United States Patent No. 8,338,470
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`Paper No. ____
`Filed: November 10, 2016
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`AMNEAL PHARMACEUTICALS, LLC,
`Petitioner
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`v.
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`HOSPIRA, INC.,
`Patent Owner
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`
`
`Inter Partes Review No. IPR2016-01578
`Patent 8,338,470
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`PATENT OWNER PRELIMINARY RESPONSE
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`PURSUANT TO 37 C.F.R. § 42.107
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`LIST OF EXHIBITS
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`1016
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`1017
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`1018
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`1019
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`1025
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`1026
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`1027
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`1028
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`1033
`1034
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`Exhibit Description
`1002 Declaration of Dr. James Cain.
`1003 Declaration of Dr. Alpaslan Yaman.
`1006 U.S. Patent No. 6,716,867 (“the ʼ867 Patent”).
`2010 Precedex® Label (“the 2010 Label”).
`1007
`1013
`FDA Memorandum by Cynthia G. McCormick, M.D., dated November
`30, 1999 (“the McCormick FDA Memorandum”).
`1015 Giorgi et al., International Journal for Quality in Health Care, Vol. 22,
`No. 3, 170-178 (2010) (“Giorgi”).
`Eichhorn, The Official Journal of the Anesthesia Patient Safety
`Foundation, Spring 2010 (“Eichhorn”).
`Palmgren, European Journal of Pharmaceutics and Biopharmaceutics,
`June 29, 2006 (“Palmgren”).
`Lavoisier Documents; Lavoisier Sodium Chloride Product Sheet, June
`2009 (“Lavoisier”).
`FDA Memorandum by Bob A. Rappaport, M.D., dated November 5,
`1999 (“the Rappaport FDA Memorandum”).
`Packaging Drugs and Pharmaceuticals, Wilmer A. Jenkins and Kenton
`R. Osborn, p. 259, 1993.
`“Pharmaceutical dosage forms, parenteral medications” edited by
`Kenneth E. Avis, et al. 2nd Edition, p. 161, 1992.
`“Sterile Pharmaceutical Packaging: Compatibility and Stability” Y. John
`Wang and Yie W. Chien, p. 16, 1984.
`Paula Youngberg Webb, et al. “The Keys to RTU Parenterals,”
`Pharmaceutical Formulation & Quality, Vol. 11, No. 5, p. 40, September
`2009.
`Liu, U.S. 6,310,094.
`Linden, P., et al., Ready-to-use injection preparations versus
`conventional reconstituted admixtures: economic evaluation in a real-
`life setting, PharmacoEconomics, Vol. 20, No. 8, 529-536 (2002).
`1035 Cain, TraumaCare, July 2007, p. 5.
`1039 G. DiSilvio, M. Jacoby, D. Weiner, A. Broussard, P. Callahan, and J.
`Cain, “Intranasal Dexmedetomidine & Midazolam: A Novel Sedation
`Technique for Infant PFT,” Society for Pediatric Anesthesia, Phoenix,
`Arizona (March 2015).
`“Injectable medicines,” WHO Collaborating Centre for Pharmaceutical
`Pricing and Reimbursement Policies,
`
`1044
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`- i -
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`2008
`
`2009
`
`2011
`
`2013
`2014
`
`http://whocc.goeg.at/Glossary/PreferredTerms.
`1049 Office Action Response, mailed Sept. 17, 2012, U.S. Application No.
`13/541,524.
`1057 Declaration of Huailiang Wu, U.S. Application No. 13/541,524 (“the
`Wu Declaration”).
`2001 U.S. Patent No. 8,242,158 (“the ’158 Patent”).
`2002 U.S. Patent No. 8,338,470 (“the ’470 Patent”).
`2003 U.S. Patent No. 8,455,527 (“the ’527 Patent”).
`2004 U.S. Patent No. 8,648,106 (“the ’106 Patent”).
`2005 Declaration of Dr. Robert Linhardt (“the Linhardt Declaration”).
`2006 Declaration of Dr. Michael Ramsay (“the Ramsay Declaration”).
`2007 Accelerated Examination Support Document, U.S. Patent Application
`Serial No. 13/541,524.
`“Guidance for Industry: Drug Stability Guidelines,” FDA Center for
`Veterinary Medicine, p. 26, Dec. 2008.
`“Guidance for Industry: Q1A (R2) Stability Testing of New Drug
`Substances and Products,” FDA Center for Drug Evaluation and
`Research, p. 10, Nov. 2003.
`2010 C.E. Blogg, M.A.E. Ramsay, and J.D. Jarvis, “Infection Hazard from
`Syringes,” Br. J. Anaesth., 46, pp. 260-262 (1974).
`Speaker T.J. et al., “A Study of the Interaction of Selected Drugs and
`Plastic Syringes,” PDA J Pharm Sci and Tech, 45:212-217 (1991).
`2012 Kaur, M. et al., “Current role of dexmedetomidine in clinical anesthesia
`and intensive care,” Anesth Essays Res. 2011 Jul-Dec., 5(2): 128-133.
`Ecoflac® Plus Brochure, B|Braun.
`P. Donyai and G. Sewell, “Physical and chemical stability of paclitaxel
`infusions in different container types,” J. Oncol. Pharm. Practice, 12, pp.
`211-222 (2006).
`2015 Anes, J. et al., “Use of Plastics for Parenteral Packaging,”
`Pharmaceutical Dosage Forms: Parenteral Medications Volume 1, 2d
`Ed. (1992).
`2016 Webb, P. et al., “Ensure Safety, Efficacy of Ready-to-Use IV Drug
`Products,” PFQ Vol. 11, No. 6, Oct./Nov. 2009.
`“Guidance for Industry: Container Closure Systems for Packaging
`Human Drugs and Biologics,” FDA Center for Drug Evaluation and
`Research, pp. 7-10, May 1999.
`2018 Dahlstrom, M. et al., “Impact of polymer surface affinity of novel
`antifouling agents,” Biotechnol Bioeng. 2004 Apr 5;86(1):1-8.
`2019 Kambia, N.K. et al., “Compatibility of nitroglycerin, diazepam and
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`2017
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`2021
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`chlorpromazine with a new multilayer material for infusion containers,”
`Journal of Pharmaceutical and Biomedical Analysis, 37: 259–
`264(2005).
`2020 Martens, H. et al., “Sorption of various drugs in polyvinyl chloride,
`glass, and polyethylene-lined infusion containers,” Am. J. Hospital
`Pharmacy, 47:2, pg. 369-373 (1990).
`T. Casey, “Hospira Slices into Plastic Medical Waste with New IV
`Bags,” Clean Technica, Dec. 4, 2009, available at
`http://cleantechnica.com/2009/12/04/hospira-slices-into-plastic-medical-
`waste-with-new-iv-bags/.
`2022 Yuen et al., “A Comparison of Intranasal Dexmedetomidine and Oral
`Midazolam for Premedication in Pediatric Anesthesia: A Double-
`Blinded Randomized Controlled Trial,” Anesthesia & Analgesia
`106(6):1715-1721 (June 2008).
`“Centralized Intravenous Additive Services (CIVAS): The state of the
`art in 2010,” Annales Pharmaceutiques Francaises (2011) 69:30-37.
`Label for 0.9% w/v Sodium Chloride Intravenous Infusion BP, B. Braun
`Melsungen AG, Dec. 2010, available at
`https://www.old.health.gov.il/units/pharmacy/trufot/alonim/Sodium_Chl
`oride_0-9_DR_1319972870952.pdf.
`2025 KetalarTM Label (ketamine hydrochloride injection), Mar. 2012, p. 4,
`available at
`http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/016812s039l
`bl.pdf.
`2026 AlkeranTM Label, June 2007, available at
`http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020207s017l
`bl.pdf.
`2027 Desmaris, R. et al., “Stability of Melphalan in 0.9% Sodium Chloride
`Solutions Prepared in Polyvinyl Chloride Bags for Intravenous
`Injection,” Drugs R. D., 14(3): 253-259, Jul. 2015.
`
`2023
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`2024
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`TABLE OF CONTENTS
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`I.
`
`INTRODUCTION ........................................................................................... 1
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`II. OVERVIEW OF THE ’470 PATENT ............................................................ 2
`
`III. SUMMARY OF DOCUMENTS CITED IN PETITION ............................... 4
`2010 Precedex® Label (the “2010 Label”) (Ex. 1007) .......................... 4
`
`A.
`
`B.
`
`Palmgren (Ex. 1017) ............................................................................. 5
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`C. U.S. Patent No. 6,716,867 (“the ’867 Patent”) (Ex. 1006) ................... 6
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`D. Giorgi (Ex. 1015) .................................................................................. 6
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`E.
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`F.
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`Eichhorn (Ex. 1016) .............................................................................. 6
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`The Lavoisier Documents (“Lavoisier”) (Ex. 1018) ............................. 7
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`IV. THE LEVEL OF ORDINARY SKILL IN THE ART .................................... 7
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`V.
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`CLAIM CONSTRUCTION ............................................................................ 8
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`A.
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`B.
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`Legal Standard ....................................................................................... 8
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`Ready to Use ......................................................................................... 9
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`C. Dexmedetomidine ............................................................................... 12
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`VI. PETITIONER HAS NOT SHOWN A REASONABLE LIKELIHOOD
`THAT AT LEAST ONE CLAIM OF THE ’470 PATENT IS
`UNPATENTABLE ........................................................................................ 12
`
`A.
`
`Legal Standard for Obviousness ......................................................... 13
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`B. Ground 1: The Petition Fails to Demonstrate that the Claims Are
`Unpatentable over the 2010 Label in View of Palmgren .................... 15
`
`1.
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`2.
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`The 2010 Label and Palmgren Do Not Disclose or Suggest All
`Claim Elements ......................................................................... 15
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`There Was No Motivation to Combine Palmgren with the 2010
`Label .......................................................................................... 27
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`C. Ground 2: The Petition Fails to Demonstrate that the Claims Are
`Unpatentable over the ’867 Patent in View of the 2010 Label and
`Palmgren .............................................................................................. 38
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`1.
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`2.
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`3.
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`Ground 2 is Redundant with Ground 1 ..................................... 39
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`The Combination of the ’867 Patent with the 2010 Label and
`Palmgren Does Not Disclose or Suggest All Claim Elements . 41
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`Petitioner’s Contentions Regarding the Orange Book Listing
`and Assertion of the ’867 Patent in Litigation Are Irrelevant. . 45
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`D. Ground 3: The Petition Fails to Demonstrate that the Claims Are
`Unpatentable over the 2010 Label in View of Giorgi, Eichhorn,
`Palmgren, and Lavoisier ...................................................................... 49
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`1.
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`2.
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`Ground 3 is Redundant with Ground 1 ..................................... 50
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`The Combination of the 2010 Label with Giorgi, Eichhorn,
`Palmgren, and Lavoisier Does Not Disclose or Suggest All
`Claim Elements ......................................................................... 51
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`VII. CONCLUSION .............................................................................................. 60
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`CASES
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`TABLE OF AUTHORITIES
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`Page(s)
`
`Abbvie Inc. v. Mathilda and Terence Kennedy Inst. of Rheumatology
`Tr.,
`764 F.3d 1366 (Fed. Cir. 2014) .......................................................................... 47
`
`ActiveVideo Networks, Inc. v. Verizon Commc’ns, Inc.,
`694 F.3d 1312 (Fed. Cir. 2012) .......................................................................... 15
`
`Corning Glass Works v. Sumitomo Elec. U.S.A., Inc.,
`868 F.2d 1251 (Fed. Cir. 1989) .......................................................................... 47
`
`Cuozzo Speed Techs. LLC v. Lee,
`136 S.Ct. 2131 (2016) ........................................................................................... 8
`
`In re Baird,
`16 F.3d 380 (Fed. Cir. 1994) .............................................................................. 47
`
`In re Corkill,
`771 F.2d 1496 (Fed. Cir. 1985) .......................................................................... 32
`
`In re Kahn,
`441 F.3d 977 (Fed. Cir. 2006) ............................................................................ 14
`
`In re Translogic Tech., Inc.,
`504 F.3d 1249 (Fed. Cir. 2007) ............................................................................ 8
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 13, 14
`
`Minnesota Min. and Mfg. Co. v. Johnson & Johnson Orthopaedics,
`Inc.,
`976 F.2d 1559 (Fed. Cir. 1992) .......................................................................... 47
`
`Prometheus Labs., Inc. v. Roxane Labs., Inc.,
`805 F.3d 1092 (Fed. Cir. 2015) .......................................................................... 47
`
`Stratoflex, Inc. v. Aeroquip Corp.,
`713 F.2d 1530 (Fed. Cir. 1983) .......................................................................... 14
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`Takeda Chem. Industries, Ltd. v. Alphapharm Pty., Ltd.,
`492 F.3d 1350 (Fed. Cir. 2007) .......................................................................... 47
`
`BOARD DECISIONS
`Cisco Sys., Inc. v. C-Cation Techs., LLC,
`IPR2014-00454, Paper 12 (P.T.A.B. Aug. 29, 2014) ......................................... 14
`
`Dominion Dealer Sols., LLC v. AutoAlert, Inc.,
`IPR2013-00223, Paper 9 (P.T.A.B. Aug. 15, 2013) ........................................... 14
`
`Kinetic Techs., Inc. v. Skyworks Sols., Inc.,
`IPR2014-00529, Paper 8 (P.T.A.B. Sept. 23, 2014) ..................................... 14, 15
`
`Liberty Mutual Ins. Co. v. Progressive Casualty Ins. Co,
`CBM2012-00003, Paper 7 (P.T.A.B. Oct. 25, 2012) ............................. 39, 41, 51
`
`TRW Auto. US LLC v. Magna Elecs. Inc.,
`IPR2014-00259, Paper 19 (P.T.A.B. June 26, 2014) ......................................... 14
`
`STATUTES
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`21 U.S.C. § 355(b)(1)............................................................................................... 46
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`35 U.S.C. § 103(a) ................................................................................................... 13
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`35 U.S.C. § 311(b) ................................................................................................... 16
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`35 U.S.C. § 314(a) ............................................................................................... 2, 12
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`REGULATIONS
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`37 C.F.R. § 42.24(a) ................................................................................................. 61
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`37 C.F.R. § 42.24(b) ................................................................................................ 61
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`37 C.F.R. § 42.24(d) ................................................................................................ 61
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`37 C.F.R. § 42.100(b) ................................................................................................ 8
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`OTHER AUTHORITIES
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`77 Fed. Reg. 48,756, at 48,756 (Aug. 14, 2012)...................................................... 12
`
`M.P.E.P. § 716.02(a) ................................................................................................ 32
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`I.
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`INTRODUCTION1
`The Board should not institute inter partes review (IPR) of claims 1-7 of
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`U.S. Patent No. 8,338,470 (“the ’470 Patent”) because Amneal Pharmaceuticals,
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`LLC (“Petitioner”) has not shown a reasonable likelihood of prevailing on any of
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`its asserted grounds of unpatentability.
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`Under Ground 1, Petitioner has failed to demonstrate how the combination
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`of the 2010 Label and Palmgren disclosed or rendered obvious a ready to use
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`dexmedetomidine composition for parenteral administration at a concentration of
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`from about 0.005 µg/mL to about 50 µg/mL that is disposed within a sealed glass
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`container. Petitioner has also failed to adequately explain how a person of
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`ordinary skill in the art (“POSA”) would have combined these references. As
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`explained below, there was no motivation to combine these references as alleged
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`by Petitioner.
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`Grounds 2 and 3 simply add additional references that are redundant over
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`and cumulative of Ground 1 as Petitioner has failed to provide the requisite bi-
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`directional explanation of the relative strengths and weaknesses of each ground.
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`Even so, the additional references of Grounds 2 and 3 do not cure the deficiencies
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`of Ground 1.
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`1 Citations are to internal page numbers of exhibits.
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`Hospira, Inc. (“Patent Owner”) provides the following Preliminary Response
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`to the Petition filed on August 10, 2016, requesting that the Board deny IPR as to
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`all grounds because Petitioner has failed to show a reasonable likelihood of
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`prevailing on any ground under 35 U.S.C. § 314(a).
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`II. OVERVIEW OF THE ’470 PATENT
`Medetomidine is “a selective and potent α2-adrenoreceptor agonist,”
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`approved for veterinary use, and has been used as an anti-hypertensive or sedative-
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`analgesic agent. Ex. 2002, 1:20-28. Medetomidine is a racemic mixture of two
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`enantiomers: levomedetomidine and dexmedetomidine. See Ex. 2005, ¶25.
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`Dexmedetomidine has been approved for human use to provide sedation,
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`and can be used for analgesia or in the treatment of hypertension or anxiety. Id.,
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`1:28-30; Ex. 1007. Dexmedetomidine can be administered via a number of
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`administration routes, including by parenteral administration. Id., 1:43-46.
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`The earliest priority date of the ’470 Patent is January 4, 2012. At that time,
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`dexmedetomidine was “provided as a concentrate that must be diluted prior to
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`administration to a patient.” Ex. 2002, 1:53-55. The dilution requirement was
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`“associated with additional costs and inconvenience, as well as the risk of possible
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`contamination or overdose due to human error.” Id., 1:55-58.
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`As of January 4, 2012, there was a need for a ready to use dexmedetomidine
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`composition
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`that could be administered
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`to a patient without dilution,
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`reconstitution, or other similar pre-administration preparation to “avoid[] the
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`expense, inconvenience, delay and risk of contamination or overdose” associated
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`with the concentrated form. Id., 3:2-6. Preparing a stable premixed composition
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`for storage that retains potency over prolonged periods was technically challenging
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`for low concentration forms. See Ex. 2005, ¶ 81. Changes in drug concentration
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`were known to affect the behavior and stability of a formulation, with particular
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`challenges specific to lower concentration solutions. For example, small amounts
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`of drug degradation, drug adsorption, or contamination would have a much more
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`significant impact on the efficacy of low concentration dexmedetomidine, as
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`compared to the concentrated form. Id., ¶ 85-93. Indeed, the ’470 Patent notes
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`that at low concentrations, “even ppb levels of impurities would have a significant
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`contribution toward the impurity limit.” Ex. 2002, 22:40-42.
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`The inventors of the ’470 Patent discovered that a ready to use, low
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`concentration dexmedetomidine composition that did not require reconstitution or
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`dilution prior to administration to a patient was stable after prolonged storage when
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`disposed in a sealed glass container. Id., 2:65-3:6.
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`The challenged claims are directed to a ready to use composition comprising
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`dexmedetomidine or a pharmaceutically acceptable salt thereof for parenteral
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`administration. The ready to use dexmedetomidine composition is disposed within
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`a sealed glass container, and dexmedetomidine is present at a concentration of
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`from about 0.005 µg/mL to about 50 µg/mL. The composition does not require
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`dilution or reconstitution prior to administration to a patient. The dependent claims
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`further define the concentration of dexmedetomidine in the ready to use
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`composition, and specify that the composition further includes sodium chloride
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`solution at certain concentrations. The dependent claims also recite a total volume
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`of the composition. Claim 1 is illustrative of the challenged claims and recites:
`
`A ready to use liquid pharmaceutical composition for parenteral
`administration to a subject, comprising dexmedetomidine or a
`pharmaceutically acceptable salt thereof at a concentration of
`about 0.005 to about 50 μg/mL disposed within a sealed glass
`container.
`
`III. SUMMARY OF DOCUMENTS CITED IN PETITION
`A.
`2010 Precedex® Label (the “2010 Label”) (Ex. 1007)
`The 2010 Label is asserted in each ground of the Petition. The 2010 Label
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`provides instructions on usage, dosage, and administration of dexmedetomidine for
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`intravenous injection, but only as to the concentrated form. In particular, the 2010
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`Label discloses dexmedetomidine at a concentration of 200 µg/2mL (which is
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`equivalent to 100 µg/mL). Ex. 1007, sec. 3; Ex. 2005, ¶ 48. The concentrated
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`dexmedetomidine is provided in a glass vial and “must be diluted in 0.9% sodium
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`chloride solution to achieve required concentration (4 mcg/mL) prior to
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`administration.” Ex. 1007, sec. 3, 2.4 (emphasis added).
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`Palmgren (Ex. 1017)
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`B.
`Palmgren is asserted in each ground of the Petition. Palmgren describes an
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`analysis of the adsorption of 10 drugs when stored in various container materials.
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`Medetomidine was one of the tested drugs. Palmgren compared drug adsorption in
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`modified polystyrene, polypropylene, polycarbonate, and glass containers at low
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`drug concentrations. With respect
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`to medetomidine, Palmgren compared
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`adsorption of an 8 nM solution (≈ 0.0016 µg/mL) after storage in these materials
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`for 4.5 hours. Ex. 1017, sec. 3.4.2-3.4.4, Table 4; Ex. 2005, ¶ 54. Medetomidine,
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`when stored in a water solution, had much higher drug loss to modified
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`polystyrene plastic as compared to glass and polypropylene. Ex. 1017, sec. 3.4.3,
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`Table 4. Medetomidine, when stored in a buffered solution (pH of 7.4), had “no
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`significant loss of drugs…to any of the tested materials.” Id., sec. 3.4.2.
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`Palmgren tested higher concentrations of medetomidine (including 1000 nM
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`and 2500 nM) in modified polystyrene. At 1000 nM (≈ 0.2 µg/mL), medetomidine
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`“losses were clearly lower than observed at [8 nM].” Ex. 1017, sec. 3.4.5. At
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`2500 nM (≈ 0.5 µg/mL) or above, “no drug loss was detected at all.” Id. (emphasis
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`added). Thus, Palmgren taught that the higher the concentration of medetomidine,
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`the lower the amount of drug loss in modified polystyrene. Ex. 1017, sec. 3.4.5;
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`Ex. 2005, ¶ 144.
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`C. U.S. Patent No. 6,716,867 (“the ’867 Patent”) (Ex. 1006)
`The ’867 Patent is asserted in Ground 2 of the Petition. The ’867 Patent
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`relates to a method of sedating a patient by administering dexmedetomidine or a
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`pharmaceutically acceptable salt thereof, wherein the patient remains arousable
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`and orientated. The ’867 Patent used dexmedetomidine in the concentrated 100
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`µg/mL form, which must be diluted prior to administration. Ex. 1006, 5:54, 7:5,
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`63. The ’867 Patent does not disclose suitable packaging or storage of
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`dexmedetomidine, and similarly, does not disclose a ready to use composition.
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`D. Giorgi (Ex. 1015)
`Giorgi is asserted in Ground 3 of the Petition. Giorgi provides a risk
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`assessment regarding the safety of injectable medications for pediatric and
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`neonatal populations. Ex. 1015, Abstract. Giorgi emphasizes the benefits of
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`centralized drug preparation (“CIVAS”), while recognizing that not all drugs can
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`be prepared in this manner. Id., p. 172. Giorgi offers several alternatives, such as
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`personnel oversight, to reduce the number of failures associated with injectable
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`drugs. Id., p. 171, Table 1. Giorgi does not discuss ready to use compositions that
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`are formulated to be suitable for administration without dilution.
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`Eichhorn (Ex. 1016)
`
`E.
`Eichhorn is asserted in Ground 3 of the Petition. Eichhorn describes
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`consensus recommendations “to reduce medication errors causing harm to patients
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`in the operating room,” and provides a compilation of perspectives from individual
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`doctors and pharmacists. Ex. 1016, p. 1. Eichhorn recommends that dilutions
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`should be prepared centrally by a hospital pharmacy with safety measures in place.
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`Ex. 1016, pp. 1, 8. Eichhorn particularly advocates for pharmacy-diluted
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`medications as an alternative to dilution by physicians in the operating room. Ex.
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`1016, pp. 1, 3. However, Eichhorn acknowledges that it is not practical to prepare
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`drug dilutions in advance for all drugs and in all situations. Ex. 1016, p. 6.
`
`The Lavoisier Documents (“Lavoisier”) (Ex. 1018)
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`F.
`Lavoisier is asserted in Ground 3 of the Petition. Lavoisier describes
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`product information for an injectable 0.9% sodium chloride solution, which was
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`available in different volumes and packaging materials. Ex. 1018, p. 1. Lavoisier
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`discloses glass, vinyl polychloride, polyethylene, and polypropylene containers.
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`Id. Lavoisier provides isotonic sodium chloride solutions, and does not relate to
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`dexmedetomidine. Lavoisier teaches that “[w]hen a drug is added to this solution,
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`admixture should be dispensed instantly.” Id.
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`IV. THE LEVEL OF ORDINARY SKILL IN THE ART
`The POSA, as of January 4, 2012, would have held an advanced degree,
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`such as a Ph.D or Pharm.D, in chemistry, pharmacology, biology, pharmaceutical
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`development, or a related science and familiarity with the principles of
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`stereochemistry, or would have held an M.D. with several years of experience
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`administering pharmaceuticals to patients. See Ex. 2005, ¶ 39; Ex. 2006, ¶ 63.
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`V. CLAIM CONSTRUCTION
`Petitioner has failed to demonstrate a reasonable likelihood that any of the
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`challenged claims are unpatentable. Patent Owner provides the following
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`responses to Petitioner’s proposed constructions. Patent Owner reserves the right
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`to offer constructions for additional terms, should those terms become relevant to
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`either this or other proceedings. Patent Owner also reserves the right to offer claim
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`constructions in other proceedings, including district court litigation, which may
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`differ from those presented in this Preliminary Response.
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`A. Legal Standard
`In an IPR, a claim term in an unexpired patent is “given its broadest
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`reasonable construction in light of the specification of the patent in which it
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`appears.” 37 C.F.R. § 42.100(b); Cuozzo Speed Techs. LLC v. Lee, 136 S.Ct. 2131,
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`2144-45 (2016). Claim terms are given their ordinary and customary meaning as
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`would be understood by a POSA at the time of the invention and in the context of
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`the entire patent disclosure. In re Translogic Tech., Inc., 504 F.3d 1249, 1257
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`(Fed. Cir. 2007). For terms not specifically listed and construed below, Patent
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`Owner interprets them for purposes of this proceeding in accordance with their
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`plain and ordinary meaning under the required broadest reasonable interpretation
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`standard.
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`B. Ready to Use
`The term “ready to use” should be construed as “formulated such that it is
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`suitable for administration to a patient upon manufacture without dilution or
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`reconstitution by a clinician, hospital personnel, caretaker, patient, or any other
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`individual.”
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`As stated in the ’470 Patent, dexmedetomidine compositions can be
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`“formulated as ‘ready to use’ compositions which refer to premixed compositions
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`that are suitable for administration to a patient without dilution.” Ex. 2002, 3:60-
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`62. The terms “premix” or “premixture” refer to a pharmaceutical formulation that
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`does not require reconstitution or dilution prior to administration to a patient. Id.,
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`3:51-53; 2:65-3:6. The ’470 Patent is clear that premixed compositions, or
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`premixtures, are “pharmaceutical formulation[s] that [do] not require reconstitution
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`or dilution prior to administration to a patient”, and that such compositions are
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`“suitable for administration to a patient without dilution by, for example, a
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`clinician, hospital personnel, caretaker, patient or any other individual.” Id., 3:51-
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`57. Petitioner concedes that “‘ready to use’ is equivalent to ‘a premixture.’” See
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`Pet., p. 12, n. 2.
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`The ’470 Patent discloses that the ready to use compositions “are ‘ready to
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`use’ upon removing the compositions from a sealed container or vessel.” Ex.
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`2002, 3:59-62. A POSA would understand that the claimed ready to use
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`composition is manufactured for direct administration to a patient without dilution,
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`reconstitution, or similar preparation. Ex. 2002, 17:52-21:20. Thus, this
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`construction finds clear support within the specification of the ’470 Patent.
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`This construction is supported by the prosecution history. For example, to
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`distinguish from the concentrated form of dexmedetomidine, the Applicants
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`explained that “the claimed composition is a ready to use premixture that does not
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`require any dilution or reconstitution prior to administration to a subject.” Ex.
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`1049, p. 6. In the initial Accelerated Examination Support Document, Applicant
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`explained that the dexmedetomidine composition as claimed is “formulated as a
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`ready to use liquid pharmaceutical composition for administration to a subject
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`upon removal from the sealed glass container” (i.e., upon manufacture). Ex. 2007,
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`p. 2.
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`References cited by Petitioner support this construction. For example, Ex.
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`1028 states: “Several drugs for IV infusion, premixed in an intravenous diluent, are
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`also commercially available. These products are referred to as ready-to-use (RTU)
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`products or ‘premix’ drug solutions.” Ex. 1028, p. 2; see also Ex. 1033, 2:5-14;
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`Ex. 1034, pp. 529-530.
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`In view of the definition in the specification, statements in the prosecution
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`history, and usage in the prior art, a POSA would have understood the term “ready
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`to use” to mean “formulated such that it is suitable for administration to a patient
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`upon manufacture without dilution or reconstitution by a clinician, hospital
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`personnel, caretaker, patient, or any other individual.” Ex. 2005, ¶ 43; Ex. 2006, ¶
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`69.
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`Petitioner’s proposed construction of “requiring no further dilution or
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`reconstitution before transfer to an administration device” is not supportable.
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`There is no support in the specification or prosecution history for Petitioner’s
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`insertion of the word “further” and the phrase “transfer to an administration
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`device” into the construction of “ready to use.”
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`Petitioner
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`relies on extrinsic evidence
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`to support
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`the proposed
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`construction—namely, an undated online definition of the term “injectable
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`medicines.” Pet., p. 11 (citing Ex. 1044). Petitioner has proffered no evidence that
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`this definition represents the understanding in the art at the time of the invention.
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`Moreover, this online definition provides as an example of a “ready-to-use”
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`medicine, “a liquid with an ampoule, of the required concentration, that only needs
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`to be drawn up into a syringe.” Ex. 1044. Even from this example, a POSA would
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`have understood that there is no dilution or reconstitution between the time of
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`formulation and the time of administration to a patient. A POSA would have
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`understood that the claimed ready to use compositions are ready for administration
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`upon manufacture, and are not prepared by an individual who dilutes a
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`concentrated solution. See Ex. 2006, ¶¶ 67-68.
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`C. Dexmedetomidine
`The term “dexmedetomidine” should be construed as “substantially pure,
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`optically active dextrorotary stereoisomer of medetomidine, as the free base or
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`pharmaceutically acceptable salt,” as proposed by Petitioner. Pet., p. 13; see also
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`Ex. 2005, ¶ 46; Ex. 2006, ¶ 72.
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`VI. PETITIONER HAS NOT SHOWN A REASONABLE LIKELIHOOD
`THAT AT LEAST ONE CLAIM OF THE ’470 PATENT IS
`UNPATENTABLE
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`The Board may only institute an IPR if it is shown “that there is a reasonable
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`likelihood that the petitioner would prevail with respect to at least 1 of the claims
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`challenged in the petition.” 35 U.S.C. § 314(a). The Petitioner bears the burden of
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`showing that this statutory threshold has been met. See Office Patent Trial Practice
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`Guide, 77 Fed. Reg. 48,756, at 48,756 (Aug. 14, 2012).
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`Petitioner has not demonstrated that there is a reasonable likelihood that any
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`of the claims of the ’470 Patent are unpatentable. Petitioner has failed to
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`demonstrate that the 2010 Label and Palmgren can be properly combined and that,
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`even
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`if combined,
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`the combination would render
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`the challenged claims
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`unpatentable. Moreover, Petitioner has failed to demonstrate that the references
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`added by Grounds 2 and 3 remedy these deficiencies. Accordingly, this Petition
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`should be denied.2
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`A. Legal Standard for Obviousness
`A patent claim is obvious under 35 U.S.C. § 103(a) only “if the differences
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`between the subject matter sought to be patented and the prior art are such that the
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`subject matter as a whole would have been obvious at the time the invention was
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`made to a person having ordinary skill in the art to which said subject matter
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`pertains.” 35 U.S.C. § 103(a) (pre-AIA). This analysis includes a determination of
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`“the scope and content of the prior art,” the “differences between the prior art and
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`the claims at issue,” the “level of ordinary skill in the pertinent art,” and the
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`existence of secondary considerations such as “commercial success, long felt but
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`unresolved needs, failure of others, etc.” KSR Int’l Co. v. Teleflex Inc., 550 U.S.
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`398, 406 (2007). Moreover, “evidence of secondary considerations may often be
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`the m