2015, Hospira served on Amneal
`
`its First Set of Requests for the
`
`Production ofDocuments and Things (Nos. 1-37).
`
`17.
`
`Hospira’s Request No. 12 requested “[t]wenty-f1ve (25) vials of Defendant’s
`
`generic dexmedetomidine product described in Defendant’s ANDA.”
`
`18.
`
`On June 9, 2016, Amneal served its response to Hospira’s Request No. 12.
`
`Amneal stated, “In addition to its General Objections, Amneal objects to this Request as unduly
`
`burdensome and not
`
`in proportion to the needs of the case. Amneal produced ANDA No.
`
`207551 on August 4, 2015, which sufficiently describes Amneal’s Proposed Product; therefore,
`
`
`
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`the Request calls for information that
`
`is neither [sic] relevant to the issues in this case and
`
`duplicative of information in Hospira’s possession. Amneal further objects to the Request to the
`
`extent
`
`that production of 25 vials of Amneal’s Proposed ANDA product are [sic] unduly
`
`burdensome. Amneal will not produce vials ofits Proposed ANDA Product.”
`
`19.
`
`Amneal has conducted stability studies of its ANDA Products and submitted the
`
`studies as part of its ANDA.
`
`20.
`
`The purpose of the studies is to demonstrate to the FDA that the Amneal ANDA
`
`Products will remain within specification over their proposed shelf-life.
`
`21.
`
`22.
`
`23.
`
`24.
`
`25.
`
`The proposed shelf-life for the Amneal ANDA Products is twenty—four months.
`
`26.
`
`A POSA would understand that the limitation of the ‘106 patent requiring that
`
`“wherein the liquid pharmaceutical composition when stored in the glass container for at least
`
`
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`five months exhibits no more than about 2% decrease in the concentration of dexmedetomidine”
`
`(“Concentration Decrease Limitation”) refers to storage at the product’s acceptable storage
`
`conditions. According to their Prescribing Information, the Amneal ANDA Products are to be
`
`stored at 20-25°C, with excursions permitted to
`
`15°C-30°C (USP Controlled Room
`
`Temperature). (DEX0000055.) A rule ofthumb is that every 10°C increase in storage temperate
`
`accelerates the rate of a decomposition reaction by a factor of two.
`
`27.
`
`28.
`
`To determine the rate of dexmedetomidine potency loss in the Amneal ANDA
`
`Products, a POSA would perform regression analysis of Amneal’s stability data. Regression
`
`analysis is typically performed using a linear rate law for adsorption and a first-order rate law for
`
`oxidative decomposition. Both rate laws are relevant with respect
`
`to the Amneal ANDA
`
`Products because dexmedetomidine may be lost in the products through either adsorption to
`
`packaging material or oxidation.
`
`29-_
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`
`
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`
`
`
`
`
`Case 1:15-cv-00697-RGA Document 99-1 Filed 08/14/17 Page 15 of 73 PageID #: 1293
`Case 1:15-cv-00697-RGA Document 99-1 Filed 08/14/17 Page 15 of 73 PageID #: 1293
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`
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`
`
`
`
`
`
`
`
`more than about 2% decrease in the concentration of dexmedetomidine after five months of
`
`storage.
`
`31.
`
`When stored in a sealed glass container for five months, the 50 mL Amneal
`
`ANDA Product exhibits no more
`
`than about 2% decrease
`
`in the
`
`concentration of
`
`dexmedetomidine.
`
`32.
`
`When stored in a sealed glass container for five months, the 100 mL Amneal
`
`ANDA Product
`
`exhibits no more
`
`than about 2% decrease
`
`in
`
`the
`
`concentration of
`
`dexmedetomidine.
`
`33.
`
`In addition, Amneal’s product specification establishes that,
`
`if approved,
`
`the
`
`Amneal ANDA Products will maintain dexmedetomidine potency of 90%-110% over its 24-
`
`month shelflife.
`
`34.
`
`Thus, Amneal seeks approval to market products that may exhibit no more than
`
`about 2% decrease in the concentration of dexmedetomidine after five months of storage in a
`
`sealed glass container.
`
`35.
`
`Therefore, Amneal seeks approval
`
`to market products that would infringe the
`
`Concentration Decrease Limitation.
`
`
`
`Case 1:15-cv-00697-RGA Document 99-1 Filed 08/14/17 Page 16 of 73 PageID #: 1294
`Case 1:15-cv-00697-RGA Document 99-1 Filed 08/14/17 Page 16 of 73 PageID #: 1294
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`2. Claims 2-9
`
`36.
`
`It is undisputed that the Amneal ANDA Products infringe the additional elements
`
`ofClaims 2-9.
`
`37.
`
`Therefore, the Amneal ANDA Products infringe each Asserted Claim of the ‘106
`
`patent.
`
`B.
`
`‘158 Patent
`
`38.
`
`Each Asserted Claim of the '158 patent (Claims 1-4) recites a “ready-to-use liquid
`
`pharmaceutical composition” disposed within a “sealed glass container.”
`
`For the reasons
`
`discussed above with respect to Claim 1 of the ‘106 patent, under either party’s constructions of
`
`the terms, the Amneal ANDA Products are “ready to use liquid pharmaceutical compositions”
`
`disposed within a “sealed glass container.”
`
`39.
`
`It is undisputed that the Amneal ANDA Products infringe the remaining elements
`
`ofthe Asserted Claims ofthe ‘158 patent.
`
`40.
`
`Therefore, the Amneal ANDA Products infringe each Asserted Claim of the ‘ 158
`
`patent.
`
`C.
`
`‘470 Patent
`
`41.
`
`Each Asserted Claim of the ‘470 patent (Claims 1-7) recites a “ready-to-use liquid
`
`pharmaceutical composition” disposed within a “sealed glass container.”
`
`For the reasons
`
`discussed above with respect to Claim 1 of the ‘106 patent, under either party’s constructions of
`
`the terms, the Amneal ANDA Products are “ready to use liquid pharmaceutical compositions”
`
`disposed within a “sealed glass container.”
`
`42.
`
`It is undisputed that the Amneal ANDA Products infringe the remaining elements
`
`ofthe Asserted Claims ofthe ‘470 patent.
`
`
`
`Case 1:15-cv-00697-RGA Document 99-1 Filed 08/14/17 Page 17 of 73 PageID #: 1295
`Case 1:15-cv-00697-RGA Document 99-1 Filed 08/14/17 Page 17 of 73 PagelD #: 1295
`
`43.
`
`Therefore, the Amneal ANDA Products infringe each Asserted Claim of the ‘470
`
`patent.
`
`D.
`
`‘527 Patent
`
`44.
`
`Amneal
`
`infringes each Asserted Claim of the ‘527 patent. The parties have
`
`stipulated that Amneal infringes these claims.
`
`III.
`
`VALIDITY
`
`A.
`
`ANTICIPATION
`
`45.
`
`Amneal cannot prove by clear and convincing evidence that any Asserted Claim
`
`is invalid as anticipated.
`
`1. Trissel
`
`46.
`
`Amneal cannot prove by clear and convincing evidence that the Trissel reference
`
`anticipates any asserted claim.
`
`47.
`
`First, Trissel does not disclose a ready-to-use liquid pharmaceutical composition,
`
`as required by all claims.
`
`48.
`
`A ready-to use dexmedetomidine composition, as recited in the Patents-in-Suit, is
`
`one that is suitable for administration to a patient upon manufacture. The prior art Precedex
`
`Concentrate product required dilution prior to administration to a patient, which entailed
`
`“additional costs and inconvenience, as well as the risk of possible contamination or overdose
`
`due to human error.” (‘158 pat. at 1:48-57.)
`
`49.
`
`The invention of the Patents-in-Suit was “based in part on the discovery that
`
`dexmedetomidine prepared in a premixed formulation that does not require reconstitution or
`
`dilution prior to administration to a patient, remains stable and active after prolonged storage.”
`
`(‘158 pat. at 1:62-23.)
`
`The premixed formulations of the invention “avoid the cost,
`
`inconvenience, and risk of contamination or overdose that can be associated with reconstituting
`
`
`
`Case 1:15-cv-00697-RGA Document 99-1 Filed 08/14/17 Page 18 of 73 PageID #: 1296
`Case 1:15-cv-00697-RGA Document 99-1 Filed 08/14/17 Page 18 of 73 PageID #: 1296
`
`or diluting a concentrated dexmedetomidine formulation prior to administration to a patient.”
`
`(‘158 pat. at 1:62-23.) The formulations “are suitable for administration to a patient without
`
`dilution by,
`
`for example, a clinician, hospital personnel, caretaker, patient, or any other
`
`individual.” (‘158 pat. at 3:48-62.)
`
`50.
`
`Thus, the patents explain that the “ready to use” formulations of the claimed
`
`invention
`
`eliminate
`
`the
`
`undesirable
`
`dilution
`
`step
`
`needed
`
`to
`
`prepare
`
`the prior
`
`art
`
`dexmedetomidine formulation and, therefore, must be suitable for use without dilution upon
`
`manufacture.
`
`51.
`
`Trissel discloses 100 ug/mL Precedex Concentrate that is diluted to 4 ug/mL at
`
`the time of study. This type of formulation was specifically distinguished from the claimed
`
`invention during prosecution of the Patents—in-Suit.
`
`52.
`
`Thus, Trissel does not disclose a ready-to—use dexmedetomidine formulation.
`
`53.
`
`Second, Trissel does not disclose a composition for parenteral administration to a
`
`subject, as required by each Asserted Claim.
`
`54.
`
`The compositions of Trissel were not administered to a patient, and were not
`
`intended to be administered to a patient. The compositions were prepared for visual inspection
`
`to assess the physical compatibility of dexmedetomidine with other drugs.
`
`55.
`
`In addition, the dilution of 100 pg/mL Precedex Concentrate to 4 ug/mL was not
`
`performed using sterilized tubes or in a manner to ensure the sterility of the sample, so the
`
`prepared solutions could not be parenterally administered to a patient.
`
`56.
`
`Third, Trissel does not disclose a dexmedetomidine composition disposed within
`
`a sealed glass container, as required by all Asserted Claims.
`
`
`
`Case 1:15-cv-00697-RGA Document 99-1 Filed 08/14/17 Page 19 of 73 PageID #: 1297
`Case 1:15-cv-00697-RGA Document 99-1 Filed 08/14/17 Page 19 of 73 PageID #: 1297
`
`57.
`
`The compositions were placed in borosilicate glass screw-cap culture tubes with
`
`polypropylene caps. There is no disclosure that this packaging was sealed, i.e., that it would pass
`
`container closure integrity testing and maintain the sterility ofthe formulation.
`
`58.
`
`Because the compositions of Trissel were not intended to be administered to a
`
`patient, and were studied for only four hours, there was no need for the compositions to be
`
`sealed.
`
`59.
`
`Fourth, Trissel does not disclose a composition having no more than about 2%
`
`decrease in the concentration of dexmedetomidine after five months of storage, as required by
`
`the claims ofthe ‘106 patent.
`
`60.
`
`Trissel does not discuss the stability ofthe formulations that he studied.
`
`61.
`
`Because the solutions were not sealed and were not prepared in the absence of
`
`oxygen, oxidation likely occurred in the samples and air contaminants could have also entered
`
`the solutions. As a result, there would likely have been a decrease in the concentration of
`
`dexmedetomidine over time and the solutions may not meet the claimed stability.
`
`62.
`
`In addition,
`
`the solutions were studied for only four hours, and presumably
`
`disposed of thereafter. Because the compositions of Trissel existed only for a few hours, Trissel
`
`cannot disclose a composition that “when stored in the glass container for at least five months
`
`exhibits no more than about 2% decrease in the concentration of dexmedetomidine.”
`
`2. Alleged Prior Public Use
`
`a)
`
`Undiluted Precedex Concentrate
`
`63.
`
`Amneal cannot prove by clear and convincing evidence that use of Precedex
`
`Concentrate constitutes an invalidating public use ofany Asserted Claim.
`
`64.
`
`A POSA would not have considered Precedex Concentrate to be a “ready to use
`
`liquid pharmaceutical composition for parenteral administration.”
`
`10
`
`
`
`Case 1:15-cv-00697-RGA Document 99-1 Filed 08/14/17 Page 20 of 73 PageID #: 1298
`Case 1:15-cv-00697-RGA Document 99-1 Filed 08/14/17 Page 20 of 73 PageID #: 1298
`
`65.
`
`Precedex Concentrate was not approved or considered suitable for administration
`
`to a patient upon manufacture without dilution or reconstitution. A POSA would understand that
`
`the 100 ug/mL composition must be diluted to 4 ug/mL prior to administration.
`
`66.
`
`A POSA would understand that it would be inappropriate to inject a patient with
`
`100 ug/mL Precedex.
`
`67.
`
`A POSA would have known that administering a highly concentrated form of
`
`sedative that is twenty-five times more potent that the approved form can have hazardous and
`
`unpredictable consequences, including hypertension, bradycardia, and cardiac arrest.
`
`68.
`
`The Precedex Label provides only for reductions, rather than increases, in dosage
`
`relative to the prescribed 4 ug/mL dosage.
`
`b)
`
`Syringes of diluted Precedex Concentrate
`
`69.
`
`Amneal cannot prove by clear and convincing evidence that preparations of
`
`diluted Precedex in syringes constitute an invalidating public use of any asserted claim.
`
`70.
`
`A dilution of Precedex Concentrate is not a “ready to use” dexmedetomidine
`
`composition. The composition is diluted prior to administration to a patient.
`
`71.
`
`The syringes of diluted Precedex are also not suitable for administration to a
`
`patient. There is no evidence that the storage of the composition in syringes for several days has
`
`been established as safe and effective. A POSA would have understood that there was no
`
`evidence that diluted Precedex could be stored for more than 24 hours prior to administration.
`
`B.
`
`NON-OBVIOUSNESS
`
`72.
`
`Amneal cannot prove by clear and convincing evidence that the claimed subject
`
`matter would have been obvious to a POSA at the time ofthe invention.
`
`11
`
`
`
`Case 1:15-cv-00697-RGA Document 99-1 Filed 08/14/17 Page 21 of 73 PageID #: 1299
`Case 1:15-cv-00697-RGA Document 99-1 Filed 08/14/17 Page 21 of 73 PageID #: 1299
`
`1. A POSA would not have had a reasonable expectation of success in
`developing a ready—to—use dexmedetomidine formulation
`
`73.
`
`None of
`
`the prior
`
`art
`
`identified
`
`by Amneal
`
`discloses
`
`a
`
`ready—to-use
`
`dexmedetomidine composition.
`
`74.
`
`Precedex Concentrate is not a ready-to-use composition because it required
`
`dilution prior to parenteral administration.
`
`It was not suitable for administration upon
`
`manufacture without dilution.
`
`
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