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.: IPR2017-01056
`
`Patent No. 8,455,527
`
`----------------
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,455,527
`
`
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`
`1
`
`

`

`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 ’527 Patent ..................................................................................... 7
`
`Prosecution History of the ’527 Patent ................................................. 7
`
`C.
`
`D.
`
`E.
`
`V.
`
`Statement of the Reasons for the Relief Requested ........................................ 8
`
`A.
`
`B.
`
`C.
`
`D.
`
`Claims for Which Review is Requested ................................................ 8
`
`Statutory Grounds of Challenge ............................................................ 8
`
`Level of Ordinary Skill in the Art ......................................................... 8
`
`Claim Construction ............................................................................... 9
`
`1.
`
`2.
`
`Ready to Use ............................................................................... 9
`
`Dexmedetomidine ..................................................................... 11
`
`VI.
`
`Identification of Challenges ........................................................................... 11
`
`A.
`
`Each Cited Reference Is Available Prior Art ...................................... 12
`
`1.
`
`2010 Precedex Label (Ex. 1007) ............................................... 13
`
`
`
`ii
`
`

`

`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`U.S. Patent No. 6,716,867 (Ex. 1006) ...................................... 13
`
`Giorgi (Ex. 1015) ...................................................................... 13
`
`Eichhorn (Ex. 1016) .................................................................. 14
`
`Palmgren (Ex. 1017) ................................................................. 14
`
`The Lavoisier Documents (Ex. 1018) ....................................... 15
`
`B.
`
`Ground 1: Claims 1–4 of the ’158 Patent Are Obvious
`Over the 2010 Precedex Label in View of Palmgren .......................... 15
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`Claim 1 ...................................................................................... 16
`
`Claims 2–5 ................................................................................ 21
`
`Claims 6 and 7 ........................................................................... 22
`
`Claim 8 ...................................................................................... 22
`
`Claim 9 ...................................................................................... 23
`
`Claim 10 .................................................................................... 23
`
`Claim 11 .................................................................................... 24
`
`Claim 13 .................................................................................... 24
`
`Claim Chart ............................................................................... 25
`
`C.
`
`Ground 2: Claims 1-11 and 13 of the ’527 Patent Are
`Obvious Over U.S. Patent No. 6,716,867 in view of the
`2010 Precedex Label and Palmgren. ................................................... 27
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Claim 1 ...................................................................................... 29
`
`Claims 2-5 ................................................................................. 35
`
`Claims 6 and 7 ........................................................................... 37
`
`Claim 8 ...................................................................................... 37
`
`Claim 9 ...................................................................................... 38
`
`
`
`iii
`
`

`

`6.
`
`7.
`
`8.
`
`9.
`
`Claim 10 .................................................................................... 39
`
`Claim 11 .................................................................................... 40
`
`Claim 13 .................................................................................... 40
`
`Claim Chart ............................................................................... 41
`
`D. Ground 3: Claims 1-11 and 13 of the ’527 Patent Would
`Have Been Obvious Over the 2010 Precedex Label in
`view of Giorgi, Eichhorn, Palmgren, and the Lavoisier
`Documents ........................................................................................... 43
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`Claim 1 ...................................................................................... 46
`
`Claims 2–5 ................................................................................ 50
`
`Claims 6 and 7 ........................................................................... 51
`
`Claim 8 ...................................................................................... 52
`
`Claim 9 ...................................................................................... 52
`
`Claim 10 .................................................................................... 53
`
`Claim 11 .................................................................................... 53
`
`Claim 13 .................................................................................... 54
`
`Claim Chart ............................................................................... 54
`
`E.
`
`Any Secondary Considerations Are Insufficient to
`Overcome the Prima Facie Case ........................................................ 57
`
`VII. Conclusion ..................................................................................................... 65
`
`VIII. Mandatory Notices ......................................................................................... 65
`
`Certificate of Service ............................................................................................... 68
`
`
`
`
`
`
`
`
`
`
`
`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
`
`

`

` LIST OF EXHIBITS
`
`Exhibit No. Description
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010 - 1011
`
`1012
`
`1013
`
`
`
`1014
`
`1015
`
`U.S. Patent No. 8,455,527
`
`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”
`INTENTIONALLY LEFT BLANK
`
`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”)
`INTENTIONALLY LEFT BLANK
`
`Giorgi, I., et al., International Journal for Quality in Health Care,
`Vol. 22, No. 3, 170-178 (2010)
`
`vii
`
`
`
`
`
`

`

`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`
`
`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.
`“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
`
`viii
`
`

`

`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`
`1039
`
`“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)
`
`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)
`
`
`
`ix
`
`

`

`1040
`
`1041
`
`1042
`
`1043
`
`1044
`
`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
`
`1045 – 1046
`
`INTENTIONALLY LEFT BLANK
`
`1047
`
`1048
`
`1049
`
`1050
`
`1051
`
`1052
`
`1053
`
`1054
`
`
`
`U.S. Patent No. 8,242,158
`
`U.S. Application No. 13/541,524
`
`Office Action Response, mailed Sep. 17, 2012, U.S. Application
`No. 13/541,524
`
`INTENTIONALLY LEFT BLANK
`
`U.S. Application No. 13/678,260
`
`INTENTIONALLY LEFT BLANK
`
`U.S. Patent No. 8,338,470
`
`U.S. Application No. 13/678,148
`
`x
`
`

`

`1055
`
`1056
`
`Notice of Allowance, Jan. 11, 2013, U.S. Application No.
`13/678,148
`
`Notice of Allowance, mailed Oct. 22, 2012, U.S. Application No.
`13/541,524
`
`1057
`
`Declaration of Huailiang Wu, U.S. Application No. 13/541,524
`
`1058 –
`1060
`
`1061
`
`1062
`
`INTENTIONALLY LEFT BLANK
`
`Tobias, “Dexmedetomidine: Applications in pediatric critical care
`and pediatric anesthesiology,” Pediatr Crit Care Med 8:2 (2007)
`
`Martin E, Ramsay G, Mantz J, Sum-Ping STJ. The role of the
`alpha2-adrenoceptor agonist dexmedetomidine in postsurgical
`sedation in the intensive care unit. J Intensive Care Med. 2003,
`18:29-41.
`
`1063
`
`Precedex 2009 Dosing Guidelines
`
`
`
`xi
`
`

`

`I.
`
`INTRODUCTION
`
`On February 9, 2017, the Board instituted Inter Partes Review (“IPR”) of
`
`claims 1–11 and 13 of U.S. Patent No. 8,455,527 (“the ’527 patent”) (Ex. 1001) in
`
`IPR2016-01579. Fresenius Kabi USA, LLC (“Fresenius Kabi”) submits this
`
`Petition for IPR (“Petition”) also seeking cancellation of claims 1–11 and 13 of the
`
`’527 patent as unpatentable under 35 U.S.C. § 103(a) over the same art and
`
`arguments presented by the Petition in IPR2016-01579, on which the Board
`
`instituted IPR. Fresenius Kabi also submits a Motion for Joinder to join this
`
`Petition with the IPR2016-01579 proceedings. Indeed, this Petition is an almost
`
`verbatim copy of the petition in IPR2016-01579.
`
`For the reasons explained below, and the reasons the Board instituted IPR in
`
`IPR2016-01579, Fresenius Kabi is likely to prevail that claims 1–11 and 13 of the
`
`’527 patent would have been obvious, at least, over the Precedex Label, 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. Aurobindo requests that the Board
`
`instituted IPR and cancel each of claims 1–11 and 13 of the ’527 patent.
`
`
`
`1
`
`

`

`II. GROUNDS FOR STANDING
`
`Petitioner certifies that, under 37 C.F.R. § 42.104(a), the ’527 patent is
`
`available for inter partes review and that Petition is not barred or estopped from
`
`requesting inter partes review of the ’527 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 1–11 and 13 of the ’527
`
`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 ’527 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 Precedex™ injection for intravenous
`
`infusion following dilution (or alternatively “Precedex™ Concentrate”). See, e.g.,
`
`Ex. 1007; Ex. 1002, ¶19.
`
`Formulation of Parenteral Drugs
`
`B.
`Parenteral pharmaceutical formulations include a variety of active
`
`ingredients, which may be incorporated into liquids. Ex. 1028, pp. 2-4. 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.
`
`“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. 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 ’527 Patent
`The specification of the ’527 patent relates to compositions and methods
`
`comprising premixed dexmedetomidine pharmaceutical compositions useful for
`
`sedation. Ex. 1001, col. 2, ll. 3 – 9, col. 10, ll. 1 – 25. The specification discloses
`
`various glass (vials, ampoules, syringes), and plastic (polyvinyl chloride (PVC),
`
`VisIV™, CR3, and polypropylene) containers. Id., col. 9, ll. 21–29. The
`
`specification discloses concentration ranges for the premixed compositions,
`
`including between about 0.005 to about 50 μg/mL. Id., col. 7, l. 44 – col. 8, l. 19.
`
`Prosecution History of the ’527 Patent
`
`E.
`The application that issued as the ’527 patent was filed on November 15,
`
`2012 as U.S. Application No. 13/678,148 (Ex. 1054, “the ’148 application”). The
`
`’148 application was a continuation of U.S. Application No. 13/541,524 (Ex. 1048,
`
`“the ’524 application”), which was 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”).
`
`The ‘148 applicants submitted a Petition to Make Special under the
`
`Accelerated Examination Program, and an Accelerated Examination Support
`
`
`
`7
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`

`

`Document asserting novelty and non-obviousness over the prior art, including a
`
`reference entitled “Dexmedetomidine HCL Draft Labeling: Precedex™
`
`Dexmedetomidine Hydrochloride Injection” (“the Precedex Draft Label”, Ex.
`
`1009). After a December 20, 2012, Examiner-Initiated Interview, applicants filed
`
`terminal disclaimers over the ’158 patent, the ’470 patent, and co-pending U.S.
`
`Application No. 13/678,260 (Ex. 1051, “the ’260 application”). The Examiner
`
`allowed the claims on January 11, 2013. Ex. 1055.
`
`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 1-11 and 13 of the ’527 patent.
`
`Statutory Grounds of Challenge
`
`B.
`Petitioner requests that claims 1-11 and 13 of the ’527 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”) held an advanced degree,
`
`such as a Ph.D or M.D., in the field of drug development and formulation, or had
`
`significant clinical experience in anesthesia or sedation, including parental
`
`administration, as of January 4, 2012. Ex. 1002, ¶23.
`
`
`
`8
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`

`

`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.
`
`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,
`
`1312-13 (Fed. Cir. 2005).2 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 challenged claim of the ’527 patent recites a “ready-to-use” liquid
`
`composition of dexmedetomidine. “Ready-to-use” is a well-known term of art in
`
`
`2 Thus, this claim construction analysis should not be viewed as a concession as to
`
`the proper scope of any claim term in litigation.
`
`
`
`9
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`

`

`the medical and pharmaceutical industry. Ex. 1002, ¶20; Ex. 1003, ¶23,24,34. 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.” Ex.
`
`1002, ¶¶28-30; Ex. 1003, ¶34; Ex. 1044. The ‘527 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
`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.”3
`
`Ex. 1001 at col. 3, ll. 59-65 (emphasis added). 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.
`
`
`3 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. 52-58.
`
`
`
`10
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`

`

`2.
`
`Dexmedetomidine
`
`Each claim of the ’527 patent likewise requires “dexmedetomidine.” Under
`
`the broadest reasonable interpretation, a POSA would understand the term
`
`“dexmedetomidine” to mean “substantially pure, optically active dextrorotary
`
`stereoisomer of medetomidine, as the free base or pharmaceutically acceptable
`
`salt.” Ex. 1001, col. 3, ll. 24-27. The specification further defines
`
`“dexmedetomidine” as “(S)-4-[1-(2,3-dimethylphenyl) ethyl]-1H-imidazole,” and
`
`provides the following chemical formula:
`
`Ex. 1001, col. 3, ll. 24-50.
`
`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
`
`
`
`11
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`

`

`1
`
`2
`
`3
`
`§ 103(a)
`
`1-11, 13 2010 Precedex Label (Ex. 1007) in
`view of Palmgren (Ex. 1017)
`
`§ 103(a)
`
`1-11, 13
`
`§ 103(a)
`
`1-11, 13
`
`US 6,716,867 (Ex. 1006) in view of the
`2010 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)
`
`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
`As described in Section IV.E, supra, the application that issued as the ’527
`
`patent claims priority to the’672 application, issued as the ’158 patent, which was
`
`filed on January 4, 2012. Accordingly, the earliest possible effective filing date of
`
`the ’527 patent is January 4, 2012.
`
`
`
`12
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`

`

`1.
`
`2010 Precedex Label (Ex. 1007)
`
`The 2010 Precedex Label published in September 2010 and qualifies as prior
`
`art against the ’527 patent under 35 U.S.C. § 102(b). The 2010 Precedex Label
`
`disclosed Precedex (dexmedetomidine hydrochloride) for intravenous infusion
`
`following dilution. Ex. 1007 at 1.
`
`2.
`
`U.S. Patent No. 6,716,867 (Ex. 1006)
`
`U.S. Patent No. 6,716,867 (“the ’867 patent”) (Ex. 1006) issued on April 6,
`
`2004, and constitutes prior art under 35 U.S.C. § 102(b). The ’867 patent disclosed
`
`a method of sedating a patient by administering dexmedetomidine or a
`
`pharmaceutically acceptable sa