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. ROBERT LINHARDT
`
`
`
`
`
`Hospira, Exh. 2005, p. 1
`
`

`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`BACKGROUND AND QUALIFICATIONS ................................................. 1
`
`LEGAL UNDERSTANDING ......................................................................... 2
`
`A.
`
`B.
`
`Level of a Person of Ordinary Skill in the Art ...................................... 3
`
`Claim Construction ............................................................................... 3
`
`C. Anticipation ........................................................................................... 4
`
`D. Obviousness ........................................................................................... 5
`
`III. BACKGROUND OF THE TECHNOLOGY .................................................. 8
`
`A.
`
`B.
`
`State of the Art ...................................................................................... 8
`
`Subject Matter of the Patents .............................................................. 10
`
`IV. CLAIM CONSTRUCTION .......................................................................... 14
`
`A.
`
`B.
`
`C.
`
`Level of a Person of Skill in the Art ................................................... 14
`
`“Ready to Use” .................................................................................... 15
`
`“Dexmedetomidine” ............................................................................ 17
`
`V.
`
`SUMMARY OF THE PRIOR ART .............................................................. 18
`
`A.
`
`B.
`
`2010 Label ........................................................................................... 18
`
`Palmgren .............................................................................................. 18
`
`C. Giorgi ................................................................................................... 21
`
`D.
`
`E.
`
`Eichhorn .............................................................................................. 22
`
`Lavoisier .............................................................................................. 24
`
`VI. OPINIONS ..................................................................................................... 24
`
`A. A Ready to Use Dexmedetomidine Composition Would Not Have
`Been Obvious to a POSA Based on the Prior Art as of January 4, 2012
` ............................................................................................................. 24
`
`
`
`- ii -
`
`Hospira, Exh. 2005, p. 2
`
`

`
`1.
`
`2.
`
`3.
`
`A Ready to Use Dexmedetomidine Composition Would Not
`Have Been Obvious to a POSA Based on the 2010 Label ....... 26
`Dr. Cain’s Stored Dilutions of Concentrated Precedex® Are Not
`“Ready to Use” Dexmedetomidine Compositions ................... 35
`
`It Would Not Have Been Obvious to a POSA on January 4,
`2012 to Make a Ready to Use Dexmedetomidine Composition
`Based on Giorgi and/or Eichhorn ............................................. 39
`
`B.
`
`It Would Not Have Been Obvious to a POSA as of January 4, 2012 to
`Store a Ready to Use Dexmedetomidine Formulation in a Sealed
`Glass Container ................................................................................... 45
`
`1.
`
`2.
`
`3.
`
`4.
`
`It Would Not Have Been Obvious to a POSA to Store a Ready
`to Use Dexmedetomidine Composition in a Sealed Glass
`Container Based on the 2010 Label .......................................... 47
`
`It Would Not Have Been Obvious to a POSA to Store a Ready
`to Use Dexmedetomidine Composition in a Sealed Glass
`Container Based on Palmgren ................................................... 52
`
`It Would Not Have Been Obvious to a POSA on January 4,
`2012 to Store a Ready to Use Dexmedetomidine Composition
`in a Sealed Glass Container ...................................................... 58
`
`The Results Described in the Wu Declaration Would Have
`Been Surprising to a POSA on January 4, 2012 ....................... 64
`
`VIII. CONCLUSION .............................................................................................. 67
`
`
`
`- iii -
`
`
`
`
`
`Hospira, Exh. 2005, p. 3
`
`

`
`Exhibit
`
`LIST OF EXHIBITS
`
`Document
`
`1007
`
`2010 Precedex® Label (“the 2010 Label”).
`
`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
`
`1025
`
`1026
`
`1027
`
`1028
`
`1044
`
`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, 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.
`
`“Injectable medicines,” WHO Collaborating Centre for Pharmaceutical
`Pricing and Reimbursement Policies,
`http://whocc.goeg.at/Glossary/PreferredTerms.
`
`
`
`- iv -
`
`Hospira, Exh. 2005, p. 4
`
`

`
`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”).
`
`2008
`
`“Guidance for Industry: Drug Stability Guidelines,” FDA Center for
`Veterinary Medicine, p. 26, Dec. 2008.
`
`2009
`
`2014
`
`2015
`
`“Guidance for Industry: Q1A (R2) Stability Testing of New Drug
`Substances and Products,” FDA Center for Drug Evaluation and
`Research, p. 10, Nov. 2003.
`Speaker, T.J. et al., “A Study of the Interaction of Selected Drugs and
`2011
`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.
`2013
`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).
`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.
`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.
`
`2017
`
`2024
`
`
`
`- v -
`
`Hospira, Exh. 2005, p. 5
`
`

`
`2025
`
`2026
`
`2027
`
`KetalarTM Label (ketamine hydrochloride injection), Mar. 2012, p. 4,
`available at
`http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/016812s039l
`bl.pdf.
`AlkeranTM Label, June 2007, available at
`http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020207s017l
`bl.pdf.
`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.
`
`- vi -
`
`
`
`
`
`Hospira, Exh. 2005, p. 6
`
`

`
`
`
`
`
`I, Robert Linhardt, declare as follows:
`
`(1)
`
`I make this declaration based upon my own personal knowledge and,
`
`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
`
`patentability of the claims of the ʼ158 Patent (claims 1-4), the ʼ470 Patent (claims
`
`1-7), the ʼ527 Patent (claims 1-11 and 13), and the ʼ106 Patent (claims 1-9).
`
`I.
`
`BACKGROUND AND QUALIFICATIONS
`
`(4)
`
`I am an expert in formulation chemistry and pharmaceutical
`
`development. In formulating my opinions, I have relied upon my knowledge,
`
`training, and experience in the relevant art. A complete listing of my
`
`qualifications, including a list of my patents, is stated more fully in my curriculum
`
`vitae. See Ex. A. Here I provide a brief summary of my qualifications.
`
`(5)
`
`I have a B.S. in Chemistry from Marquette University, and an M.A.
`
`and Ph.D. in Organic Chemistry from the Johns Hopkins University. I also
`
`completed a Postdoctoral fellowship
`
`in Biochemical Engineering at
`
`the
`
`Massachusetts Institute of Technology.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`- 1 -
`
`Hospira, Exh. 2005, p. 7
`
`

`
`(6)
`
`I am currently a Professor of Chemistry, Biology, Chemical and
`
`Biological Engineering, and Biomedical Engineering at Rensselaer Polytechnic
`
`Institute. I have held this position for the last 13 years. I also work as an Adjunct
`
`Professor of Pharmaceutical Sciences at Albany College of Pharmacy, and as
`
`Adjunct Professor of Orthopedics at Mount Sinai Medical School. I have also
`
`been an industry consultant in the areas of biocatalysis, biopolymers, carbohydrate
`
`chemistry, and drug delivery since 1982.
`
`(7)
`
`Prior to joining the staff of Rensselaer Polytechnic Institute, I spent
`
`several years teaching Medicinal and Natural Products Chemistry at the University
`
`of Iowa’s College of Pharmacy. During that time, I taught courses relating to drug
`
`synthesis, formulation, delivery, and pharmacokinetics. In one of my courses,
`
`entitled “Medicinal and Natural Products Chemistry,” I taught a section that
`
`focused specifically on sedatives and hypnotics.
`
`II. LEGAL UNDERSTANDING
`
`(8) My opinions are also formed by my understanding of the relevant law.
`
`I understand that patentability of a patent is analyzed on a claim-by-claim basis,
`
`from the perspective of a hypothetical person of ordinary skill in the art (“POSA”).
`
`(9)
`
`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
`
`
`
`- 2 -
`
`Hospira, Exh. 2005, p. 8
`
`

`
`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.
`
`A. Level of a Person of Ordinary Skill in the Art
`
`(10)
`
` I understand that I must undertake my assessment of the claims of the
`
`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 earliest claimed priority date for the Premix Patents is January 4, 2012.
`
`Accordingly, the opinions and statements that I provide herein regarding the
`
`Premix Patents and the cited references are made from the perspective of a POSA
`
`on January 4, 2012.
`
`(11) 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
`
`encountered in the art; (b) prior art solutions to those problems; (c) the rapidity
`
`with which innovations are made in the field; (d) the sophistication of the
`
`technology in question; and (e) the educational level of active workers in the field.
`
`I further understand that the actual inventor’s level of skill is not determinative of
`
`the level of ordinary skill.
`
`B. Claim Construction
`
`(12) I understand that before claims may be analyzed for anticipation or
`
`obviousness based on the prior art, the scope of the claims must be defined. I
`
`
`
`- 3 -
`
`Hospira, Exh. 2005, p. 9
`
`

`
`understand that when the definition of a claim term is in dispute, it will be defined
`
`through a process called “claim construction.”
`
`(13) I understand that this proceeding is an inter partes review (“IPR”)
`
`proceeding before the Patent Trial and Appeal Board (“PTAB”). I understand that,
`
`in an IPR proceeding, claim terms are given their “broadest reasonable
`
`construction” in light of the patent specification. I understand that claim terms are
`
`generally given their ordinary and customary meaning, which is the meaning that
`
`the term would have to a POSA at the time of the invention, consistent with the
`
`broadest reasonable construction. I also understand that the claim construction in
`
`patent litigation in a United States District Court could be under a different
`
`standard than that used before the PTAB.
`
`C. Anticipation
`
`(14) I understand that a single prior art reference, article, patent or
`
`publication “anticipates” a claim if each and every element of the claim is
`
`disclosed in that prior art reference. I further understand that, where a claim
`
`element is not explicitly disclosed in a prior art reference, the reference may
`
`nonetheless anticipate a claim if the missing claim element is necessarily present in
`
`the apparatus or a natural result of the method disclosed—i.e., the missing element
`
`is “inherent.” I further understand that an IPR petition constitutes a challenge to the
`
`
`
`- 4 -
`
`Hospira, Exh. 2005, p. 10
`
`

`
`patentability of one or more claims of a patent based on earlier publications and
`
`patents.
`
`(15) I understand that, in the current matter, Amneal Pharmaceuticals (the
`
`“Petitioner”) has not challenged any claim in the Premix Patents as unpatentable
`
`based on anticipation.
`
`D. Obviousness
`
`(16) I understand that the prior art may render a patent claim “obvious.” I
`
`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
`
`the prior art and the knowledge of a POSA at the time of the invention.
`
`(17) I understand that a claim may be deemed invalid for obviousness in
`
`light of a single prior art reference, without the need to combine references, if the
`
`elements of the claim that are not found in the reference can be supplied by the
`
`knowledge or common sense of one of ordinary skill in the relevant art.
`
`(18) 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
`
`to combine the references in a manner that would result in the claimed invention or
`
`render it obvious. I understand that this motivation to combine need not be explicit
`
`
`
`- 5 -
`
`Hospira, Exh. 2005, p. 11
`
`

`
`in any of the prior art, but may be inferred from the knowledge of a POSA at the
`
`time the patent was filed.
`
`(19) I further understand that a claim may be obvious where fewer than all
`
`of the elements of the claim are disclosed by the prior art references if including
`
`the missing element would have been obvious to a POSA (e.g., the missing
`
`element represents only an insubstantial difference over the prior art or a
`
`reconfiguration of a known system).
`
`(20) I understand that obviousness is based on the scope and content of the
`
`prior art, the differences between the prior art and the claim, the level of ordinary
`
`skill in the art, and secondary indications of obviousness and non-obviousness to
`
`the extent they exist. Under the doctrine of obviousness, a claim may be invalid if
`
`the differences between the invention and the prior art are such that the subject
`
`matter as a whole would have been obvious at the time the invention was made to a
`
`POSA.
`
`(21) I understand that secondary indications of both obviousness and non-
`
`obviousness should be considered when evaluating whether a claimed invention
`
`would have been obvious to one of ordinary skill at the time of invention. I
`
`understand that there must be a relationship between any secondary indications and
`
`the claimed invention. These secondary indications of non-obviousness may
`
`include, for example:
`
`
`
`- 6 -
`
`Hospira, Exh. 2005, p. 12
`
`

`
`
`
`a long felt but unmet need in the prior art that was satisfied by the
`
`claimed invention;
`
`
`
`
`
`
`
`
`
`
`
`commercial success of processes claimed by the patent;
`
`unexpected results achieved by the invention;
`
`praise of the invention by others skilled in the art;
`
`the taking of licenses under the patent by others; and
`
`deliberate copying of the invention.
`
`(22) It is also my understanding that there are additional considerations
`
`that may be taken into account when evaluating whether a claim is obvious,
`
`including whether:
`
`
`
`the claimed invention is simply a combination of prior art elements
`
`according to known methods to yield predictable results;
`
`
`
`the claimed invention is a simple substitution of one known element
`
`for another to obtain predictable results;
`
`
`
`the claimed invention uses known techniques to improve similar
`
`devices or methods in the same way;
`
`
`
`the claimed invention applies a known technique to a known device or
`
`method that is ready for improvement to yield predictable results;
`
`
`
`- 7 -
`
`Hospira, Exh. 2005, p. 13
`
`

`
`
`
`the claimed invention would have been “obvious to try” choosing
`
`from a finite number of identified, predictable solutions, with a reasonable
`
`expectation of success;
`
`
`
`there is known work in one field of endeavor that may prompt
`
`variations of it for use in either the same field or a different one based on
`
`design incentives or other market forces if the variations would have been
`
`predictable to one of ordinary skill in the art;
`
`
`
`there existed at the time of invention a known problem for which there
`
`was an obvious solution encompassed by the patent’s claims; and
`
`
`
`there is some teaching, suggestion, or motivation in the prior art that
`
`would have led one of ordinary skill to modify the prior art reference or to
`
`combine prior art reference teachings to arrive at the claimed invention.
`
`(23) I understand that all challenges to the claims of the Premix Patents are
`
`based on assertions that the claims are obvious in light of two or more prior art
`
`references.
`
`III. BACKGROUND OF THE TECHNOLOGY
`
`A.
`
`State of the Art
`
`(24) Dexmedetomidine is an imidazole compound having the chemical
`
`formula: (S)-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole. Dexmedetomidine is
`
`used in medicine as a sedative agent.
`
`
`
`- 8 -
`
`Hospira, Exh. 2005, p. 14
`
`

`
`(25) Dexmedetomidine is one of two enantiomers that comprise the
`
`synthetic drug medetomidine, which I understand is used as a sedative in
`
`veterinary medicine. Medetomidine is a racemic mixture, which means that it is
`
`comprised of two compounds that are mirror images of one another (specifically, a
`
`“dextrorotary” form and a “levorotary” form). The two isomers that comprise
`
`medetomidine are dexmedetomidine and levomedetomidine. Dexmedetomidine
`
`and levomedetomidine are chiral molecules, meaning that their structures are non-
`
`superimposable mirror images of one another. Dexmedetomidine is referred to as
`
`the S-enantiomer form, and levomedetomidine is the R-enantiomer form.
`
`(26) A composition that is “optically pure” is one in which there is only
`
`one enantiomer component (either the S or the R form).
`
`(27) I understand that a pharmaceutical dexmedetomidine hydrochloride
`
`solution was developed several years ago as an injectable sedative in humans. It
`
`was granted initial FDA approval in 1999 and is approved for sedation of ICU
`
`patients via continuous infusion, as well as for sedation of non-intubated patients
`
`prior to and/or during surgical and other procedures. See Ex. 1007, p. 1.
`
`Pharmaceutical dexmedetomidine is marketed under the trade name Precedex®.
`
`(28) I understand that dexmedetomidine (Precedex®) was initially only
`
`available as a concentrated solution of 100 mcg/mL, which requires dilution prior
`
`to administration. Id.
`
`
`
`- 9 -
`
`Hospira, Exh. 2005, p. 15
`
`

`
`(29) I further understand that in 2013, the FDA approved a 4 mcg/mL
`
`dexmedetomidine composition, which is also marketed under the Precedex® brand.
`
`See FDA Approval Letter for Premix Formulation (March 13, 2013).1 I understand
`
`the Premix Patents are listed in the FDA’s Orange Book for approved drug
`
`products as covering the 4 mcg/mL Precedex® product.
`
`B.
`
`Subject Matter of the Patents
`
`(30) I have reviewed the Premix Patents, which relate to ready to use liquid
`
`pharmaceutical compositions of dexmedetomidine. The claims of the ʼ158 Patent,
`
`ʼ470 Patent, and ʼ106 Patent are all directed to ready to use compositions, and the
`
`claims of the ʼ527 Patent are directed to methods of sedating a patient by
`
`administering a ready to use composition. See Ex. 2001 (the ʼ158 Patent), Ex.
`
`2002 (the ʼ470 Patent), Ex. 2004 (the ʼ106 Patent), and Ex. 2003 (the ʼ527 Patent).
`
`I understand that all four patents have an effective filing date of January 4, 2012,
`
`because that is the date that the ʼ158 Patent was filed, and the other three patents
`
`claim priority to the ʼ158 Patent.
`
`(31) The ready to use compositions of the Premix Patents are ready to use
`
`compositions of dexmedetomidine, or a pharmaceutically acceptable salt thereof,
`
`that are formulated to be suitable for administration to a patient upon manufacture
`
`without dilution or reconstitution. Ready to use dexmedetomidine compositions
`
`1 Available at
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/021038Orig1s020.pdf.
`
`
`
`- 10 -
`
`Hospira, Exh. 2005, p. 16
`
`

`
`are distinguishable from the concentrated dexmedetomidine composition that
`
`received approval in 1999 in that the previous formulation is a 100 mcg/mL
`
`concentrated form that requires dilution to 4 mcg/mL prior to administration to a
`
`patient.
`
`(32) Claim 1 of the ʼ158 Patent is directed to 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 4 mcg/mL disposed within a sealed glass container.” Claims 2-4 of the
`
`ʼ158 Patent depend (directly or indirectly) from claim 1. Claims 2-3 of the ʼ158
`
`Patent require, in addition to the limitations of claim 1, that the ready to use
`
`composition comprise sodium chloride (at a concentration of between about 0.01%
`
`and 2% for claim 2, and in concentration of about 0.9% for claim 3), and claim 4
`
`requires that the ready to use composition comprise a total volume of 20 mL, 50
`
`mL, or 100 mL.
`
`(33) Claim 1 of the ʼ470 Patent is directed to 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 mcg/mL disposed within a sealed glass container.” Each
`
`of claims 2-7 of the ʼ470 Patent depends directly or indirectly from claim 1.
`
`Claims 2-4 narrow the concentration of dexmedetomidine in the claimed
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`Hospira, Exh. 2005, p. 17
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`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. Claims 5-6 add a
`
`limitation
`
`that
`
`the composition also comprises sodium chloride
`
`in
`
`the
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`concentrations specified in Claims 2-3 of the ʼ158 Patent (i.e., about 0.01-2.0% and
`
`about 0.9%, respectively). Claim 7 of the ʼ470 Patent requires that the
`
`composition comprise a total volume of 20 mL, 50 mL, or 100 mL.
`
`(34) Claim 1 of the ʼ527 Patent is directed to a “method of providing
`
`sedation to a patient in need thereof, the method comprising administering to the
`
`patient an effective amount of a composition, wherein the composition comprises
`
`dexmedetomidine or a pharmaceutically acceptable salt thereof at a concentration
`
`of about 0.005 to about 50 mcg/mL, wherein the composition is a ready to use
`
`liquid pharmaceutical composition for parenteral administration to the patient
`
`disposed within a sealed glass container.” Claims 2-15 depend directly or
`
`indirectly from claim 1. Claim 2-5 of the ʼ527 Patent are directed to the
`
`composition of claim 1, wherein the concentration of dexmedetomidine in the
`
`composition is “about 0.05 to about 15 mcg/mL,” “about 0.5 to about 10 mcg/mL,”
`
`“about 1 to about 7 mcg/mL,” and “about 4 mcg/mL,” respectively. Claims 6-11
`
`and 13 are directed to different contexts and circumstances under which the ready
`
`to use composition is administered, including perioperatively, before or after
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`
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`Hospira, Exh. 2005, p. 18
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`surgery, in an intensive care unit, to a non-ventilated or intubated patient, to a
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`critically ill patient, as an intravenous infusion, or as an adjunct to an anesthetic.
`
`(35) Claim 1 of the ʼ106 Patent is directed to a “ready to use liquid
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`pharmaceutical composition for parenteral administration to a subject, comprising
`
`dexmedetomidine or a pharmaceutically acceptable salt thereof disposed within a
`
`sealed glass container, wherein the liquid pharmaceutical composition when stored
`
`in the glass container for at least five months exhibits no more than about 2%
`
`decrease in the concentration of dexmedetomidine.” Claims 2-9 depend directly or
`
`indirectly from claim 1. Claims 2-6 are directed to the composition of claim 1,
`
`wherein the concentration of dexmedetomidine is “about 0.005 to about 50
`
`mcg/mL,” “about 0.05 to about 15 mcg/mL,” “about 0.5 to about 10 mcg/mL,”
`
`“about 1 to about 7 mcg/mL,” and “about 4 mcg/mL,” respectively. Claims 7-9
`
`add the same limitations of claims 2-4 of the ʼ158 Patent (i.e., the claims requiring
`
`that
`
`the composition further comprise sodium chloride at a particular
`
`concentration, or that the total volume of the composition be 20, 50, or 100 mL).
`
`(36) I understand that each challenged claim of the Premix Patents requires
`
`(a) a “ready to use” liquid pharmaceutical composition of dexmedetomidine, or a
`
`pharmaceutically acceptable salt thereof, for parenteral administration that is (b)
`
`disposed in a sealed glass container.
`
`
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`Hospira, Exh. 2005, p. 19
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`(37) I also understand that several claims in each of the Premix Patents are
`
`directed to ready to use pharmaceutical compositions of dexmedetomidine (or to
`
`methods of their use), which contain a concentration of dexmedetomidine within a
`
`specific range or at a particular amount. I understand that the claims, which
`
`include a limitation for a particular concentration of dexmedetomidine are directed,
`
`at their broadest, to a range of about 0.005 to about 50 mcg/mL, and at their
`
`narrowest, to about 4 mcg/mL.
`
`(38) I understand that each of the Premix Patents that are directed to ready
`
`to use compositions (i.e., the ʼ158, ʼ470, and ʼ106 Patents) contain claims directed
`
`to ready to use dexmedetomidine compositions in sealed glass containers, which
`
`further comprise sodium chloride at a concentration of between about 0.01 and
`
`about 2.0 weight percent, and about 0.9 weight percent. I further understand that
`
`each of these patents contain a claim directed to a ready to use dexmedetomidine
`
`composition that has a total volume of 20, 50, or 100 mL.
`
`IV. CLAIM CONSTRUCTION
`
`A. Level of a Person of Skill in the Art
`
`(39) It is my opinion that a POSA would have an advanced degree, such as
`
`a Ph.D. or Pharm.D., in chemistry, pharmacology, biology, pharmaceutical
`
`development, or a related science, and would be familiar with the principles of
`
`
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`Hospira, Exh. 2005, p. 20
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`stereochemistry, or a POSA would be an M.D. with several years of experience
`
`administering pharmaceuticals to patients.
`
`B.
`
`“Ready to Use”
`
`(40) Each claim of the Premix Patents recites or incorporates a “ready to
`
`use”
`
`liquid pharmaceutical
`
`composition of dexmedetomidine, or
`
`a
`
`pharmaceutically acceptable salt thereof, formulated for parenteral administration
`
`to a patient.
`
`(41) According to the specifications for the Premix Patents, compositions
`
`that are formulated as “ready
`
`to use” compositions refer “to premixed
`
`compositions that are suitable for administration to a patient without dilution. For
`
`example, in certain embodiments, the compositions of the present invention are
`
`‘ready to use’ upon removing the compositions from a sealed container or vessel.”
`
`See Ex. 2001, 3:57-62; Ex. 2002, 3:60-65; Ex. 2003, 3:60-65; Ex. 2004, 3:67-4:5.
`
`In my opinion, this equivalency between “ready to use” and “premix” is consistent
`
`with the understanding of a POSA, who would consider ready to use compositions
`
`to be compositions that are formulated in a ready to use, premixed form suitable
`
`for administration upon manufacture and without dilution or reconstitution. This
`
`understanding of “ready to use” is further evidenced by the literature cited by the
`
`Petitioner. See, e.g., Ex. 1028 (“Several drugs for IV infusion, premixed as an
`
`
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`- 15 -
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`Hospira, Exh. 2005, p. 21
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`intravenous diluent, are also commercially available. These products are referred
`
`to as ready-to-use (RTU) products or ‘premix’ drug solutions.”).
`
`(42) The patent specifications define the terms “premix” and “premixture”
`
`as “a pharmaceutical formulation that does not require reconstitution or dilution
`
`prior to administration to a patient. For example, in contrast to non-premixed
`
`formulations of dexmedetomidine, the premixed compositions provided herein are
`
`suitable for administration to a patient without dilution by, for example, a clinician,
`
`hospital personnel, caretaker, patient or any other individual.” See Ex. 2001, 3:48-
`
`55; Ex. 2002, 3:51-58; Ex. 2003, 3:51-58; Ex. 2004, 3:58-65. This definition is
`
`also supported by the literature. See, e.g., Ex. 2016, Webb et al., “Ensure Safety,
`
`Efficacy of Ready-to-Use IV Drug Products,” PFQ Vol. 11, No. 6, Oct./Nov. 2009,
`
`p. 2 (“Ready-to-use (RTU) intravenous drug products are pre-mixed solutions of
`
`drug and intravenous diluents that are typically packaged in 50 mL to 1,000 mL
`
`flexible plastic containers.”); Ex. 1028, p. 2 (“Parenteral RTU products for IV
`
`infusion offer many benefits compared to admixed IV drugs. One of the primary
`
`benefits is elimination of complex procedures required for traditional IV admixture
`
`and compounding, saving both time and labor. The use of RTU drug products in
`
`hospitals allows the pharmacist to allocate more time to clinical and other
`
`activities.”); Ex. 1044, p. 1 (“An injectable medicine is Ready-to-use when it
`
`requires no further dilution or reconstitution before transfer to an administration
`
`
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`Hospira, Exh. 2005, p. 22
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`

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`device. For example, a liquid with an ampoule, of the required concentration, that
`
`only needs to be drawn up into a syringe.”).
`
`(43) Based on the descriptions in the specification, the relevant literature,
`
`and my understanding of how this term is used by POSAs, it is my opinion that the
`
`broadest reasonable interpretation of a “ready to use” pharmaceutical composition
`
`is one that is formulated such that it is suitable for administration to a patient upon
`
`manufacture without dilution or reconstitution by a clinician, hospital personnel,
`
`caretaker, patient, or any other individual.
`
`C.
`
`“Dexmedetomidine”
`
`(44) Each claim of
`
`the Premix Patents recites or
`
`incorporates a
`
`composition comprising “dexmedetomidine or a pharmaceutically acceptable salt
`
`thereof.”
`
`(45) The specification recites that “dexmedetomidine” refers to “a
`
`substantially pure, optically active dextrorotary stereoisomer of medetomidine, as
`
`the free base or pharmaceutically acc