UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEALS BOARD
`
`
`AMNEAL PHARMACEUTICALS LLC
`Petitioner
`
`v.
`
`HOSPIRA, INC
`Patent Owner
`
`
` Inter Partes Review No. IPR2016-01578
`Patent 8,338,470
`
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,338,470
`
`
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`
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`
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`

`

`TABLE OF CONTENTS
`
`INTRODUCTION ........................................................................................... 1
`
`
`I.
`
`II. GROUNDS FOR STANDING ........................................................................ 1
`
`III. STATEMENT OF THE PRECISE RELIEF REQUESTED .......................... 1
`
`IV. BACKGROUND ............................................................................................. 2
`
`A. History of Dexmedetomidine ................................................................ 2
`
`B.
`
`Formulation of Parenteral Drugs ........................................................... 3
`
`1.
`
`2.
`
`Storage material studies .............................................................. 3
`
`Tonicity ....................................................................................... 5
`
`C.
`
`D.
`
`E.
`
`“Ready to Use” Formulations ............................................................... 5
`
`The ’470 Patent ..................................................................................... 6
`
`Prosecution History of the ’470 Patent ................................................. 7
`
`V.
`
`STATEMENT OF THE REASONS FOR THE RELIEF REQUESTED ....10
`
`A.
`
`B.
`
`C.
`
`D.
`
`Claims for Which Review is Requested ..............................................10
`
`Statutory Grounds of Challenge ..........................................................10
`
`Level of Ordinary Skill in the Art .......................................................10
`
`Claim Construction..............................................................................10
`
`1.
`
`2.
`
`Ready to Use .............................................................................11
`
`Dexmedetomidine .....................................................................13
`
`VI.
`
`IDENTIFICATION OF CHALLENGES ......................................................13
`
`A.
`
`Each Cited Reference is Available Prior Art ......................................14
`
`1.
`
`2010 Precedex Label (Ex. 1007) ...............................................15
`
`
`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
`CHICAGO, ILLINOIS 60606
`TELEPHONE (312) 913-0001
`
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`ii
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`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`U.S. Patent No. 6,716,867 (Ex. 1006) ......................................15
`
`Giorgi (Ex. 1015) ......................................................................15
`
`Eichhorn (Ex. 1016) ..................................................................16
`
`Palmgren (Ex. 1017) .................................................................16
`
`The Lavoisier Documents (Ex. 1018) .......................................17
`
`B. Ground 1: Claims 1-7 of the ’470 Patent Are Obvious Over the 2010
`Precedex Label in view of Palmgren ..................................................18
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Claim 1 ......................................................................................18
`
`Claims 2-4 .................................................................................22
`
`Claims 5-6 .................................................................................23
`
`Claim 7 ......................................................................................24
`
`Claim Chart ...............................................................................24
`
`C. Ground 2: Claims 1-7 of the ’470 Patent Are Obvious Over U.S.
`6,716,867 in view of the 2010 Precedex Label and Palmgren ............27
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Claim 1 ......................................................................................28
`
`Claims 2-4 .................................................................................33
`
`Claims 5-6 .................................................................................35
`
`Claim 7 ......................................................................................35
`
`Claim Chart ...............................................................................37
`
`D. Ground 3: Claims 1-7 of the ’470 Patent Are Obvious Over the 2010
`Precedex Label in view of Giorgi, Eichhorn, Palmgren and the
`Lavoisier Documents ...........................................................................39
`
`1.
`
`Claim 1 ......................................................................................42
`
`
`
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`iii
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`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
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`TELEPHONE (312) 913-0001
`
`

`

`2.
`
`3.
`
`4.
`
`5.
`
`Claims 2-4 .................................................................................47
`
`Claims 5 and 6 ...........................................................................48
`
`Claim 7 ......................................................................................49
`
`Claim Chart ...............................................................................49
`
`E.
`
`Any Secondary Considerations are Insufficient to Overcome the
`Prima Facie Case ................................................................................52
`
`VII. CONCLUSION ..............................................................................................61
`
`VIII. MANDATORY NOTICES ...........................................................................61
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`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
`CHICAGO, ILLINOIS 60606
`TELEPHONE (312) 913-0001
`
`
`
`
`iv
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`

`

`TABLE OF AUTHORITIES
`
`
`Cases
`
`Cuozzo Speed Techs. LLC v. Lee, 136 S.Ct. 2131 (2016) .......................................11
`
`Graham v. John Deere Co., 383 U.S. 1 (1966) .......................................................14
`
`Hospira Inc. v. Ben Venue Laboratories, Inc., No. 14-cv-01008 (D. Del. filed
`
`August 1, 2014) ....................................................................................................28
`
`Hospira, Inc. et al. v. Ben Venue Laboratories, et al. No. 14-cv-00487 (D. Del.
`
`filed April 18, 2014) .............................................................................................28
`
`KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) .................................. 14, 40, 46
`
`Microsoft Corp. v. Proxyconn, Inc., 789 F.3d 1292 (Fed. Cir. 2015) .....................11
`
`Phillips v. AWH Corp., 415 F.3d 1303, 1312-13 (Fed. Cir. 2005) ..........................11
`
`Statutes
`
`35 U.S.C. § 102(b) ...................................................................................... 15, 16, 17
`
`35 U.S.C. § 103 ....................................................................................... 1, 10, 14, 27
`
`35 U.S.C. § 311 ........................................................................................................10
`
`35 U.S.C. §§ 311-319................................................................................................. 1
`
`Other Authorities
`
`M.P.E.P. § 708.02 ...................................................................................................... 7
`
`
`
` v
`
`
`
`Regulations
`
`
`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
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`TELEPHONE (312) 913-0001
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`

`

`37 C.F.R. § 1.102 ....................................................................................................... 7
`
`37 C.F.R. § 1.132 .....................................................................................................53
`
`37 C.F.R. § 42.100(b) ..............................................................................................10
`
`37 C.F.R. § 42.103 ...................................................................................................63
`
`37 C.F.R. § 42.104(a) ................................................................................................. 1
`
`37 C.F.R. § 42.104(b)(4)-(5) ....................................................................................13
`
`37 C.F.R. § 42.105 ...................................................................................................64
`
`37 C.F.R. § 42.105(b) ..............................................................................................64
`
`37 C.F.R. § 42.15(a)(1) ............................................................................................63
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`37 C.F.R. § 42.8(b)(1) ..............................................................................................61
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`37 C.F.R. § 42.8(b)(2) ..............................................................................................61
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`37 C.F.R. § 42.8(b)(3) ..............................................................................................62
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`37 C.F.R. § 42.8(b)(4) ..............................................................................................62
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`37 C.F.R. §§ 42.100-42.123 ....................................................................................... 1
`
`37 C.F.R. §§ 42.1-42.80 ............................................................................................. 1
`
`37 C.F.R. §§ 42.6(e)(1) ............................................................................................64
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`
`
`
`
`
`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
`CHICAGO, ILLINOIS 60606
`TELEPHONE (312) 913-0001
`
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`vi
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`
`
`Exhibit
`No.
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`LIST OF EXHIBITS
`
`Description
`
`U.S. Patent No. 8,338,470
`
`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”
`
`1010 – 1012
`
`INTENTIONALLY LEFT BLANK
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`FDA Memorandum by Cynthia G. McCormick, M.D., dated November
`30, 1999 (“the McCormick FDA Memorandum”)
`
`INTENTIONALLY LEFT BLANK
`
`Giorgi 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
`
`
`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
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`vii
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`

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`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`FDA Memorandum by Bob A. Rappaport, M.D., dated November 5,
`1999 (“the Rappaport FDA Memorandum”)
`
`Gerlach 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
`
`“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
`
`“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
`
`
`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
`CHICAGO, ILLINOIS 60606
`TELEPHONE (312) 913-0001
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`1034
`
`1035
`
`1036
`
`1037
`
`1038
`
`1039
`
`1040
`
`1041
`
`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”) - PrecedexTM
`Listing
`
`Hospira June 2015 Form 10-Q p. 24 (Note 24).
`
`Anderson et al., Am. J. Health Syst. Pharm. 69:595-7 (2012)
`
`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)
`
`1042 Merry et al., Pediatric Anesthesia 21:743-753 (2011)
`
`1043
`
`1044
`
`1045
`
`1046
`
`1047
`
`1048
`
`1049
`
`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)
`
`INTENTIONALLY LEFT BLANK
`
`U.S. Patent No. 8,242,158 to Priyanka Roychowdhury & Robert A.
`Cedergren, issued August 14, 2012
`
`U.S. Application No. 13/541,524
`
`Office Action Response, mailed Sept. 17, 2012, U.S. Application No.
`13/541,524
`
`
`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
`CHICAGO, ILLINOIS 60606
`TELEPHONE (312) 913-0001
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`1050 – 1055
`
`INTENTIONALLY LEFT BLANK
`
`1056
`
`1057
`
`1058
`
`Notice of Allowance, mailed Oct. 22, 2012, U.S. Application No.
`13/541,524
`
`Declaration of Huailiang Wu, U.S. Application No. 13/541,524
`
`Office Action, issued Aug. 17, 2012, U.S. Application No. 13/541,524
`
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`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
`CHICAGO, ILLINOIS 60606
`TELEPHONE (312) 913-0001
`
`

`

`I.
`
`INTRODUCTION
`
`Amneal Pharmaceuticals LLC (“Petitioner”) submits this Petition for Inter
`
`Partes Review seeking cancellation of claims 1-7 of U.S. Patent No. 8,338,470
`
`(Ex. 1001; “the ’470 patent”) as unpatentable under 35 U.S.C. §103(a) in view of
`
`the prior art.
`
`The claims of the ‘470 patent do not represent patentable subject matter and
`
`are merely an obvious combination of well-established prior art and common
`
`practices in the drug formulation and clinical arts. For the reasons explained
`
`below, Petitioner is at least reasonably likely to prevail on the asserted Grounds 1,
`
`2 and/or 3, with respect to the challenged claims. Accordingly, Petitioner
`
`respectfully requests that this Board institute IPR and cancel each of challenged
`
`claims 1-7 of the ’470 patent.
`
`II. GROUNDS FOR STANDING
`
`In accordance with 37 C.F.R. § 42.104(a), Petitioner certifies that the ’470
`
`patent is available for IPR and Petitioner is not barred or estopped from requesting
`
`IPR of any of the challenged claims.
`
`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 1-7 of the ’470 patent as
`
`unpatentable under 35 U.S.C. § 103, as set forth herein.
`
`
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` 1
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`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
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`

`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
`
`medetomidine (4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole), has the following
`
`structure:
`
`N
`
`HN
`
`N
`
`HN
`
`
`
`
`
`Dexmedetomidine
`
`medetomidine
`
`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.
`
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` 2
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`
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`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
`
`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
`
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`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
`
`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.
`
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`
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`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
`CHICAGO, ILLINOIS 60606
`TELEPHONE (312) 913-0001
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`

`

`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
`
`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. For at least these reasons, 0.9%
`
`sodium chloride solutions are typically chosen for parenteral administration. Ex.
`
`1029 at p. 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 p. 40. Commercially available
`
`in 50 mL to 1000 mL glass or plastic containers, such products are referred to as
`
`
`
` 5
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`HULBERT & BERGHOFF LLP
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`

`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
`
`savings in using RTU pharmaceutical products compared to conventional
`
`admixtures).
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`D. The ’470 Patent
`
`The specification of the ‘470 patent discloses premixed, or ready-to-use
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`pharmaceutical compositions of dexmedetomidine for parenteral administration.
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`Ex. 1001, col. 1, ll. 61-66. The specification identifies, as suitable containers for
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`these formulations of the drug, glass vials, ampoules, syringes, and plastic flexible
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`containers, such as polyvinyl chloride (PVC), VisIV™, polypropylene, and CR3
`
`containers. Id. at col. 9, ll. 17-23. The specification also provides numerous
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`suitable concentrations for the premixed concentrations, including the claimed
`
`concentration of 4 μg/mL. Id. at col. 7, l. 64 – col. 8, l. 16.
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`
`
`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
`CHICAGO, ILLINOIS 60606
`TELEPHONE (312) 913-0001
`
`

`

`E.
`
`Prosecution History of the ’470 Patent
`
`The application that issued as the ’470 patent was filed on July 3, 2012, as
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`U.S. Application No. 13/541,524. Ex. 1048, (“the ’524 application”). The ’524
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`application was a continuation of U.S. Application No. 13/343,672 (Ex. 1008),
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`now U.S. Patent No. 8,242,158 (Ex. 1047; “the ’158 patent”). Concurrently with
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`the filing of the ‘524 application, the applicants submitted a Petition to Make
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`Special under Accelerated Examination Program under 37 C.F.R. § 1.102, as set
`
`forth in M.P.E.P. § 708.02. With the Petition, the applicants submitted Accelerated
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`Examination Support Document in which applicants argued that the claims are
`
`novel
`
`and
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`inventive over numerous prior
`
`art
`
`references,
`
`including
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`“Dexmedetomidine HCL Draft Labeling: Precedex™ Dexmedetomidine
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`Hydrochloride Injection” (“the Precedex Draft Label,” Ex 1009).
`
`On August 17, 2012, the Examiner issued an Office Action rejecting the
`
`claims as obvious over numerous references including PrecedexTM Package Insert
`
`(“the Precedex Label,” Ex. 1007) in combination with several other references. Ex.
`
`1058, pp. 3, 6, 8. The Office Action asserted that the Precedex Label provides
`
`dexmedetomidine HCl solution formulated as a liquid for intravenous infusion
`
`(i.e., parenteral administration). Id. The dexmedetomidine solution is provided by
`
`the label at a concentration of 100 μg/mL, and the Precedex Label instructs that
`
`this solution must be diluted to 4 μg/mL concentration prior to use. Id. at p. 9. The
`
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` 7
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`
`
`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
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`

`

`Examiner recognized that the diluted dexmedetomidine is not provided in a sealed
`
`glass container but provided that “the use of such containers for parenteral
`
`pharmaceuticals is common and well known” as evidenced by other drugs that are
`
`provided in sealed glass containers. Id. at pp. 9-10. The Examiner also rejected all
`
`of the claims for nonstatutory obviousness-type double patenting over all claims of
`
`the ’158 patent. Id. at pp. 11-12.
`
`The applicants responded on September 17, 2012 traversing all rejections
`
`without amending the claims. Ex. 1049, p. 2. The applicants argued that the
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`Precedex Label fails to suggest or describe a premixture composition comprising
`
`about 0.005 to about 50 μg/mL of dexmedetomidine disposed within a sealed glass
`
`container that is ready to use without dilution. Id. at p. 5. Specifically, the
`
`applicants argued that “upon withdrawing the claimed composition from a sealed
`
`glass container, an artisan of ordinary skill can administer the composition directly
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`to a subject” whereas the Precedex Label composition would “not suitable for
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`administering to a patient upon withdrawing the composition from a sealed
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`container.” Id. at p. 6.
`
`Citing Examples 1 and 3 in the specification, applicants further argued that a
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`ready-to-use premixture composition in a sealed glass container is more stable over
`
`a prolonged period compared to, for example, the premixture composition stored in
`
`a plastic container. Id. at p. 6. Applicants did not rebut the Examiner’s
`
`
`
` 8
`
`
`
`
`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
`CHICAGO, ILLINOIS 60606
`TELEPHONE (312) 913-0001
`
`

`

`obviousness determination by showing 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 hours) in glass. Ex. 1049, p. 8.
`
`Instead, applicants submitted a Declaration of Huailiang Wu (“The Wu
`
`Declaration,” Ex. 1057) to further support the stability of the glass-stored
`
`composition compared to PVC-stored composition. Id., pp. 6, 8. Applicants
`
`argued that the Wu Declaration demonstrated that “storing a ready to use
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`dexmedetomidine composition at concentrations of 1, 10, 15 and 50 μg/mL in glass
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`containers surprisingly
`
`increased
`
`the stability of
`
`the dexmedetomidine
`
`compositions compared to storage in plastic PVC bags.” Id. at pp. 8-9.
`
`Applicants also relied upon an FDA Memorandum by Cynthia G.
`
`McCormick, M.D., dated November 30, 1999 (“the FDA Memorandum”) to
`
`support their argument that adiluted 4 μg/mL dexmedetomidine composition was
`
`expected to be stable for only 24 hours. Ex. 1049, p. 8 citing to Ex. 1013, p. 8. The
`
`Examiner took applicants’ arguments at face value and allowed the claims on
`
`December 22, 2012 following the applicants’ filing of a terminal disclaimer on
`
`September 17, 2012. Ex. 1056.
`
`
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` 9
`
`
`
`
`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
`CHICAGO, ILLINOIS 60606
`TELEPHONE (312) 913-0001
`
`

`

`V.
`
`STATEMENT OF THE REASONS FOR THE RELIEF REQUESTED
`
`A. Claims for Which Review is Requested
`
`Under 35 U.S.C. § 311, Petitioner respectfully requests review and
`
`cancellation of claims 1-7 of the ’470 patent.
`
`B.
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`Statutory Grounds of Challenge
`
`Petitioner requests that claims 1-7 of the ’470 patent be cancelled under 35
`
`U.S.C. § 103(a). This petition offers claim construction,
`
`reasons
`
`for
`
`unpatentability, and specific evidence supporting this request.
`
`C. Level of Ordinary Skill in the Art
`
`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
`
`formulation, or in the alternative would have significant clinical experience in
`
`anesthesia or sedation with familiarity using parental injection as of January 4,
`
`2012. Ex. 1002, ¶23. The amount of experience in the field would depend upon
`
`the level of formal education and particular experience with pharmaceutical
`
`formulations. Id.
`
`D. Claim Construction
`
`For purposes of an inter partes review, a claim should be given its broadest
`
`reasonable interpretation in light of the specification of the patent in which it
`
`appears. See 37 C.F.R. § 42.100(b); Cuozzo Speed Techs. LLC v. Lee, 136 S.Ct.
`
`
`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
`CHICAGO, ILLINOIS 60606
`TELEPHONE (312) 913-0001
`
`
`
`
`10
`
`

`

`2131 (2016). Accordingly, claims as construed before the Board may not
`
`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).1 Nevertheless, the Board’s construction “cannot be
`
`divorced from the specification and the record evidence, and must be consistent
`
`with the one that those skilled in the art would reach.” Microsoft Corp. v.
`
`Proxyconn, Inc., 789 F.3d 1292, 1298 (Fed. Cir. 2015) (internal citations and
`
`quotations omitted).
`
`The claim terms are construed from the point of view of a person of ordinary
`
`skill in the art at the time of invention, as identified above.
`
`1.
`
`Ready to Use
`
`Each claim of the ’470 patent recites a “ready-to-use” liquid composition of
`
`dexmedetomidine. “Ready-to-use” is a well-known term of art in the medical and
`
`pharmaceutical industry. Ex. 1002, ¶30; Ex. 1003, ¶¶47-49. One of skill in the art
`
`would understand the term “ready-to-use” to mean “requiring no further dilution or
`
`reconstitution before transfer to an administration device.” Ex. 1002, ¶31; Ex.
`
`1003, ¶48; Ex. 1044. The ‘470 patent specification states that:
`
`
`1 Thus, this claim construction analysis should not be viewed as a concession as to
`
`the proper scope of any claim term in litigation.
`
`
`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
`CHICAGO, ILLINOIS 60606
`TELEPHONE (312) 913-0001
`
`
`
`
`11
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`

`

`[i]n certain embodiments, the compositions of the present invention
`
`can be formulated as ‘ready to use’ compositions which 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.”2
`
`Ex. 1001 at col. 3, ll. 56-63 (emphasis added). These two definitions provide the
`
`same result: under the broadest reasonable interpretation standard, the term “ready-
`
`
`2 The specification defines “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.” Ex. 1001 at col. 3, ll. 48-55. In addition, applicants
`
`agreed to an Examiner’s Amendment that removed the limitation “wherein the
`
`composition is disposed… as a ready to use premixture” and amended the
`
`preamble to “A ready to use liquid pharmaceutical composition…” (Ex. 1056,
`
`Examiner’s Amendment, p. 2), thereby acknowledging that “ready to use” is
`
`equivalent to “ready to use premixture”.
`
`
`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
`CHICAGO, ILLINOIS 60606
`TELEPHONE (312) 913-0001
`
`
`
`
`12
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`

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`to-use” should be construed as requiring no further dilution or reconstitution before
`
`administration to a patient. Ex. 1002, ¶31.
`
`2.
`
`Dexmedetomidine
`
`Each cla