UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`AMNEAL PHARMACEUTICALS, LLC,
`Petitioner
`
`
`v.
`
`HOSPIRA, INC.,
`Patent Owner
`
`
`
`Inter Partes Review No. IPR2016-01578
`Patent 8,338,470
`
`
`
`
`DECLARATION OF DR. MICHAEL RAMSAY
`
`
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`Hospira, Exh. 2006, p. 1
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`

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`TABLE OF CONTENTS
`
`I.
`II.
`
`V.
`
`BACKGROUND AND QUALIFICATIONS ................................................. 1
`LEGAL UNDERSTANDING ......................................................................... 4
`A.
`Level of a Person of Ordinary Skill in the Art ...................................... 4
`B.
`Claim Construction ............................................................................... 5
`C. Anticipation ........................................................................................... 6
`D. Obviousness ........................................................................................... 6
`III. BACKGROUND OF THE TECHNOLOGY ................................................ 10
`A.
`State of the Art .................................................................................... 10
`B.
`Subject Matter of the Patents .............................................................. 12
`IV. CLAIM CONSTRUCTION .......................................................................... 20
`A.
`Level of a Person of Skill in the Art ................................................... 20
`B.
`“Ready to Use” .................................................................................... 21
`C.
`“Dexmedetomidine” ............................................................................ 24
`SUMMARY OF THE PRIOR ART .............................................................. 24
`A.
`2010 Label ........................................................................................... 24
`B.
`Palmgren .............................................................................................. 26
`C. US 6,716,867 (“the ʼ867 Patent”) ....................................................... 27
`D. Giorgi ................................................................................................... 30
`E.
`Eichhorn .............................................................................................. 32
`F.
`Lavoisier .............................................................................................. 35
`VI. OPINIONS ..................................................................................................... 35
`A.
`The Prior Art Does Not Disclose a Ready to Use Dexmedetomidine
`Composition for Parenteral Administration ........................................ 36
`1.
`The 100 mcg/mL Concentration of Dexmedetomidine
`Disclosed by the 2010 Label is Not Ready to Use ................... 37
`The ʼ867 Patent Does Not Disclose a Ready
`to Use
`Dexmedetomidine Composition ............................................... 46
`Dilutions Prepared From a 100 mcg/mL Dexmedetomidine
`Composition Are Not Ready to Use Compositions .................. 49
`
`2.
`
`3.
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`- ii -
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`Hospira, Exh. 2006, p. 2
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`B. A Ready to Use Dexmedetomidine Composition in a Sealed Glass
`Container Would Not Have Been Obvious to a POSA Based on the
`Prior Art ............................................................................................... 54
`1.
`A Ready to Use Dexmedetomidine Composition Would Not
`Have Been Obvious to a POSA on January 4, 2012 Based on
`the 2010 Label and/or the ʼ867 Patent ...................................... 54
`A Ready to Use Dexmedetomidine Composition Would Not
`Have Been Obvious to a POSA on January 4, 2012 in View of
`Giorgi and/or Eichhorn ............................................................. 55
`It Would Not Have Been Obvious to a POSA to Create a Ready
`to Use Dexmedetomidine Composition Based on Lavoisier .... 63
`It Would Not Have Been Obvious to a POSA on January 4, 2012 to
`Store a Ready to Use Dexmedetomidine Composition for Parenteral
`Administration in a Sealed Glass Container ....................................... 67
`VII. CONCLUSION .............................................................................................. 71
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`2.
`
`3.
`
`C.
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`- iii -
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`Hospira, Exh. 2006, p. 3
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`LIST OF EXHIBITS
`
`Exhibit Document
`
`1002 Declaration of Dr. James Cain.
`
`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”).
`
`1016
`
`1017
`
`1018
`
`1019
`
`1028
`
`1029
`
`1039
`
`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”).
`
`Paula Youngberg Webb, et al. “The Keys to RTU Parenterals,”
`Pharmaceutical Formulation & Quality, Vol. 11, No. 5, p. 40, September
`2009.
`
`“Parenteral Preparations”, Ch. 84, p. 1469, Remington’s Pharmaceutical
`Sciences 16th Edition (1980).
`
`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).
`
`1044
`
`“Injectable medicines,” WHO Collaborating Centre for Pharmaceutical
`Pricing and Reimbursement Policies,
`
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`- iv -
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`Hospira, Exh. 2006, p. 4
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`http://whocc.goeg.at/Glossary/PreferredTerms.
`1046 A. Desai and Mary Lee, “Gibaldi’s Drug Delivery Systems,” American
`Society of Health-System Pharmacists, Bethesda (2007).
`
`2001 U.S. Patent No. 8,242,158 (“the ʼ158 Patent”).
`
`2002 U.S. Patent No. 8,338,470 (“the ʼ470 Patent”).
`
`2003 U.S. Patent No. 8,455,527 (“the ʼ527 Patent”).
`
`2004 U.S. Patent No. 8,648,106 (“the ʼ106 Patent”).
`2010 C.E. Blogg, M.A.E. Ramsay, and J.D. Jarvis, “Infection Hazard from
`Syringes,” Br. J. Anaesth., 46, pp. 260-262 (1974).
`2016 Webb, P. et al., “Ensure Safety, Efficacy of Ready-to-Use IV Drug
`Products,” PFQ Vol. 11, No. 6, Oct./Nov. 2009.
`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.
`
`
`2022
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`2023
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`2024
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`- v -
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`Hospira, Exh. 2006, p. 5
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`

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`I, Michael Ramsay, declare as follows:
`
`(1)
`
`I make this declaration based upon my own personal knowledge and,
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`if called upon to testify, would testify competently to the matters contained herein.
`
`(2)
`
`I have been asked by Baker Botts, LLP on behalf of Hospira, Inc. to
`
`provide technical assistance in the inter partes review of U.S. Patent Nos.
`
`8,242,158 (“the ʼ158 Patent”); 8,338,470 (“the ʼ470 Patent”); 8,455,527 (“the ʼ527
`
`Patent”); and 8,648,106 (“the ʼ106 Patent”) (collectively, the “Premix Patents”).
`
`(3) This declaration is a statement of my opinions on issues related to the
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`patentability of the claims of the ʼ158 Patent (claims 1-4), the ʼ470 Patent (claims
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`1-7), the ʼ527 Patent (claims 1-11 and 13), and the ʼ106 Patent (claims 1-9).
`
`I.
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`BACKGROUND AND QUALIFICATIONS
`(4)
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`I am an expert in the field of anesthetics and sedation. In formulating
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`my opinions, I have relied upon my knowledge, training, and experience in the
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`relevant art. A complete listing of my qualifications is stated more fully in my
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`curriculum vitae. See Ex. A. Here, I provide a brief summary of my
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`qualifications.
`
`(5)
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`I have over 45 years of experience working in the medical field as an
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`anesthesiologist. A significant amount of my practice has been devoted to
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`anesthetics and patient safety in the context of intensive care and transplantations.
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`Early in my career, I developed the Ramsay Sedation Scale, which is a widely-used
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`- 1 -
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`Hospira, Exh. 2006, p. 6
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`sedation scoring system for intensive care patients. I am very familiar with drugs
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`that are used for sedation in intensive care units.
`
`(6)
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`I am currently
`
`the Chief of Service of
`
`the Department of
`
`Anesthesiology and Pain Management at Baylor University Medical Center. I am
`
`also the Medical Director of Anesthesia Services, Director of Anesthesia Resident
`
`Education, and Director of Anesthesia for Organ Transplantation at Baylor
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`Medical Center. I am also the President of the Baylor Research Institute.
`
`(7) After receiving my medical degree from The London Hospital
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`Medical College in 1968, I spent six years completing anesthetics residences and
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`fellowships in England, including a fellowship at The Hospital for Sick Children in
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`London. I then worked as a Consultant Anesthesiologist and Anesthesia Instructor
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`for hospitals and clinics in London and Sweden, with six months of that time being
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`spent in the Pediatric Anesthesia and Intensive Care department at the Gothenburg
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`Children’s Hospital in Sweden. I was recruited by the Anesthesiology and Pain
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`Management Department of Baylor Medical Center in 1976, and I have been the
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`department’s Chief of Service since 1989.
`
`(8)
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`In addition to my work at Baylor, I also serve as a Consulting
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`Anesthesiologist for several other medical centers in the Dallas area, including
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`Texas Health Presbyterian Hospital, Parkland Memorial Hospital, and Baylor Jack
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`and Jane Hamilton Heart and Vascular Hospital (for which I am also the Medical
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`- 2 -
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`Hospira, Exh. 2006, p. 7
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`Director of Anesthesia Services). Until recently, I also served as a Consulting
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`Anesthesiologist for Children’s Health (Children’s Medical Center Dallas). I am
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`also a Clinical Professor in the Department of Anesthesiology and Pain
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`Management for the University of Texas Southwestern Medical Center since 1989.
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`I am also a Professor with Texas A&M Health Science Center’s College of
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`Medicine Affiliate Faculty.
`
`(9)
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`I am currently a member of the American Society of Anesthesiologists
`
`Committee on Transplant Anesthesia, and am also on the Board of Directors for
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`The Patient Safety Movement Foundation. I am also a member of the Society of
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`Critical Care Medical Task Force, which I was invited to join for the purpose of
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`developing Guidelines for Pain, Agitation and Delirium in the ICU, which were
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`completed in 2013.
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`(10) I have received several awards for my achievements in anesthesiology
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`and for my contributions to patient safety and critical care medicine, including a
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`Lifetime Achievement Award by the Dallas County Anesthesiology Society in
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`2010.
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`(11) I have published hundreds of articles, abstracts, textbook chapters, and
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`presentations in the field of anesthesiology and intensive care treatment. See Ex. A.
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`(12) I have also studied and worked extensively with dexmedetomidine. In
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`addition to publishing articles on the drug, I have given presentations in several
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`- 3 -
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`Hospira, Exh. 2006, p. 8
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`countries across the world on the use of dexmedetomidine as a sedative,
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`specifically its use in critical care settings, and as an anesthetic agent.
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`II. LEGAL UNDERSTANDING
`(13) My opinions are also formed by my understanding of the relevant law.
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`I understand that patentability of a patent is analyzed on a claim-by-claim basis,
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`from the perspective of a hypothetical person of ordinary skill in the art (“POSA”).
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`(14) I understand that earlier publications and patents, which may be
`
`referred to as “prior art,” may act to render a patent unpatentable for one of two
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`reasons: (a) anticipation, and (b) obviousness. I further understand that the prior
`
`art must be viewed from the perspective of a POSA at the time of the invention.
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`A. Level of a Person of Ordinary Skill in the Art
`(15) I understand that I must undertake my assessment of the claims of the
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`Premix Patents from the perspective of what would have been known or
`
`understood by a POSA as of the earliest-claimed priority date. I understand that the
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`earliest claimed priority date for the Premix Patents is January 4, 2012.
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`Accordingly, the opinions and statements that I provide herein regarding the
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`Premix Patents and the cited references are made from the perspective of a POSA
`
`on January 4, 2012.
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`(16) I understand that, to determine the appropriate level of ordinary skill
`
`in the art, I may consider the following factors: (a) the types of problems
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`- 4 -
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`Hospira, Exh. 2006, p. 9
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`encountered in the art; (b) prior art solutions to those problems; (c) the rapidity
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`with which innovations are made in the field; (d) the sophistication of the
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`technology in question; and (e) the educational level of active workers in the field.
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`I further understand that the actual inventor’s level of skill is not determinative of
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`the level of ordinary skill.
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`B. Claim Construction
`(17) I understand that before claims may be analyzed for anticipation or
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`obviousness based on the prior art, the scope of the claims must be defined. I
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`understand that when the definition of a claim term is in dispute, it will be defined
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`through a process called “claim construction.”
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`(18) I understand that this proceeding is an inter partes review (“IPR”)
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`proceeding before the Patent Trial and Appeal Board (“PTAB”). I understand that,
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`in an IPR proceeding, claim terms are given their “broadest reasonable
`
`construction” in light of the patent specification. I understand that claim terms are
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`generally given their ordinary and customary meaning, which is the meaning that
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`the term would have to a POSA at the time of the invention, consistent with the
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`broadest reasonable construction. I also understand that the claim construction in
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`patent litigation in a United States District Court could be under a different
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`standard than that used before the PTAB.
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`Hospira, Exh. 2006, p. 10
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`C. Anticipation
`(19) I understand that a single prior art reference, article, patent or
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`publication “anticipates” a claim if each and every element of the claim is
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`disclosed in that prior art reference. I further understand that, where a claim
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`element is not explicitly disclosed in a prior art reference, the reference may
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`nonetheless anticipate a claim if the missing claim element is necessarily present in
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`the apparatus or a natural result of the method disclosed—i.e., the missing element
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`is “inherent.” I further understand that an IPR petition constitutes a challenge to
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`the patentability of one or more claims of a patent based on earlier publications and
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`patents.
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`(20) I understand that, in the current matter, Amneal Pharmaceuticals (the
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`“Petitioner”) has not challenged any claim in the Premix Patents as unpatentable
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`based on anticipation.
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`D. Obviousness
`(21) I understand that the prior art may render a patent claim “obvious.” I
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`understand that one or more prior art references (e.g., articles, patents, or other
`
`publications) that individually disclose fewer than all elements of a patent claim
`
`may nevertheless be relied upon to render a patent claim obvious if the claimed
`
`invention would have been obvious to a POSA based on the collective teachings of
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`the prior art and the knowledge of a POSA at the time of the invention.
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`- 6 -
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`Hospira, Exh. 2006, p. 11
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`(22) I understand that a claim may be deemed invalid for obviousness in
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`light of a single prior art reference, without the need to combine references, if the
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`elements of the claim that are not found in the reference can be supplied by the
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`knowledge or common sense of one of ordinary skill in the relevant art.
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`(23) I understand that a claim may be obvious in light of multiple prior art
`
`references that disclose the claim elements if a POSA would have been motivated
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`to combine the references in a manner that would result in the claimed invention or
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`render it obvious. I understand that this motivation to combine need not be explicit
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`in any of the prior art, but may be inferred from the knowledge of a POSA at the
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`time the patent was filed.
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`(24) I further understand that a claim may be obvious where fewer than all
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`of the elements of the claim are disclosed by the prior art references if including
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`the missing element would have been obvious to a POSA (e.g., the missing
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`element represents only an insubstantial difference over the prior art or a
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`reconfiguration of a known system).
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`(25) I understand that obviousness is based on the scope and content of the
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`prior art, the differences between the prior art and the claim, the level of ordinary
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`skill in the art, and secondary indications of obviousness and non-obviousness to
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`the extent they exist. Under the doctrine of obviousness, a claim may be invalid if
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`the differences between the invention and the prior art are such that the subject
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`- 7 -
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`Hospira, Exh. 2006, p. 12
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`matter as a whole would have been obvious at the time the invention was made to a
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`POSA.
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`(26) I understand that secondary indications of both obviousness and non-
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`obviousness should be considered when evaluating whether a claimed invention
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`would have been obvious to one of ordinary skill at the time of invention. I
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`understand that there must be a relationship between any secondary indications and
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`the claimed invention. These secondary indications of non-obviousness may
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`include, for example:
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`
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`a long felt but unmet need in the prior art that was satisfied by the
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`claimed invention;
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`
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`
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`
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`
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`
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`commercial success of processes claimed by the patent;
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`unexpected results achieved by the invention;
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`praise of the invention by others skilled in the art;
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`the taking of licenses under the patent by others; and
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`deliberate copying of the invention.
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`(27) It is also my understanding that there are additional considerations
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`that may be taken into account when evaluating whether a claim is obvious,
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`including whether:
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`
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`the claimed invention is simply a combination of prior art elements
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`according to known methods to yield predictable results;
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`- 8 -
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`Hospira, Exh. 2006, p. 13
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`
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`the claimed invention is a simple substitution of one known element
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`for another to obtain predictable results;
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`
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`the claimed invention uses known techniques to improve similar
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`devices or methods in the same way;
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`
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`the claimed invention applies a known technique to a known device or
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`method that is ready for improvement to yield predictable results;
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`
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`the claimed invention would have been “obvious to try” choosing
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`from a finite number of identified, predictable solutions, with a reasonable
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`expectation of success;
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`
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`there is known work in one field of endeavor that may prompt
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`variations of it for use in either the same field or a different one based on
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`design incentives or other market forces if the variations would have been
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`predictable to one of ordinary skill in the art;
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`
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`there existed at the time of invention a known problem for which there
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`was an obvious solution encompassed by the patent’s claims; and
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`
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`there is some teaching, suggestion, or motivation in the prior art that
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`would have led one of ordinary skill to modify the prior art reference or to
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`combine prior art reference teachings to arrive at the claimed invention.
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`- 9 -
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`Hospira, Exh. 2006, p. 14
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`(28) I understand that all challenges to the claims of the Premix Patents are
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`based on assertions that the claims are obvious in light of two or more prior art
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`references.
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`III. BACKGROUND OF THE TECHNOLOGY
`A.
`State of the Art
`(29) Dexmedetomidine is an α2-adrenergic receptor agonist having the
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`chemical formula: (S)-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole.
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`(30) α2-adrenergic receptor agonists are drugs that bind to and activate α2-
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`adrenergic receptors, which are primarily located in structures throughout the
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`central nervous system (CNS).
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`(31) While there are different subtypes of α2-adrenergic receptors and the
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`mechanisms of action for these receptors are not fully understood, activation of α2-
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`adrenergic receptors modulates the release of norepinephrine from sympathetic
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`nerve endings, and has been shown to result in sedation and analgesia, as well as
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`reduced heart rate and blood pressure.
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`(32) The sedative effects of α2-adrenergic receptor activation (e.g., by
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`receptor agonists) is attributed to a particular region of the CNS called the locus
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`coeruleus, which is located in the brain stem and contains one of the highest
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`densities of α2-adrenergic receptors. The locus coeruleus is involved with a
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`- 10 -
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`Hospira, Exh. 2006, p. 15
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`person’s physiological responses to stress and anxiety, and also plays a central role
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`in the regulation of arousal, the sleep-wake cycle, and cognitive control.
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`(33) Dexmedetomidine is a unique drug among other α2-adrenergic
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`receptor agonist drugs in that it has shown to be an extremely potent sedative and
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`analgesic, but also result in less delirium, greater cognitive awareness, and less
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`depressed respiration as compared to other sedatives. These unique properties of
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`dexmedetomidine have been attributed to greater specificity for the α2-adrenergic
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`receptor, and direct action on the α2-adrenergic receptors in the locus coeruleus.
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`(34) Dexmedetomidine is the active enantiomer form in medetomidine,
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`which is a racemic mixture comprised of two enantiomers: dexmedetomidine and
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`levomedetomidine. Medetomidine is a synthetic drug that is known for its use as
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`an anesthetic and analgesic in veterinary medicine. I am unaware of any
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`medetomidine pharmaceutical formulations that are directed for use in humans.
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`(35) A pharmaceutical dexmedetomidine hydrochloride solution was
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`developed years ago as an injectable sedative in humans. It was granted FDA
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`approval in 1999 for short-term sedation of ICU patients via continuous infusion,
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`and was later approved for use in non-intubated patients prior to and/or during
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`surgical and other procedures. Pharmaceutical dexmedetomidine is marketed under
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`the trade name Precedex®.
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`- 11 -
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`Hospira, Exh. 2006, p. 16
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`(36) Dexmedetomidine is administered as a continuous infusion, wherein a
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`certain quantity of drug for an individual of a given weight is administered over a
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`period of minutes or hours.
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`(37) For more than a decade after its initial approval, dexmedetomidine
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`(Precedex®) was only available as a concentrated solution of 100 mcg/mL which
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`required dilution prior to administration.
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`(38) In 2013, a 4 mcg/mL composition comprising dexmedetomidine
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`hydrochloride became available under the Precedex® brand. I understand the
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`Premix Patents are listed in the FDA’s Orange Book for approved drug products as
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`covering the 4 mcg/mL Precedex® product.
`
`B.
`Subject Matter of the Patents
`(39) I have reviewed the Premix Patents. The ʼ158 Patent, ʼ470 Patent,
`
`and ʼ106 Patent are all entitled “Dexmedetomidine Premix Formulation.” See Ex.
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`2001, Ex. 2002, and Ex. 2004. The ʼ527 Patent is entitled “Methods of Treatment
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`Using a Dexmedetomidine Premix Formulation.” See Ex. 2003.
`
`(40) I understand that the Premix Patents all claim priority to the January
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`4, 2012 priority date and are related to one another. The ʼ158 Patent was filed on
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`January 4, 2012, and issued August 14, 2012. The ʼ470 Patent was filed on July 3,
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`2012 as a continuation of the application that issued as the ʼ158 Patent, and issued
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`on December 25, 2012. The ʼ527 Patent was filed on November 15, 2012 as a
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`- 12 -
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`Hospira, Exh. 2006, p. 17
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`continuation of the application that issued as the ʼ470 Patent, and issued on June 4,
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`2013. Finally, the ʼ106 Patent was filed on April 22, 2013 as a continuation U.S.
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`Application No. 13/678,260, which is a continuation of the ʼ470 Patent and issued
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`as U.S. Patent No. 8,436,033 on May 7, 2013 (“the ʼ033 Patent”). The ʼ106 Patent
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`issued on February 11, 2014.
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`(41) The Premix Patents relate to ready to use liquid pharmaceutical
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`compositions of dexmedetomidine. The compositions disclosed in the Premix
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`Patents are ready to use compositions of dexmedetomidine, or a pharmaceutically
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`acceptable salt thereof, which are formulated to be suitable for administration to a
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`patient upon manufacture without dilution or reconstitution. These compositions
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`are distinguishable from a previously marketed dexmedetomidine composition,
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`which was sold under the brand name Precedex®, in that the previous formulation
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`was manufactured at a concentration of 100 mcg/mL and required dilution prior to
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`administration to a patient.
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`(42) The ʼ158 Patent has 4 claims, including a single independent claim
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`and 3 dependent claims. Claim 1, the single independent claim, is directed to a
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`“ready to use liquid pharmaceutical composition for parenteral administration to a
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`subject, comprising dexmedetomidine or a pharmaceutically acceptable salt thereof
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`at a concentration of about 4 mcg/mL disposed within a sealed glass container.”
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`Because claims 2-4 depend from claim 1 of the ʼ158 Patent, I understand that each
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`- 13 -
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`Hospira, Exh. 2006, p. 18
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`claim of the ʼ158 Patent is directed to a dexmedetomidine composition that (a) is
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`“ready to use,” (b) has a concentration of 4 mcg/mL, and (c) is disposed in a sealed
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`glass container.
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`(43) Claim 2 of the ʼ158 Patent is directed to a composition of claim 1, but
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`further requires that the composition comprise sodium chloride at a concentration
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`between about 0.01% and about 2.0% by weight. Claim 3 of the ʼ158 Patent is
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`directed to a composition of claim 2, but further narrows the concentration of
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`sodium chloride to about 0.9% by weight.
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`(44) Claim 4 of the ʼ158 Patent is directed to the composition of claim 1,
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`wherein the composition is formulated in a solution that has a total volume of 20
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`mL, 50 mL, or 100 mL.
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`(45) The ʼ470 Patent has 7 claims, including a single independent claim
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`and 6 dependent claims. Claim 1, the single independent claim, is directed to a
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`“ready to use liquid pharmaceutical composition for parenteral administration to a
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`subject, comprising dexmedetomidine or a pharmaceutically acceptable salt thereof
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`at a concentration of about 0.005 to about 50 mcg/mL disposed within a sealed
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`glass container.” Because claims 2-7 depend from claim 1 of the ʼ470 Patent, I
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`understand that each claim of the ʼ470 Patent is directed to a dexmedetomidine
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`composition that (a) is “ready to use,” (b) has a concentration of about 0.005 to
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`about 50 mcg/mL, and (c) is disposed in a sealed glass container.
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`- 14 -
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`Hospira, Exh. 2006, p. 19
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`(46) Claim 2-4 of the ʼ470 Patent are directed to the composition of claim
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`1, but each of claims 2-4 further narrow the concentration of dexmedetomidine in
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`the composition to about “0.05 to about 15 mcg/mL,” about “0.5 to about 10
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`mcg/mL,” and “about 1 to about 7 mcg/mL,” respectively.
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`(47) Claim 5 of the ʼ470 Patent is directed to a composition of claim 1, but
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`further requires that the composition comprise sodium chloride at a concentration
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`between about 0.01% and about 2.0% by weight. Claim 6 of the ʼ470 Patent is
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`directed to a composition of claim 5, but further narrows the concentration of
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`sodium chloride to about 0.9% by weight.
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`(48) Claim 7 of the ʼ470 Patent is directed to the composition of claim 1,
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`wherein the composition is formulated in a solution that has a total volume of 20
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`mL, 50 mL, or 100 mL.
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`(49) The ʼ527 Patent has 15 total claims, including a single independent
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`claim and 14 dependent claims. Claim 1, the single independent claim, is directed
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`to a “method of providing sedation to a patient in need thereof, the method
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`comprising administering to the patient an effective amount of a composition,
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`wherein the composition comprises dexmedetomidine or a pharmaceutically
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`acceptable salt thereof at a concentration of about 0.0005 to about 50 mcg/mL,
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`wherein the composition is a ready to use liquid pharmaceutical composition for
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`parenteral administration to the patient disposed within a sealed glass container.”
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`- 15 -
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`Hospira, Exh. 2006, p. 20
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`Because claims 2-15 depend from claim 1 of the ʼ527 Patent, I understand that
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`each claim of the ʼ470 Patent is directed to a method of providing sedation to a
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`patient by administering a dexmedetomidine composition that (a) is “ready to use,”
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`(b) has a concentration of about 0.005 to about 50 mcg/mL, and (c) is disposed in a
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`sealed glass container.
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`(50) Claim 2-4 of the ʼ527 Patent are directed to the composition of claim
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`1, but the claims further narrow the concentration of dexmedetomidine in the
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`administered composition to “about 0.05 to about 15 mcg/mL,” “about 0.5 to about
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`10 mcg/mL,” and “about 1 to about 7 mcg/mL,” respectively.
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`(51) Claim 5 of the ʼ527 Patent is directed to the composition of claim 1,
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`wherein the concentration of dexmedetomidine is about 4 mcg/mL.
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`(52) Claim 6 of the ʼ527 Patent is directed to the method of claim 1,
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`wherein the composition is administered perioperatively, and claim 7 is directed to
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`the method of claim 6, wherein the composition is administered before or after
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`surgery.
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`(53) Claims 8-10 of the ʼ527 Patent are directed to the method of claim 1,
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`wherein the composition is administered to a patient under different conditions.
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`Specifically, claim 8 is directed to administration of the dexmedetomidine
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`composition to a patient in an intensive care unit; claim 9 is directed to
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`- 16 -
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`Hospira, Exh. 2006, p. 21
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`administration to a patient who is non-ventilated or intubated; and claim 10 is
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`directed to administration to a patient who is critically ill.
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`(54) Claims 11-15 of the ʼ527 Patent are directed to the method of claim 1,
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`wherein the composition is administered in a certain manner or for a particular
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`purpose. Specifically, claim 11 is directed to the method of claim 1, wherein the
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`composition is administered by an intravenous infusion. Claim 12 is directed to
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`the method of claim 1, wherein the composition is administered as an anxiolytic.
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`Claim 13 is directed to the method of claim 1, wherein the composition is
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`administered as an adjunct to an anesthetic. Finally, Claims 14-15 are directed to
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`the method of claim 1, wherein the composition is administered as an analgesic
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`and an anti-hypertensive agent, respectively.
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`(55) The ʼ106 Patent has 9 total claims, including a single independent
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`claim and 8 dependent claims. Claim 1, the single independent claim, is directed
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`to a “ready to use liquid pharmaceutical composition for parenteral administration
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`to a subject, comprising dexmedetomidine or a pharmaceutically acceptable salt
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`thereof disposed within a sealed glass container, wherein the liquid pharmaceutical
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`composition when stored in the glass container for at least five months exhibits no
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`more than about 2% decrease in the concentration of dexmedetomidine.” Because
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`claims 2-9 depend from claim 1 of the ʼ106 Patent, I understand that each claim of
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`the ʼ106 Patent is directed to a dexmedetomidine composition that (a) is “ready to
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`- 17 -
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`Hospira, Exh. 2006, p. 22
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`use,” (b) is disposed in a sealed glass container, and (c) exhibits no more than 2%
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`decrease in concentration after five months of storage in the sealed glass container.
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`(56) Claim 2-5 of the ʼ106 Patent are directed to the composition of claim
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`1, but the claims successively narrow the concentration of dexmedetomidine in the
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`composition to “about 0.005 to about 50 mcg/mL,” “about 0.05 to about 15
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`mcg/mL,” “about 0.5 to about 10 mcg/mL,” and “about 1 to about 7 mcg/mL,”
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`respectively.
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`(57) Claim 6 of the ʼ106 Patent is directed to the composition of claim 1,
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`wherein the concentration of dexmedetomidine is about 4 mcg/mL.
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`(58) Claim 7 of