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. IPR2016-01580
`Patent 8,648,106
`
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,648,106
`
`
`
`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
`
`
`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. Storage material studies ........................................................................ 3
`
`2. Tonicity.................................................................................................. 5
`
`C. “Ready to Use” Formulations ..................................................................... 5
`
`D. The ’106 Patent ........................................................................................... 6
`
`E. Prosecution History of the ’106 Patent....................................................... 7
`
`V.
`
`STATEMENT OF THE REASONS FOR THE RELIEF REQUESTED ...... 8
`
`A. Claims for Which Review is Requested ..................................................... 8
`
`B. Statutory Grounds of Challenge ................................................................. 8
`
`C. Level of Ordinary Skill in the Art .............................................................. 8
`
`D. Claim Construction ..................................................................................... 8
`
`1. Ready to Use ......................................................................................... 9
`
`2. Dexmedetomidine ...............................................................................10
`
`VI.
`
`IDENTIFICATION OF CHALLENGES ......................................................11
`
`A. Each Cited Reference is Available Prior Art ...........................................12
`
`1. 2010 Precedex Label (Ex. 1007) .........................................................13
`
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`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
`CHICAGO, ILLINOIS 60606
`TELEPHONE (312) 913-0001
`
`

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`2. U.S. Patent No. 6,716,867 (Ex. 1006) .................................................13
`
`3. Giorgi (Ex. 1015) ................................................................................13
`
`4. Eichhorn (Ex. 1016) ............................................................................14
`
`5. Palmgren (Ex. 1017)............................................................................14
`
`6. The Lavoisier Documents (Ex. 1018) .................................................15
`
`B. Ground 1: Claims 1-9 of the ’106 Patent Are Obvious Over the 2010
`Precedex Label in view of Palmgren ........................................................15
`
`1. Claim 1 ................................................................................................16
`
`2. Claims 2-6 ...........................................................................................23
`
`3. Claims 7-8 ...........................................................................................24
`
`4. Claim 9 ................................................................................................25
`
`C. Ground 2: Claims 1-9 of the ’106 Patent Are Obvious Over U.S.
`6,716,867 in view of the 2010 Precedex Label and Palmgren .................31
`
`1. Claim 1 ................................................................................................32
`
`2. Claims 2-6 ...........................................................................................38
`
`3. Claims 7-8 ...........................................................................................40
`
`4. Claim 9 ................................................................................................41
`
`D. Ground 3: Claims 1-9 of the ’106 Patent Are Obvious Over the 2010
`Precedex Label in view of Giorgi, Eichhorn, Palmgren and the Lavoisier
`Documents ................................................................................................48
`
`1. Claim 1 ................................................................................................50
`
`2. Claims 2-6 ...........................................................................................57
`
`3. Claims 7-8 ...........................................................................................58
`
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`iii
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`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
`CHICAGO, ILLINOIS 60606
`TELEPHONE (312) 913-0001
`
`

`
`4. Claim 9 ................................................................................................59
`
`E. Any Secondary Considerations are Insufficient to Overcome the Prima
`Facie Case ................................................................................................65
`
`VII. CONCLUSION ..............................................................................................74
`
`VIII. MANDATORY NOTICES ...........................................................................74
`
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`iv
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`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
`CHICAGO, ILLINOIS 60606
`TELEPHONE (312) 913-0001
`
`

`
`TABLE OF AUTHORITIES
`
`
`Cases
`
`Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342 (Fed. Cir. 1999) ................ 23, 38, 56
`
`Cuozzo Speed Techs. LLC v. Lee, 136 S.Ct. 2131 (2016)) ........................................ 9
`
`Graham v. John Deere Co., 383 U.S. 1 (1966) .......................................................12
`
`Hospira Inc. v. Amneal Pharmaceuticals LLC, 1:15-cv-00697-RGA (D.Del.) ......74
`
`Hospira Inc. v. Ben Venue Laboratories, Inc., No. 14-cv-01008 (D. Del. filed
`
`August 1, 2014) ....................................................................................................32
`
`Hospira, Inc. et al. v. Ben Venue Laboratories, et al. No. 14-cv-00487 (D. Del.
`
`filed April 18, 2014) .............................................................................................32
`
`KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) .................................. 12, 48, 56
`
`Microsoft Corp. v. Proxyconn, Inc., 789 F.3d 1292 (Fed. Cir. 2015) ....................... 9
`
`Phillips v. AWH Corp., 415 F.3d 1303 (Fed. Cir. 2005) ........................................... 9
`
`Statutes
`
`35 U.S.C. § 102(b) ...................................................................................... 13, 14, 15
`
`35 U.S.C. § 103 ......................................................................................... 1, 8, 11, 31
`
`35 U.S.C. § 311 .......................................................................................................... 8
`
`35 U.S.C. §§ 311-319................................................................................................. 1
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` v
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`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
`CHICAGO, ILLINOIS 60606
`TELEPHONE (312) 913-0001
`
`

`
`Regulations
`
`37 C.F.R. § 1.132 .....................................................................................................65
`
`37 C.F.R. § 42.100(b) ................................................................................................ 8
`
`37 C.F.R. § 42.103 ...................................................................................................75
`
`37 C.F.R. § 42.104(a) ................................................................................................. 1
`
`37 C.F.R. § 42.104(b)(4)-(5) ....................................................................................11
`
`37 C.F.R. § 42.105 ...................................................................................................77
`
`37 C.F.R. § 42.105(b) ..............................................................................................77
`
`37 C.F.R. § 42.15(a)(1) ............................................................................................76
`
`37 C.F.R. § 42.8(b)(1) ..............................................................................................74
`
`37 C.F.R. § 42.8(b)(2) ..............................................................................................74
`
`37 C.F.R. § 42.8(b)(3) ..............................................................................................75
`
`37 C.F.R. § 42.8(b)(4) ..............................................................................................75
`
`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) ............................................................................................77
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`vi
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`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
`CHICAGO, ILLINOIS 60606
`TELEPHONE (312) 913-0001
`
`

`
`
`
`Exhibit
`No.
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`LIST OF EXHIBITS
`
`Description
`
`U.S. Patent No. 8,648,106 to Priyanka Roychowdhury & Robert A.
`Cedergren, issued February 11, 2014.
`
`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. 13/541,524
`
`1009 – 1011
`INTENTIONALLY LEFT BLANK
`
`Office Action Response, mailed Mar. 13, 2012, U.S. Application No.
`13/343,672
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`FDA Memorandum by Cynthia G. McCormick, M.D., dated November
`30, 1999 (“the McCormick FDA Memorandum”)
`
`INTENTIONALLY LEFT BLANK
`
`
`
`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.
`
`1018
`
`Lavoisier Documents
`
`
`
`vii
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`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
`CHICAGO, ILLINOIS 60606
`TELEPHONE (312) 913-0001
`
`

`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`
`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, 1992
`
`INTENTIONALLY LEFT BLANK
`
`“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)
`
`
`
`viii
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`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
`CHICAGO, ILLINOIS 60606
`TELEPHONE (312) 913-0001
`
`

`
`1035
`
`1036
`
`1037
`
`1038
`
`1039
`
`1040
`
`1041
`
`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)
`
`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)
`
`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)
`
`A. Desai and Mary Lee, “Gibaldi’s Drug Delivery Systems,” American
`Society of Health-System Pharmacists, Bethesda (2007)
`
`U.S. Patent No. 8,242,158 to Priyanka Roychowdhury & Robert A.
`Cedergren, issued August 14, 2012
`
`U.S. Application No. 13/343,672
`Office Action Response, mailed Sept. 17, 2012, U.S. Application No.
`13/541,524
`
`U.S. Application No. 13/867,861
`
`U.S. Application No. 13/678,260
`
`
`
`ix
`
`1043
`
`1044
`
`1045
`
`1046
`
`1047
`
`1048
`
`1049
`
`1050
`
`1051
`
`
`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
`CHICAGO, ILLINOIS 60606
`TELEPHONE (312) 913-0001
`
`

`
`U.S. Patent No. 8,436,033
`
`U.S. Patent No. 8,338,470 to Priyanka Roychowdhury & Robert A.
`Cedergren, issued December 25, 2012
`
`INTENTIONALLY LEFT BLANK
`
`INTENTIONALLY LEFT BLANK
`Notice of Allowance, Oct. 22, 2012, U.S. Application No. 13/541,524
`
`Declaration of Huailiang Wu submitted with Office Action Response,
`mailed Sep. 17, 2012, U.S. Application No. 13/541,524
`INTENTIONALLY LEFT BLANK
`
`U.S. Patent No. 8,455,527
`
`Notice of Allowance, Oct. 2, 2013, U.S. Application No. 13/867,861
`
`
`
` x
`
`
`
`1052
`
`1053
`
`1054
`
`1055
`
`1056
`
`1057
`
`1058
`
`1059
`
`1060
`
`
`
`
`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 1-9 of U.S. Patent No. 8,648,106
`
`(Ex. 1001; “the ’106 patent”) as unpatentable under 35 U.S.C. §103(a) in view of
`
`the prior art.
`
`The claims of the ‘106 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 1-9 of the ’106 patent.
`
`II. GROUNDS FOR STANDING
`In accordance with 37 C.F.R. § 42.104(a), Petitioner certifies that the ’106
`
`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 1-9 of the ’106 patent as
`
`unpatentable under 35 U.S.C. § 103, as set forth herein.
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`
`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
`CHICAGO, ILLINOIS 60606
`TELEPHONE (312) 913-0001
`
`

`
`IV. BACKGROUND
`A. History of Dexmedetomidine
`The medical field has recognized dexmedetomidine as a general
`
`sedation/analgesic agent since 1988. Ex. 1002, ¶12; Ex. 1003, ¶13; vEx. 1005,
`
`4,910,214, “the ‘214 patent,” col. 3, ll. 55-59. Dexmedetomidine ((S)-4-[1-(2,3-
`
`dimethylphenyl)ethyl]-1H-imidazole), the S-enantiomer of medetomidine (4-[1-
`
`(2,3-dimethylphenyl)ethyl]-1H-imidazole), has the following structure:
`
`N
`
`HN
`
`Dexmedetomidine
`
`
`
`N
`
`HN
`
`medetomidine
`
`
`
`
`Ex. 1002, ¶13; Ex. 1003, ¶13; Ex. 1001, col. 3, ll. 31-57.
`
`Medetomidine, a racemic mixture, was 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. 1002, ¶14; Ex.
`
`1003, ¶14; Ex. 1005, col. 1, ll. 8-43.
`
` Dexmedetomidine administration
`
`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; Ex. 1003, ¶15;See Ex. 1004; Ex. 1005; Ex. 1021; Ex. 1022; Ex. 1023.
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`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
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`TELEPHONE (312) 913-0001
`
`

`
`As early as 1999, the art disclosed methods of sedating a patient by
`
`administering dexmedetomidine, or a pharmaceutically acceptable salt thereof. Ex.
`
`1002, ¶15; Ex. 1003, ¶16; Ex. 1024; Ex. 1006, U.S. Pat. No. 6,716,867.
`
`The prior art provided dexmedetomidine as a concentrate to be diluted prior
`
`to administration. See, e.g., Ex. 1007, Sec. 2.4; Ex. 1002, ¶19; Ex. 1003, ¶17.
`
`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; Ex. 1003, ¶17.
`
`Formulation of Parenteral Drugs
`
`B.
`Parenteral pharmaceutical formulations
`
`include a variety of active
`
`ingredients, which may be incorporated into liquids. Ex. 1003, ¶18; Ex. 1028, pp.
`
`2-4. A given formulation may require certain parameters such as tonicity,
`
`particular storage material, and 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 must make certain that a selected storage
`
`container does not interact physically or chemically with the pharmaceutical
`
`solution placed in it. Ex. 1003, ¶19; Ex. 1025 at p. 259. For this reason,
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`
`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. 1003, ¶19; Ex.
`
`1026, p. 161. Typical formulation studies include storing, in various glass and
`
`plastic containers, prepared admixtures at a desired concentration of the active
`
`pharmaceutical ingredient. Ex. 1003, ¶19; Ex. 1026, p. 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. 1003, ¶20; Ex. 1028. For example,
`
`medetomidine, in which dexemedetomidine is one enantiomer, is known to display
`
`deleterious interactions with polyvinylchloride. Ex. 1003, ¶20; Ex. 1017,
`
`Palmgren. For at least this reason, glass has been traditionally considered “the
`
`container material of choice for most sterile pharmaceutical products.” Ex. 1003,
`
`¶20; Ex. 1028 at 3. Glass containers are generally classified according to their
`
`degree of chemical resistance. Ex. 1003, ¶20; Ex. 1028 at 7.
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`
`MCDONNELL BOEHNEN
`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 have approximate isotonicity with body fluid. Ex.
`
`1003, ¶21; 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.
`
`Introduction of isotonic fluids can reduce the risk of hemolysis in patient cells as
`
`compared to solutions with different tonicity. Ex. 1003, ¶21; Ex. 1030. It is well
`
`known that a buffer system of 0.9% sodium chloride at 37°C mimics the
`
`approximate isotonicity of body fluid. Id. 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. 1003, ¶21; Ex. 1029 at 1469.
`
` “Ready to Use” Formulations
`
`C.
`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. 1003, ¶23; Ex. 1028 at 40.
`
`Commercially available in 50 mL to 1000 mL glass or plastic containers, such
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`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
`CHICAGO, ILLINOIS 60606
`TELEPHONE (312) 913-0001
`
`

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`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). Ex. 1003, ¶23.
`
`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). Ex. 1003, ¶24.
`
`D. The ’106 Patent
`
`The specification of the ’106 patent relates to premixed, or ready-to-use
`
`pharmaceutical compositions of dexmedetomidine for parenteral administration.
`
`Ex. 1002, ¶21; Ex. 1003, ¶25; Ex. 1001, col. 2, ll. 5 – 10. 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. Ex. 1002, ¶21; Ex. 1003,
`
`¶25; Ex. 1001, col. 9, ll. 26–33. The specification also exemplifies long term
`
`storage
`
`results of
`
`several premixed pharmaceutical
`
`compositions of
`
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`
`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
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`
`dexmedetomidine. Ex. 1002, ¶21; Ex. 1003, ¶25; Ex. 1001, col. 13, l. 22 – col. 14,
`
`l. 58.
`
`E.
`
`Prosecution History of the ’106 Patent
`
`The application that issued as the ’106 patent was filed on November 15,
`
`2012 as U.S. Application No. 13/867,861 (Ex. 1050, “the ’861 application”). The
`
`’861 application was a continuation of U.S. Application No. 13/678,260 (Ex. 1051,
`
`“the ’260 application”), filed on November 15, 2012, and issued as U.S. Patent No.
`
`8,436,033 (Ex. 1052; “the ’033 patent”). The ’260 application was, in turn, a
`
`continuation of U.S. Application No. 13/541,524 (Ex. 1048, “the ’524
`
`application”), filed on July 3, 2012, and issued as U.S. Patent No. 8,338,470 (Ex.
`
`1053; “the ’470 patent”). The ’524 application, in turn, was a continuation of the
`
`U.S. Application No. 13/343,672 (Ex. 1008), now U.S. Patent No. 8,242,158 (Ex.
`
`1047; “the ’158 patent”).
`
`After an interview that took place on September 17, 2013, applicants filed
`
`terminal disclaimers over the ’158 patent, the ’470 patent, the ’033 patent, and U.S.
`
`Patent No. 8,455,527 (Ex. 1059, “the ’527 patent”) on April 22, 2013. The
`
`Examiner allowed the claims on October 2, 2013 (Ex. 1060) citing the results
`
`presented in Example 1 in the specification and a Declaration of Huailiang Wu
`
`submitted during prosecution of the ‘524 application (“The Wu Declaration,” Ex.
`
`1057) as reasons for allowance.
`
` 7
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`
`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
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`

`
`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 1-9 of the ’106 patent.
`
`Statutory Grounds of Challenge
`
`B.
`Petitioner requests that claims 1-9 of the ’106 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; Ex. 1003, ¶27. The amount of experience in the field would
`
`depend upon the level of formal education and particular experience with
`
`pharmaceutical formulations.
`
`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.
`
` 8
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`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
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`
`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 Phillips v. AWH Corp., 415 F.3d 1303, 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 ’106 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, ¶34. 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.” Id. The ‘470 patent
`
`specification states that
`
`[i]n certain embodiments, the compositions of the present invention
`
`can be formulated as ‘ready to use’ compositions which refer to
`
`1 Accordingly, 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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`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
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`TELEPHONE (312) 913-0001
`
`

`
`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); Ex. 1002, ¶29; Ex. 1003, ¶33.
`
`These two definitions provide the same result: under the broadest reasonable
`
`interpretation standard, the term “ready-to-use” should be construed as
`
`requiring no further dilution or reconstitution before administration to a
`
`patient. Ex. 1002, ¶¶30-31; Ex. 1003, ¶¶34-35.
`
`2.
`
`Dexmedetomidine
`
`Each claim of the ’106 patent likewise requires “dexmedetomidine.” Under
`
`the broadest reasonable interpretation, one of skill in the art would understand the
`
`term “dexmedetomidine” to mean “substantially pure, optically active dextrorotary
`
`
`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. 58-65.
`
`
`
`10
`
`
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`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
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`

`
`stereoisomer of medetomidine, as the free base or pharmaceutically acceptable
`
`salt.” Ex. 1001, col. 3, ll. 31-36; Ex. 1002, ¶34; Ex. 1003, ¶37.
`
`The
`
`specification
`
`defines
`
`“dexmedetomidine”
`
`as
`
`“(S)-4-[1-(2,3-
`
`dimethylphenyl) ethyl]-1H-imidazole,” and provides the following chemical
`
`formula:
`
`Ex. 1001, col. 3, ll. 31-55; Ex. 1002, ¶33; Ex. 1003, ¶37.
`
`
`
`VI.
`
`IDENTIFICATION OF CHALLENGES
`
`Pursuant to 37 C.F.R. § 42.104(b)(4)-(5), the following sections identify the
`
`statutory grounds for challenging the validity of the Challenged Claims and
`
`provide a detailed analysis of how the claims are unpatentable under the identified
`
`statutory grounds. Petitioner respectfully submits that there is a reasonable
`
`likelihood that it will prevail on each challenge for the reasons set forth below.
`
`Ground 35 U.S.C. Claims
`
`Prior Art References
`
`§ 103(a)
`
`1-9
`
`2010 Precedex Label (Ex. 1007) in view of
`
`Palmgren (Ex. 1017)
`
`§ 103(a)
`
`1-9
`
`US 6,716,867 (Ex. 1006) in view of the 2010
`
`1
`
`2
`
`
`
`11
`
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`MCDONNELL BOEHNEN
`HULBERT & BERGHOFF LLP
`300 SOUTH WACKER DRIVE
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`
`Precedex Label (Ex. 1007) and Palmgren
`
`(Ex. 1017)
`
`2010 Precedex Label (Ex. 1007) in view of
`
`Giorgi (Ex. 1015), Eichhorn (Ex. 1016),
`
`Palmgren (Ex. 1017) and the Lavoisier
`
`Documents (Ex. 1018)
`
`3
`
`§ 103(a)
`
`1-9
`
`For each asserted ground, Petitioner demonstrates below where each limitation is
`
`found in the prior art and that the combination of the cited art renders the claims
`
`obvious, by evaluating the scope and content of the prior art, any differences
`
`between the art and the challenged claims, the knowledge of a person of ordinary
`
`skill in the art, and any available objective indicia of nonobviousness, in
`
`accordance with Graham v. John Deere Co., 383 U.S. 1 (1966) and KSR Int’l Co.
`
`v. Teleflex, Inc., 550 U.S. 398 (2007).
`
`A. Each Cited Reference is Available Prior Art
`The application that issued as the ’106 patent was filed on April 22, 2013 as
`
`U.S. Application No. 13/867,861 (Ex. 1050, “the ’861 application”). The ’861
`
`application is a continuation of U.S. Application No. 13/678,260 (Ex. 1051), now
`
`U.S. Patent No. 8,436,033 (Ex. 1052; “the ’033 patent”), and claims priority to
`
`the’672 application, issued as the ’158 patent, which was filed on January 4, 2012.
`
`
`
`12
`
`
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`HULBERT & BERGHOFF LLP
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`
`Accordingly, the earliest possible effective filing date of the ’106 patent is January
`
`4, 2012.
`
`2010 Precedex Label (Ex. 1007)
`
`1.
`The 2010 Precedex Label qualifies as prior art against the ’158 patent under
`
`35 U.S.C. § 102(b). The 2010 Precedex Label was published in September 2010
`
`and disclosed Precedex (dexmedetomidine hydrochloride) injection for intravenous
`
`infusion following dilution. Ex. 1007 at 1.
`
`U.S. Patent No. 6,716,867 (Ex. 1006)
`
`2.
`U.S. Patent No. 6,7