UNITED STATES PATENT AND TRADEMARK OFFICE
`
`-------------------------------------
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`-----------------------------------
`
`
`
`FRESENIUS KABI USA, LLC,
`Petitioner,
`
`v.
`
`HOSPIRA, INC.,
`Patent Owner
`
`
`-------------------------------
`
`Case No.: IPR2017-01054
`
`Patent No. 8,242,158
`
`----------------
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,242,158
`
`
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`
`
`
`

`

`TABLE OF CONTENTS
`
`
`Introduction ...................................................................................................... 1
`
`Grounds for Standing ....................................................................................... 2
`
`
`
`I.
`
`II.
`
`III.
`
`Statement of the Precise Relief Requested ...................................................... 2
`
`IV. Background ...................................................................................................... 2
`
`A. History of Dexmedetomidine ................................................................ 2
`
`B.
`
`Formulation of Parenteral Drugs ........................................................... 4
`
`1.
`
`2.
`
`Storage material studies .............................................................. 4
`
`Tonicity ....................................................................................... 5
`
`“Ready to Use” Formulations ............................................................... 6
`
`The ’158 Patent ..................................................................................... 7
`
`Prosecution History of the ’158 Patent ................................................. 7
`
`C.
`
`D.
`
`E.
`
`V.
`
`Statement of the Reasons for the Relief Requested ...................................... 11
`
`A.
`
`B.
`
`C.
`
`D.
`
`Claims for Which Review is Requested .............................................. 11
`
`Statutory Grounds of Challenge .......................................................... 11
`
`Level of Ordinary Skill in the Art ....................................................... 11
`
`Claim Construction ............................................................................. 12
`
`1.
`
`2.
`
`Ready to Use ............................................................................. 12
`
`Dexmedetomidine ..................................................................... 14
`
`VI.
`
`Identification of Challenges ........................................................................... 15
`
`A.
`
`Each Cited Reference Is Available Prior Art ...................................... 16
`
`1.
`
`2010 Precedex Label (Ex. 1007) ............................................... 16
`
`
`
`ii
`
`

`

`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`U.S. Patent No. 6,716,867 (Ex. 1006) ...................................... 16
`
`De Giorgi (Ex. 1015) ................................................................ 16
`
`Eichhorn (Ex. 1016) .................................................................. 17
`
`Palmgren (Ex. 1017) ................................................................. 18
`
`The Lavoisier Documents (Ex. 1018) ....................................... 18
`
`B.
`
`Ground 1: Claims 1–4 of the ’158 Patent Are Obvious
`Over the 2010 Precedex Label in View of Palmgren .......................... 19
`
`1.
`
`2.
`
`3.
`
`4.
`
`Claim 1 ...................................................................................... 19
`
`Claims 2–3 ................................................................................ 23
`
`Claim 4 ...................................................................................... 24
`
`Claim Chart ............................................................................... 25
`
`C.
`
`Ground 2: Claims 1–4 of the ’158 Patent Would Have
`Been Obvious Over U.S. 6,716,867 in view of the 2010
`Precedex Label and Palmgren ............................................................. 26
`
`1.
`
`2.
`
`3.
`
`4.
`
`Claim 1 ...................................................................................... 28
`
`Claims 2-3 ................................................................................. 32
`
`Claim 4 ...................................................................................... 33
`
`Claim Chart ............................................................................... 34
`
`D. Ground 3: Claims 1–4 of the ’158 Patent Would Have
`Been Obvious Over the 2010 Precedex Label in view of
`Giorgi, Eichhorn, Palmgren, and the Lavoisier
`Documents ........................................................................................... 36
`
`1.
`
`2.
`
`3.
`
`4.
`
`Claim 1 ...................................................................................... 38
`
`Claims 2–3 ................................................................................ 43
`
`Claim 4 ...................................................................................... 44
`
`Claim Chart ............................................................................... 44
`iii
`
`
`
`

`

`E.
`
`Any Secondary Considerations Are Insufficient to
`Overcome the Prima Facie Case ........................................................ 46
`
`VII. Conclusion ..................................................................................................... 53
`
`VIII. Mandatory Notices ......................................................................................... 53
`
`Certificate of Service ............................................................................................... 57
`
`
`
`
`
`
`
`
`
`
`
`iv
`
`

`

`TABLE OF AUTHORITIES
`
`
`Cases
`Cuozzo Speed Techs. LLC v. Lee,
`136 S.Ct. 2131 (2016) .......................................................................................... 12
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) ................................................................................................. 15
`
`Hospira Inc. v. Amneal Pharmaceuticals LLC,
`1:15-cv-00697-RGA (D. Del.) ............................................................................. 53
`
`Hospira Inc. v. Ben Venue Laboratories, Inc.,
`No. 14-cv-01008 (D. Del. filed August 1, 2014) ................................................. 27
`
`Hospira Inc. v. Fresenius Kabi USA, LLC,
`1:16-cv-00651 (N.D. Ill.) ..................................................................................... 53
`
`Hospira, Inc. et al. v. Ben Venue Laboratories, et al.
`No. 14-cv-00487 (D. Del. filed April 18, 2014) .................................................. 27
`
`KSR Int’l Co. v. Teleflex, Inc.,
`550 U.S. 398 (2007) ...................................................................................... 15, 36
`
`Microsoft Corp. v. Proxyconn, Inc.,
`789 F.3d 1292 (Fed. Cir. 2015)............................................................................ 12
`
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) (en banc) ........................................................... 12
`
`
`
`Statutes
`
`35 U.S.C. § 102(b) ...................................................................................... 16, 17, 18
`
`35 U.S.C. § 103(a) .................................................................................... 1, 2, 11, 26
`
`35 U.S.C. § 311 ........................................................................................................ 11
`
`35 U.S.C. §§ 311-319 ................................................................................................ 2
`
`
`
`
`
`v
`
`

`

`Regulations
`Regulations
`
`37 C.F.R. § 1.102 ....................................................................................................... 7
`37 CPR. § 1.102 ..................................................................................................... ..7
`
`37 C.F.R. § 42.100(b) .............................................................................................. 12
`37 CPR. § 42.100(b) ............................................................................................ ..12
`
`37 C.F.R. § 42.103 ................................................................................................... 55
`37 CPR. § 42.103 ................................................................................................. ..55
`
`37 C.F.R. § 42.104(a) ................................................................................................. 2
`37 CPR. §42.104(a) ............................................................................................... ..2
`
`37 C.F.R. § 42.104(b)(4)-(5), ................................................................................... 15
`37 C.F.R. §42.104(b)(4)—(5), ................................................................................. ..15
`
`37 C.F.R. § 42.15(a) ................................................................................................. 55
`37 CPR. § 42.15(a) ............................................................................................... ..55
`
`37 C.F.R. § 42.8(b) ........................................................................................... 53, 54
`37 C.F.R. §42.8(b) ......................................................................................... .. 53, 54
`
`37 C.F.R. §§ 42.1-42.80 ............................................................................................. 2
`37 CPR. §§ 42.1-42.80 ........................................................................................... ..2
`
`42 C.F.R. §§ 42.100-42.123 ....................................................................................... 2
`42 CPR. §§ 42100-42123 ..................................................................................... ..2
`
`
`
`
`
`
`
`
`
`
`vi
`
`Vi
`
`

`

`Exhibit No. Description
`
`LIST OF EXHIBITS
`
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`
`
`U.S. Patent No. 8,242,158 to Priyanka Roychodhury &Robert A.
`Cedergren, issued August 14, 2012
`
`Declaration of Dr. James Cain
`
`Declaration of Dr. Alpaslan Yaman
`
`U.S. Patent No. 4,544,664
`
`U.S. Patent No. 4,910,214
`
`U.S. Patent No. 6,716,867
`
`2010 Precedex™ Label
`
`U.S. Application No. 13/343,672
`
`“Dexmedetomidine HCL Draft Labeling: Precedex™
`Dexmedetomidine Hydrochloride Injection”
`Office Action, issued Feb. 13, 2012, U.S. Application No.
`13/343,672
`
`Examiner Interview Summary, Interview conducted February 28,
`2012, U.S. Application No. 13/343,672
`Office Action Response, mailed Mar. 13, 2012, U.S. Application
`No. 13/343,672
`FDA Memorandum by Cynthia G. McCormick, M.D., dated
`November 30, 1999 (“the McCormick FDA Memorandum”)
`
`vii
`
`

`

`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`
`
`Notice of Allowance, April 18, 2012, U.S. Application No.
`13/343,672
`
`Giorgi, I., et al., International Journal for Quality in Health Care,
`Vol. 22, No. 3, 170-178 (2010)
`Eichhorn, The Official Journal of the Anesthesia Patient Safety
`Foundation, Spring 2010
`Palmgren, European Journal of Pharmaceutics and
`Biopharmaceutics, June 29, 2006
`Lavoisier Documents; Lavoisier Sodium Chloride Product Sheet,
`June 2009
`FDA Memorandum by Bob A. Rappaport, M.D., dated November
`5, 1999 (“the Rappaport FDA Memorandum”)
`Gerlach, A., et al., A new dosing protocol reduces
`dexmedetomidine-associated hypotension in critically ill surgical
`patients, Journal of Critical Care, Vol. 24, No. 4, 568-574 (2009)
`Dyck, et al., Anesthesiology 78:813-820 (1993)
`
`Scheinin, et al, Anesthesiology 78:1065-1075 (1993
`
`Yuen, et al. Anesth Analg 105:374-380 (2007)
`
`Venn, et al. Anaesthesia 54:1136-1142 (1999)
`
`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.
`
`viii
`
`

`

`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`
`
`
`“Sterile Pharmaceutical Packaging: Compatibility and Stability” Y.
`John Wang and Yie W. Chien, p. 16, 1984
`“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)
`Ponder, The Tonicity-Volume Relations for Systems Containing
`Human Red Cells and the Chlorides of Monovalent Cations, The
`Journal of General Physiology, 398 (1949)
`INTENTIONALLY LEFT BLANK
`
`Pacheco, US 2010/0041769 A1
`
`Liu, US 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)
`Cain, TraumaCare, July 2007, p. 5
`
`US Food and Drug Administration Approved Drug Products with
`Therapeutic Equivalence Evaluations (“Orange Book”) -
`Precedex™ Listing
`
`Hospira June 2015 Form 10-Q p. 24 (Note 24)
`
`Anderson et al., Am. J. Health Syst. Pharm. 69:595-7 (2012)
`
`ix
`
`

`

`1039
`
`1040
`
`1041
`
`1042
`
`1043
`
`1044
`
`1045
`
`1046
`
`
`
`
`
`
`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)
`
`Neu et al., Crit. Care Med. 10:610-12 (1982)
`
`Potts et al., Pediatrics 113:59-62 (2004)
`
`Merry et al., Pediatric Anesthesia 21:743-753 (2011)
`
`Rodriguez-Gonzalez et al., J. Am. Med. Info. Assoc. 1:72-78
`(2012)
`
`“Injectable medicines,” WHO Collaborating Centre for
`Pharmaceutical Pricing and Reimbursement Policies,
`http://whocc.goeg.at/Glossary/PreferredTerms
`
`Chrysostomou et al., Pediatric Crit. Care Med. 10:654-60 (2009)
`
`“Gibaldi’s Drug Delivery Systems,” A. Desai and Mary Lee,
`American Society of Health-System Pharmacists, Bethesda, p. 108
`(2007)
`
`
`
`x
`
`

`

`I.
`
`INTRODUCTION
`
`On February 9, 2017, the Board instituted Inter Partes Review (“IPR”) of
`
`claims 1–4 of U.S. Patent No. 8,242,158 (“the ’158 patent”) (Ex. 1001) in
`
`IPR2016-01577. Fresenius Kabi USA, LLC (“Fresenius Kabi”) submits this
`
`Petition for IPR (“Petition”) also seeking cancellation of claims 1–4 of the ’158
`
`patent as unpatentable under 35 U.S.C. § 103(a) over the same art and arguments
`
`presented by the Petition in IPR2016-01577, on which the Board instituted IPR.
`
`Fresenius Kabi also submits a Motion for Joinder to join this Petition with the
`
`IPR2016-01577 proceedings. Indeed, this Petition is an almost verbatim copy of
`
`the petition in IPR2016-01577.
`
`For the reasons explained below, and the reasons the Board instituted IPR in
`
`IPR2016-01577, Fresenius Kabi is likely to prevail that claims 1–4 of the ’158
`
`patent would have been obvious, at least, over the Precedex Label (Ex. 1007), in
`
`view of the knowledge of one of skill in the art at the time of filing, as evidenced
`
`by De Giorgi, Eichhorn, Palmgrén, and Lavoisier. Fresenius Kabi requests that the
`
`Board institute IPR and cancel each of claims 1–4 of the ’158 patent.
`
`
`
`1
`
`

`

`II. GROUNDS FOR STANDING
`
`Petitioner certifies that, under 37 C.F.R. § 42.104(a), the ’158 patent is
`
`available for inter partes review and that Petition is not barred or estopped from
`
`requesting inter partes review of the ’158 patent on the grounds identified.1
`
`III. STATEMENT OF THE PRECISE RELIEF REQUESTED
`
`The Office should institute IPR under 35 U.S.C. §§ 311-319 and 37 C.F.R.
`
`§§ 42.1-42.80 and 42.100-42.123, and cancel claims 1-4 of the ’158 patent as
`
`unpatentable under 35 U.S.C. § 103, as set forth herein.
`
`IV. BACKGROUND
`
`A. History of Dexmedetomidine
`
`The medical field has recognized dexmedetomidine as a general
`
`sedation/analgesic agent since 1988. Ex. 1005, U.S. Patent No. 4,910,214, “the
`
`‘214 patent,” col. 3, ll. 55-59; Ex. 1002, ¶12. Dexmedetomidine ((S)-4-[1-(2,3-
`
`dimethylphenyl)-ethyl]-1H-imidazole), which is the S-enantiomer of
`
`
`1 Fresenius Kabi is not barred from bringing this Petition, even though it was
`
`served with a complain asserting infringement of the ’158 patent more than one
`
`year before filing the Petition, as Fresenius Kabi concurrently seeks joinder with
`
`IPR2016-01577. See 35 U.S.C. § 315(b)-(c).
`
`
`
`2
`
`

`

`medetomidine (4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole), has the following
`
`structure:
`
`
`
`Ex. 1002, ¶¶12-13.
`
`Medetomidine, a racemic mixture, was first disclosed in the prior art in 1985
`
`(Ex. 1004, U.S. Pat. No. 4,544,664, col. 19, l. 47 – col. 20, l. 38) and separated into
`
`two enantiomers, one of which was dexmedetomidine, in 1988. Ex. 1005, col. 1, ll.
`
`8-43; Ex. 1002, ¶14. Administration of dexmedetomidine to a patient parenterally,
`
`including by intravenous bolus or infusion, intramuscular injection, intranasal and
`
`buccal, as well as oral routes was also disclosed in the prior art. Ex. 1002, ¶18. See
`
`Ex. 1004; Ex. 1005; Ex. 1021; Ex. 1022; Ex. 1023.
`
`Additionally, as early as in 1999, the prior art disclosed methods of sedating
`
`a patient by administering dexmedetomidine, or a pharmaceutically acceptable salt
`
`thereof, to the patient. Ex. 1024; Ex. 1006; Ex. 1002, ¶¶15-16.
`
`In the prior art, dexmedetomidine was provided as a concentrate to be
`
`diluted prior to administration to a patient. See, e.g., Ex. 1007, Sec. 2.4; Ex. 1002,
`
`¶19. Dexmedetomidine formulations for sedation were commercially available in
`
`
`
`3
`
`

`

`the U.S. as early as December 23, 1999, as PrecedexTM injection for intravenous
`
`infusion following dilution (or alternatively “PrecedexTM Concentrate”). See, e.g.,
`
`Ex. 1007; Ex. 1002, ¶19.
`
`B.
`
`Formulation of Parenteral Drugs
`
`Parenteral pharmaceutical formulations include a variety of active
`
`ingredients, which may be incorporated into liquids. Ex. 1028. A given formulation
`
`may require certain formulation or physiochemical parameters such as tonicity,
`
`particular storage material, and/or active ingredient stability, of which one with
`
`ordinary skill in the field of parenteral drug formulation would routinely select, test
`
`for and analyze. Id.
`
`1.
`
`Storage material studies
`
`A pharmaceutical producer has a responsibility to make certain that a
`
`selected storage container does not interact physically or chemically with the
`
`pharmaceutical solution placed in it. Ex. 1025. For this reason, pharmaceutical
`
`producers routinely perform studies to evaluate interactions with materials
`
`involved in parenteral administration to determine, for example, the appropriate
`
`storage materials for any particular formulation. Ex. 1026. Typical formulation
`
`studies include storing, in various glass and plastic containers, prepared admixtures
`
`at a desired concentration of the active pharmaceutical ingredient. Id. at 162.
`
`Samples are periodically withdrawn from the containers as a function of time and
`
`
`
`4
`
`

`

`evaluated for potency, pH, color and particulate matter. Id. The container in which
`
`essentially no potency change is observed, from the initial potency that is
`
`measured, is then recommended for clinical use. Id.
`
`In some studies, plastic containers have been shown to absorb or adsorb
`
`active drug ingredients into or onto the plastic material, causing reduced potency
`
`and efficacy of the formulation. Ex. 1027. For example, medetomidine, from
`
`which dexemedetomidine is the optically active stereoisomer, is known to display
`
`deleterious interactions with polyvinylchloride. Ex. 1017. For at least this reason,
`
`glass has been traditionally considered “the container material of choice for most
`
`sterile pharmaceutical products.” Ex. 1027 at 3. Glass containers are generally
`
`classified according to their degree of chemical resistance by the United States
`
`Pharmacopeia. Id. at 7.
`
`2.
`
`Tonicity
`
`For solutions intended for parenteral administration, it is well known in the
`
`art that patient discomfort (and even injury) is often minimized by adjusting the
`
`pharmaceutical solution to include a buffer system that has approximate isotonicity
`
`with body fluid. See Ex. 1029. When introduced into a patient, an isotonic solution
`
`has an osmotic pressure equal to that of the patient’s cells. Id. Consequently, the
`
`intracellular volume of cells in the patient stays constant because the osmotic
`
`pressure on the cell membrane due to the parenteral solution is equalized. Id. It is
`
`
`
`5
`
`

`

`well known that a buffer system of 0.9% sodium chloride at 37°C mimics the
`
`approximate isotonicity of body fluid. Id. Introduction of isotonic fluids can reduce
`
`the risk of hemolysis in patient cells as compared to solutions with different
`
`tonicity. Ex. 1030 at 395. Furthermore, it is known in the art that human red cells
`
`are least fragile in isotonic NaCl solutions. Id. at 393. For at least these reasons,
`
`0.9% sodium chloride solutions are typically chosen for parenteral administration.
`
`Ex. 1029 at 1469.
`
`C.
`
`“Ready to Use” Formulations
`
`It is well known in the art that some drug products intended for parenteral
`
`administration may be premixed in an intravenous diluent and stored in a container
`
`until time of administration to a patient. Ex. 1028 at 40. Commercially available in
`
`50 mL to 1000 mL glass or plastic containers, such products are referred to as
`
`ready-to-use (RTU) intravenous products or “premix” drug solutions. Id. There are
`
`many other examples of active pharmaceutical ingredients available in RTU form,
`
`such as nitroglycerine (Id.), propofol microemulsions (Ex. 1032), and esmolol
`
`hydrochloride (Ex. 1033).
`
`Historically, RTU medications were proposed as a way to standardize drug
`
`preparation and improve medication safety. Ex. 1020; see also Ex. 1015
`
`(advocating that the most effective way to reduce microbial contamination and
`
`dilution error is use of ready to use solution) and Ex. 1034 (citing substantial cost
`
`
`
`6
`
`

`

`savings in using RTU pharmaceutical products compared to conventional
`
`admixtures).
`
`D. The ’158 Patent
`
`The specification of the ’158 patent discloses premixed, or ready-to-use
`
`pharmaceutical compositions of dexmedetomidine for parenteral administration.
`
`Ex. 1001, col. 1, ll. 61-66. The specification identifies, as suitable containers for
`
`these formulations of the drug, glass vials, ampoules, syringes, and plastic flexible
`
`containers, such as polyvinyl chloride (PVC), VisIV™, polypropylene, and CR3
`
`containers. Id. at col. 9, ll. 17-23. The specification also provides numerous
`
`suitable concentrations for the premixed concentrations, including the claimed
`
`concentration of 4 μg/mL. Id. at col. 7, l. 64 – col. 8, l. 16.
`
`E.
`
`Prosecution History of the ’158 Patent
`
`The application that issued as the ’158 patent was filed on January 4, 2012
`
`as U.S. Application No. 13/343,672 (Ex. 1008, “the ’672 application”).
`
`Concurrently with the filing of the ’672 application, applicants submitted a Petition
`
`to Make Special under the Accelerated Examination Program under 37 C.F.R. §
`
`1.102, as set forth in M.P.E.P. § 708.02. With the Petition, applicants submitted an
`
`Accelerated Examination Support Document in which they argued that the claims
`
`were novel and inventive over numerous prior art references, including
`
`
`
`7
`
`

`

`“Dexmedetomidine HCL Draft Labeling: Precedex™ Dexmedetomidine
`
`Hydrochloride Injection” (“the Precedex™ draft label”, Ex 1009).
`
`On February 13, 2012, the Examiner issued an Office Action rejecting the
`
`claims as anticipated by or, in the alternative, obvious over the Precedex™ draft
`
`label. Ex. 1010, p. 3. The originally-filed claims read, as follows:
`
`1. (Original) A pharmaceutical composition comprising
`
`dexmedetomidine or a pharmaceutically acceptable salt thereof at a
`
`concentration of about 4 μg/mL, wherein the composition is
`
`formulated as a liquid for parenteral administration to a subject, and
`
`wherein the composition is disposed within a sealed container as a
`
`premixture.
`
`Ex. 1008, p. 38, claim 1. The claims as filed did not include any limitations on the
`
`container to be used, and particularly did not recite a “sealed glass container.” The
`
`Office Action asserted that the Precedex™ draft label provides a dexmedetomidine
`
`HCl solution formulated as a liquid for intravenous infusion (i.e., parenteral
`
`administration). Ex. 1010, p. 3. The dexmedetomidine solution is provided by the
`
`label at a concentration of 100 μg/mL, and the Precedex™ draft label instructs that
`
`this solution must be diluted to a concentration of 4 μg/mL prior to use. Id. at pp.
`
`3-5. The Examiner asserted that it would be obvious to one of skill in the art to
`
`make the “dilution in a sealed container (such as a sealed glass vial or an infusion
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`bag) to maintain the sterility of the formulation, which is administered by
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`intravenous infusion,” Id. at p. 5, consistent with the scope of disclosure in the
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`specification. Ex. 1001, col. 2, l. 66 – col. 3, l. 3.
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`In response to rejection of all of the claims of the ’672 application,
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`applicants requested an interview with the Examiner, which took place on
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`February 28, 2012. Ex. 1011. According to the interview summary, during this
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`interview applicants argued that the claimed composition is provided as a
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`“premixture” at a concentration of 4 μg/mL and that the Precedex™ draft label
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`discloses that 100 μg/mL dexmedetomidine solution must be diluted to 4 μg/mL
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`prior to use and, thus, fails to disclose a “premixture.” Id. at p. 1. The Examiner
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`maintained that “the cited prior art implicitly teaches and clearly makes [prima
`
`facie] obvious the invention.” Id.
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`Applicants responded on March 13, 2012, with an amendment to
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`independent claim 1 requiring that the claimed composition be disposed within a
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`sealed glass container as a “ready-to-use” premixture. Ex. 1012, p. 2. Applicants
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`argued that the Precedex™ draft label failed to suggest or describe that the diluted
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`4 μg/mL dexmedetomidine composition is disposed within a sealed glass container
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`as a ready-to-use premixture:
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`Applicants note that a primary difference between the claimed 4
`
`μg/mL premixture composition and the 4 μg/mL diluted composition
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`described by the Draft Labeling, is that the claimed composition is a
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`ready to use premixture that does not require any dilution or
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`reconstitution prior to administration to a subject. (See the
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`specification, p. 5, paras. [0024][0025]).
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`Id. at p. 7. Applicants argued that “upon withdrawing the claimed composition
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`from a sealed glass container, an artisan of ordinary skill can administer the
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`composition directly to a subject” whereas the Precedex™ draft label composition
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`would “not suitable for administering to a patient upon withdrawing the
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`composition from a sealed container.” Id.
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`Applicants further argued that a ready-to-use premixture composition in a
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`sealed glass container is more stable over a prolonged period compared to, for
`
`example, the premixture composition in a plastic container. Ex. 1012, p. 8.
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`Applicants did not rebut the Examiner’s obviousness determination by showing
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`that one of skill in the art would not have had a reasonable expectation of success
`
`of storing the diluted formulation for extended periods of time (i.e., longer than 24
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`hours) in glass. Ex. 1012, p. 8. Instead, applicants relied upon an FDA
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`Memorandum by Cynthia G. McCormick, M.D., dated November 30, 1999 (“the
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`McCormick FDA Memorandum”) to support their argument that the diluted 4
`
`μg/mL dexmedetomidine composition was known in the art to be stable for only 24
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`hours. Ex. 1012, p. 8 citing to Ex. 1013, p. 8. The Examiner took applicants’
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`arguments at face value and allowed the claims on April 18, 2012. Ex. 1014.
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`V.
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`STATEMENT OF THE REASONS FOR THE RELIEF REQUESTED
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`A. Claims for Which Review is Requested
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`Under 35 U.S.C. § 311, Petitioner respectfully requests review and
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`cancellation of claims 1-4 of the ’158 patent.
`
`B.
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`Statutory Grounds of Challenge
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`Petitioner requests that claims 1-4 of the ’158 patent be cancelled under 35
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`U.S.C. § 103(a). This petition offers claim construction, reasons for
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`unpatentability, and specific evidence supporting this request.
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`C. Level of Ordinary Skill in the Art
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`The person of ordinary skill in the art (“POSA”) would have held an
`
`advanced degree, such as a Ph.D or M.D., in the field of drug development and
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`formulation, or in the alternative would have significant clinical experience in
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`anesthesia or sedation with familiarity using parental injection as of January 4,
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`2012. Ex. 1002, ¶23. The amount of experience in the field would depend upon the
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`level of formal education and particular experience with pharmaceutical
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`formulations. Id.
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`D. Claim Construction
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`For purposes of an inter partes review, a claim should be given its broadest
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`reasonable interpretation in light of the specification of the patent in which it
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`appears. See 37 C.F.R. § 42.100(b); Cuozzo Speed Techs. LLC v. Lee, 136 S.Ct.
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`2131 (2016). Accordingly, claims as construed before the Board may not
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`necessarily be the same as a federal court would construe them using an “ordinary
`
`and customary meaning” standard under Phillips v. AWH Corp., 415 F.3d 1303,
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`1312-13 (Fed. Cir. 2005).2 Nevertheless, the Board’s construction “cannot be
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`divorced from the specification and the record evidence, and must be consistent
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`with the one that those skilled in the art would reach.” Microsoft Corp. v.
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`Proxyconn, Inc., 789 F.3d 1292, 1298 (Fed. Cir. 2015) (internal citations and
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`quotations omitted).
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`The claim terms are construed from the point of view of a person of ordinary
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`skill in the art at the time of invention, as identified above.
`
`1.
`
`Ready to Use
`
`Each claim of the ’158 patent recites a “ready-to-use” liquid composition of
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`dexmedetomidine. “Ready-to-use” is a well-known term of art in the medical and
`
`
`2 Thus, this claim construction analysis should not be viewed as a concession as to
`
`the proper scope of any claim term in litigation.
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`pharmaceutical industry. See, e.g., Ex. 1002, ¶30; Ex. 1003, ¶46-48. One of skill in
`
`the art would understand the term “ready-to-use” to mean “requiring no further
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`dilution or reconstitution before transfer to an administration device.” Ex. 1002,
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`¶31; Ex. 1003, ¶47; Ex. 1044. The ‘158 patent specification states that,
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`“[i]n certain embodiments, the compositions of the present invention
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`can be formulated as ‘ready to use’ compositions which refer to
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`premixed compositions that are suitable for administration to a
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`patient without dilution. For example, in certain embodiments, the
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`compositions of the present invention are ‘ready to use’ upon
`
`removing the compositions from a sealed container or vessel.”3
`
`
`3 The specification defines “premixture” as “a pharmaceutical formulation that
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`does not require reconstitution or dilution prior to administration to a patient. For
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`example, in contrast to non-premixed formulations of dexmedetomidine, the
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`premixed compositions provided herein are suitable for administration to a patient
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`without dilution by, for example, a clinician, hospital personnel, caretaker, patient
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`or any other individual.” Ex. 1001, col. 3, ll. 48-55. In addition, applicants agreed
`
`to an Examiner’s Amendment that removed the limitation “wherein the
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`composition is disposed… as a ready to use premixture” and amended the
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`preamble to “A ready to use liquid pharmaceutical composition…” (Ex. 1014,
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`
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`13
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`Ex. 1001, col. 3, ll. 56-63 (emphasis added). These two definitions provide the
`
`same result: under the broadest reasonable interpretation standard, the term “ready-
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`to-use” should be construed as requiring no further dilution or reconstitution before
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`administration to a patient. Ex. 1002, ¶31.
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`2.
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`Dexmedetomidine
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`Each claim of the ’158 patent likewise requires “dexmedetomidine.” Under
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`the broadest reasonable interpretation, one of skill in the art would understand the
`
`term “dexmedetomidine” to mean a “substantially pure, optically active
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`dextrorotary stereoisomer of medetomidine, as the free base or pharmaceutically
`
`acceptable salt.” Ex. 1001, col. 3, ll. 21-24; Ex. 1002, ¶33. The specification
`
`defines “dexmedetomidine” as “(S)-4-[1-(2,3-dimethylphenyl) ethyl]-1H-
`
`imidazole,” and provides the following chemical formula:
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`Ex. 1001, col. 3, ll. 21-45; Ex. 1002, ¶¶32-33.
`
`
`
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`Examiner’s Amendment, p. 2), thereby acknowledging that “ready to use” is
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`equivalent to “a premixture”