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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`PATENT TRIAL AND APPEAL BOARD
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`ADAMIS PHARMACEUTICALS CORPORATION
`Petitioner
`
`v.
`
`BELCHER PHARMACEUTICALS, LLC
`Patent Owner
`
`_____________________
`
`CASE: IPR2019-01021
`U.S. PATENT NO. 9,283,197
`_____________________
`
`
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`
`
`PETITION FOR INTER PARTES REVIEW
`
`
`
`
`Mail Stop PATENT BOARD
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`PO Box 1450
`Alexandria, Virginia 22313–1450
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`

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`Petition for Inter Partes Review of U.S. Patent No. 9,283,197
`
`Table of Contents
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`Page
`
`INTRODUCTION ........................................................................................... 1 
`
`
`I. 
`
`II.  OVERVIEW OF THE TECHNOLOGY ...................................................... 2 
`
`A.  Epinephrine Compound ............................................................................. 2 
`
`B.  Epinephrine Injection Formulations ......................................................... 3 
`
`C.  Racemization and Oxidation Processes .................................................... 5 
`
`D.  Adrenalone and Other Impurities ............................................................. 7 
`
`III.  U.S. PATENT NO. 9,283,197 ......................................................................... 8 
`
`A. 
`
`‘197 Patent Overview .................................................................................. 8 
`
`B.  Prosecution History of the ‘197 Patent ..................................................... 9 
`
`IV.  GROUNDS FOR STANDING (37 C.F.R. §42.104(a)) .............................. 11 
`
`V.  PAYMENT OF FEES (37 C.F.R. §§42.15 AND 42.103) ........................... 11 
`
`VI.  MANDATORY NOTICES (37 C.F.R. §42.8) ............................................. 11 
`
`A.  Real Parties-In-Interest ............................................................................ 11 
`
`B.  Related Matters ......................................................................................... 11 
`
`C.  Lead and Backup Counsel and Service ................................................... 12 
`
`D.  The Petition Relies on Previously Unapplied Prior Art ........................ 12 
`
`VII.  PERSON OF ORDINARY SKILL IN THE ART ..................................... 14 
`
`VIII. CLAIM CONSTRUCTION ......................................................................... 15 
`
`IX.  STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFOR (37 C.F.R. §§42.22(a) AND 42.104(b)) ............. 17 
`
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`Petition for Inter Partes Review of U.S. Patent No. 9,283,197
`
`A.  Ground 1: Claim 6 is Unpatentable Under 35 U.S.C. §102 as
`Anticipated by Stepensky .......................................................................... 18 
`
`1.  Overview of the Prior Art of Ground 1 ............................................... 18 
`
`a. 
`
`Stepensky ............................................................................................. 18 
`
`2.  Claim 6 .................................................................................................... 21 
`
`a. 
`
`b. 
`
`c. 
`
`d. 
`
`e. 
`
`Preamble ............................................................................................. 21 
`
`said liquid pharmaceutical formulation having a pH between 2.8
`and 3.3 ................................................................................................. 21 
`
`said injectable liquid pharmaceutical formulation compounded in
`an aqueous solution as 1.0 to 1.06 mg/mL l-epinephrine, and further
`including a tonicity agent ................................................................... 22 
`
`said liquid pharmaceutical formulation including no more than
`about 6% d-epinephrine and no more than about 0.5% adrenalone
`at release ............................................................................................. 22 
`
`said liquid pharmaceutical formulation including no more than
`about 12% d-epinephrine and no more than about 0.5% adrenalone
`over a shelf-life of at least 12 months ................................................ 24 
`
`B.  Ground 2: The Challenged Claims are Unpatentable Under 35 U.S.C.
`§103 Over Stepensky in view of USP ....................................................... 25 
`
`1.  Overview of the Prior Art of Ground 2 ............................................... 25 
`
`a. 
`
`Stepensky ............................................................................................. 25 
`
`b.  USP ...................................................................................................... 25 
`
`c.  The Combination of Stepensky and USP ......................................... 26 
`
`2.  Claim 6 .................................................................................................... 27 
`
`a. 
`
`Preamble ............................................................................................. 27 
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`Petition for Inter Partes Review of U.S. Patent No. 9,283,197
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`b. 
`
`c. 
`
`d. 
`
`e. 
`
`said liquid pharmaceutical formulation having a pH between 2.8
`and 3.3 ................................................................................................. 28 
`
`said injectable liquid pharmaceutical formulation compounded in
`an aqueous solution as 1.0 to 1.06 mg/mL l-epinephrine, and further
`including a tonicity agent ................................................................... 29 
`
`said liquid pharmaceutical formulation including no more than
`about 6% d-epinephrine and no more than about 0.5% adrenalone
`at release ............................................................................................. 30 
`
`said liquid pharmaceutical formulation including no more than
`about 12% d-epinephrine and no more than about 0.5% adrenalone
`over a shelf-life of at least 12 months ................................................ 30 
`
`3.  Claim 7 .................................................................................................... 31 
`
`a. 
`
`The said injectable liquid pharmaceutical formulation of claim 6
`further having a concentration of 1 mg per mL l-epinephrine ........ 31 
`
`C.  Ground 3: The Challenged Claims are Unpatentable Under 35 U.S.C.
`§103 Over Stepensky in View of Gupta .................................................... 32 
`
`1.  Overview of the Prior Art of Ground 3 ............................................... 32 
`
`a.  Gupta ................................................................................................... 32 
`
`b.  The Combination of Stepensky and Gupta ...................................... 35 
`
`2.  Claim 6 .................................................................................................... 36 
`
`a. 
`
`b. 
`
`c. 
`
`Preamble ............................................................................................. 36 
`
`said liquid pharmaceutical formulation having a pH between 2.8
`and 3.3 ................................................................................................. 37 
`
`said injectable liquid pharmaceutical formulation compounded in
`an aqueous solution as 1.0 to 1.06 mg/mL l-epinephrine, and further
`including a tonicity agent ................................................................... 37 
`
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`Petition for Inter Partes Review of U.S. Patent No. 9,283,197
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`d. 
`
`e. 
`
`said liquid pharmaceutical formulation including no more than
`about 6% d-epinephrine and no more than about 0.5% adrenalone
`at release ............................................................................................. 38 
`
`said liquid pharmaceutical formulation including no more than
`about 12% d-epinephrine and no more than about 0.5% adrenalone
`over a shelf-life of at least 12 months ................................................ 39 
`
`3.  Claim 7 .................................................................................................... 40 
`
`a. 
`
`The said injectable liquid pharmaceutical formulation of claim 6
`further having a concentration of 1 mg per mL l-epinephrine ........ 40 
`
`D.  Ground 4: the Challenged Claims are Unpatentable Under 35 U.S.C.
`§103 Over Bruss in View of USP and Fyllingen ..................................... 40 
`
`1.  Overview of the Prior Art of Ground 4 ............................................... 41 
`
`a.  Bruss.................................................................................................... 41 
`
`b.  USP ...................................................................................................... 42 
`
`c.  Fyllingen ............................................................................................. 42 
`
`d.  The Combination of Bruss in view of USP and Fyllingen ............. 43 
`
`2.  Claim 6 .................................................................................................... 44 
`
`a. 
`
`b. 
`
`c. 
`
`d. 
`
`Preamble ............................................................................................. 44 
`
`said liquid pharmaceutical formulation having a pH between 2.8
`and 3.3 ................................................................................................. 45 
`
`said injectable liquid pharmaceutical formulation compounded in
`an aqueous solution as 1.0 to 1.06 mg/mL l-epinephrine, and further
`including a tonicity agent ................................................................... 46 
`
`said liquid pharmaceutical formulation including no more than
`about 6% d-epinephrine and no more than about 0.5% adrenalone
`at release ............................................................................................. 47 
`iv
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`Petition for Inter Partes Review of U.S. Patent No. 9,283,197
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`e. 
`
`said liquid pharmaceutical formulation including no more than
`about 12% d-epinephrine and no more than about 0.5% adrenalone
`over a shelf-life of at least 12 months ................................................ 48 
`
`3.  Claim 7 .................................................................................................... 49 
`
`a. 
`
`The said injectable liquid pharmaceutical formulation of claim 6
`further having a concentration of 1 mg per mL l-epinephrine ........ 49 
`
`E.  Ground 5: the Challenged Claims Are Unpatentable Under 35 U.S.C.
`§103 Over Gupta In View Of Fyllingen And Zeleznick ......................... 49 
`
`1.  Overview of the Prior Art of Ground 6 ............................................... 50 
`
`a.  Gupta ................................................................................................... 50 
`
`b.  Fyllingen ............................................................................................. 50 
`
`c. 
`
`Zeleznick ............................................................................................. 50 
`
`d.  The Combination of Gupta in view of Fyllingen and Zeleznick .... 51 
`
`2.  Claim 6 .................................................................................................... 52 
`
`a. 
`
`b. 
`
`c. 
`
`d. 
`
`e. 
`
`Preamble ............................................................................................. 52 
`
`said liquid pharmaceutical formulation having a pH between 2.8
`and 3.3 ................................................................................................. 53 
`
`said injectable liquid pharmaceutical formulation compounded in
`an aqueous solution as 1.0 to 1.06 mg/mL l-epinephrine, and further
`including a tonicity agent ................................................................... 54 
`
`said liquid pharmaceutical formulation including no more than
`about 6% d-epinephrine and no more than about 0.5% adrenalone
`at release ............................................................................................. 55 
`
`said liquid pharmaceutical formulation including no more than
`about 12% d-epinephrine and no more than about 0.5% adrenalone
`over a shelf-life of at least 12 months ................................................ 56 
`v
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`3.  Claim 7 .................................................................................................... 57 
`
`a. 
`
`The said injectable liquid pharmaceutical formulation of claim 6
`further having a concentration of 1 mg per mL l-epinephrine ........ 57 
`
`F.  Ground 6: The Challenged Claims are Unpatentable Under 35 U.S.C.
`§103 Over Szulczewski in View of Fyllingen ........................................... 57 
`
`1.  Overview of the Prior Art of Ground 6 ............................................... 57 
`
`a. 
`
`Szulczewski ......................................................................................... 57 
`
`b.  Fyllingen ............................................................................................. 59 
`
`c.  The Combination of Szulczewski and Fyllingen ............................. 59 
`
`2.  Claim 6 .................................................................................................... 60 
`
`a. 
`
`b. 
`
`c. 
`
`d. 
`
`e. 
`
`Preamble ............................................................................................. 60 
`
`said liquid pharmaceutical formulation having a pH between 2.8
`and 3.3 ................................................................................................. 60 
`
`said injectable liquid pharmaceutical formulation compounded in
`an aqueous solution as 1.0 to 1.06 mg/mL l-epinephrine, and further
`including a tonicity agent ................................................................... 61 
`
`said liquid pharmaceutical formulation including no more than
`about 6% d-epinephrine and no more than about 0.5% adrenalone
`at release ............................................................................................. 62 
`
`said liquid pharmaceutical formulation including no more than
`about 12% d-epinephrine and no more than about 0.5% adrenalone
`over a shelf-life of at least 12 months ................................................ 63 
`
`3.  Claim 7 .................................................................................................... 64 
`
`a. 
`
`The said injectable liquid pharmaceutical formulation of claim 6
`further having a concentration of 1 mg per mL l-epinephrine ........ 64 
`
`
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`Petition for Inter Partes Review of U.S. Patent No. 9,283,197
`
`G.  Ground 7: the Challenged Claims are Unpatentable Under 35 U.S.C.
`§103 Over Szulczewski in View of Fyllingen and Gupta ........................ 64 
`
`a. 
`
`Szulczewski ......................................................................................... 64 
`
`b.  Fyllingen ............................................................................................. 64 
`
`c.  Gupta ................................................................................................... 65 
`
`d.  The Combination of Szulczewski in view of Fyllingen and Gupta 65 
`
`2.  Claim 6 .................................................................................................... 66 
`
`a. 
`
`b. 
`
`c. 
`
`d. 
`
`e. 
`
`Preamble ............................................................................................. 66 
`
`said liquid pharmaceutical formulation having a pH between 2.8
`and 3.3 ................................................................................................. 66 
`
`said injectable liquid pharmaceutical formulation compounded in
`an aqueous solution as 1.0 to 1.06 mg/mL l-epinephrine, and further
`including a tonicity agent ................................................................... 67 
`
`said liquid pharmaceutical formulation including no more than
`about 6% d-epinephrine and no more than about 0.5% adrenalone
`at release ............................................................................................. 67 
`
`said liquid pharmaceutical formulation including no more than
`about 12% d-epinephrine and no more than about 0.5% adrenalone
`over a shelf-life of at least 12 months ................................................ 68 
`
`3.  Claim 7 .................................................................................................... 69 
`
`a. 
`
`The formulation has a concentration of 1 mg per mL l-epinephrine
` ............................................................................................................. 69 
`
`X.  SECONDARY CONSIDERATIONS .......................................................... 69 
`
`XI.  CONCLUSION ............................................................................................. 70 
`
`
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`vii
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`Petition for Inter Partes Review of U.S. Patent No. 9,283,197
`
`List of Exhibits
`
`Ex. 1001: U.S. Patent No. 9,283,197 (“‘197 Patent”), filed August 15, 2014,
`
`issued March 15, 2016
`
`Ex. 1002: Declaration of James Kipp, Ph.D.
`
`Ex. 1003: Curriculum vitae of James Kipp, Ph.D.
`
`Ex. 1004: Prosecution History of U.S. Patent No. 9,283,197
`
`Ex. 1005: Stepensky, D., Long-Term Stability Study of L-Adrenaline Injections:
`
`Kinetics of Sulfonation and Racemization Pathways of Drug
`
`Degradation, Journal of Pharmaceutical Sciences, Vol. 93 No. 4
`
`(“Stepensky”), published in April 2004
`
`Ex. 1006: U.S. Patent Application Publication No. 2008/0269347 to Bruss et al.
`
`(“Bruss”)
`
`Ex. 1007: Fyllingen, G., Racemisation and oxidation in adrenaline injections,
`
`Acta Pharm. Nord. 2(5) (“Fyllingen”), published in 1990
`
`Ex. 1008: Vidal-Ollivier, E., Assay for epinephrine and its impurities using
`
`reversed-phase high-performance liquid chromatography, Journal of
`
`Chromatography (“Vidal”), published in 1987
`
`Ex. 1009: Kerddonfak, S., The Stability and Sterility of Epinephrine Prefilled
`
`Syringe, Asian Pacific Journal of Allergy and Immunology,
`
`(“Kerddonfak”), published in 2010
`
`
`
`viii
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`Petition for Inter Partes Review of U.S. Patent No. 9,283,197
`
`Ex. 1010: U.S. Patent No. 5,002,973 to Zeleznick et al. (“Zeleznick”)
`
`Ex. 1011:
`
`International Patent Publication No. WO 2014/127015 to Gupta et al.
`
`(“Gupta”).
`
`Ex. 1012: Connors, K.A., Chemical Stability of Pharmaceuticals: A Handbook
`
`for Pharmacists, 2nd Edition (“Connors”), published in 1986
`
`Ex. 1013:
`
`2004 United States Pharmacopeia Monograph for Epinephrine (“2004
`
`USP”)
`
`Ex. 1014:
`
`2014 United States Pharmacopeia Monograph for Epinephrine (“2009
`
`USP” or “USP”)
`
`Ex. 1015: 2014 United States Pharmacopeia Monograph for Epinephrine (“2014
`
`USP”)
`
`Ex. 1016: Szulczewski, D. et al., Analytical Profiles of Drug Substances, 7,
`
`Epinephrine (“Szulczewski”), published in 1978
`
`
`
`Ex. 1017: Moed H.D. et al., Synthesis of beta-phenyl-ethylamine derivatives III
`
`Bronchodilators. Rec. Trav. Chim. 74 (“Moed”), published in 1955
`
`Ex. 1018:
`
`IMS Product Information
`
`Ex. 1019: Claim Construction Order
`
`in Case No. 17-775-LPS, Belcher
`
`Pharmaceuticals, LLC v. Hospira, Inc.
`
`
`
`ix
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`Petition for Inter Partes Review of U.S. Patent No. 9,283,197
`
`Ex. 1020: Belcher Initial Infringement Contentions in Case No. 8:18-cv-02379-
`
`WFJ-AAS,
`
`Adamis
`
`Pharmaceuticals
`
`Corp.
`
`v.
`
`Belcher
`
`Pharmaceuticals, LLC
`
`Ex. 1021: U.S. Patent Application Publication No. 12/846,656 to MacKay
`
`(“MacKay”)
`
`Ex. 1022: Goodman, L.S., The Pharmacological Basis of Therapeutics, 5th
`
`Edition, (“Goodman”) published in 1975
`
`Ex. 1023: Belcher Expert Report
`
`in Case No. 17-775-LPS, Belcher
`
`Pharmaceuticals, LLC v. Hospira, Inc.
`
`
`
`
`
`
`
`
`
`x
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`Petition for Inter Partes Review of U.S. Patent No. 9,283,197
`
`I.
`
`INTRODUCTION
`
`Adamis Pharmaceuticals Corporation (“Petitioner” or “Adamis”) requests
`
`Inter Partes Review (“IPR”) of the Challenged Claims (“Challenged Claims”) of
`
`U.S. Patent No. 9,283,197 (“‘197 Patent”) (Ex. 1001) under 35 U.S.C. §§311–319.
`
`The Challenged Claims recite a pharmaceutical formulation of l-epinephrine
`
`made in accordance with controlling standards and optimized as suggested and
`
`taught by the prior art. (Ex. 1002, ¶¶61–71). What is claimed is an injectable
`
`liquid pharmaceutical formulation of l-epinephrine sterile solution, having a pH
`
`between 2.8 and 3.3, compounded in an aqueous solution as 1.0 to 1.06 mg/mL l-
`
`epinephrine, and further including a tonicity agent. The Challenged Claims recite
`
`that the said liquid pharmaceutical formulation includes no more than about 6% d-
`
`epinephrine and no more than about 0.5% adrenalone at release, and no more than
`
`about 12% d-epinephrine and no more than about 0.5% adrenalone over a shelf-life
`
`of at least 12 months.
`
`The ‘197 Patent asserts “[t]he thought of raising the in-process pH above the
`
`2.2–2.6 of previous methods…was contradictory to one skilled in the art.” (Ex.
`
`1001, 4:44–47). This is simply not true. There is nothing surprising or new about
`
`the claimed pH range of the formulation. (Ex. 1002, ¶62). In fact, the prior art
`
`teaches the precise claimed pH range, as well as its known ability to optimize
`
`epinephrine stability. (Ex. 1002, ¶¶34, 51, 137–143). The prior art presented
`
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`Petition for Inter Partes Review of U.S. Patent No. 9,283,197
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`herein uses controlling guidelines, known epinephrine formulations, and prior art
`
`studies of epinephrine stability, alone and in combination, to show the claimed
`
`pharmaceutical formulation was not new as of August 15, 2014. More specifically,
`
`the prior art demonstrates that products in the field were already sufficiently stable
`
`so as to meet the asserted racemization and impurity limits of the Challenged
`
`Claims. (Ex. 1002, ¶¶63, 66).
`
`II. OVERVIEW OF THE TECHNOLOGY
`A. Epinephrine Compound
`The chemistry of epinephrine1 is well-known. (Ex. 1002, ¶¶20–41).
`
`Epinephrine is among the earliest hormones discovered and applied to the
`
`treatment of disease. Epinephrine is one of the neural hormones responsible for
`
`the regulation of the heart, blood pressure, airway resistance, and energy
`
`metabolism. (Ex. 1006, [0004]).
`
`Epinephrine generates an inotropic effect, in that it increases the heart rate,
`
`narrows the blood vessels thus increasing blood pressure, reduces airway resistance
`
`to make it easier to breathe, and raises blood glucose and blood fatty acids to
`
`
`1 Epinephrine is also referred to as adrenalin or adrenaline. The term epinephrine
`
`is used throughout the Petition for consistency. The compounds are identical in
`
`chemical structure.
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`Petition for Inter Partes Review of U.S. Patent No. 9,283,197
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`supply the body energy during stress. (Id.). For this reason, epinephrine is
`
`commonly applied by intravenous injection in emergency medicine. (Ex. 1005,
`
`969).
`
`Epinephrine is a catecholamine compound. (Id.). The full chemical name of
`
`epinephrine is 4-[1-hydroxy-2-(methylamino)ethyl]-1,2-benzenediol. (Ex. 1012,
`
`438). The structure of epinephrine is shown below:
`
`
`
`(Id.).
`
`Epinephrine
`
`shares
`
`similar chemical
`
`features with many other
`
`catecholamines, such as norepinephrine (noradrenaline), and dopamine. All of
`
`these molecules share a common catechol (3,4-dihydroxybenzene) moiety. (Ex.
`
`1002, ¶23).
`
`B.
`
`Epinephrine Injection Formulations
`
`Epinephrine is commonly applied by intravenous injection to treat allergic
`
`shock, asthma attacks, reduce nasal congestion and/or as a performance aid in an
`
`emergency situation. (Ex. 1002, ¶24). Epinephrine injection formulations are well
`
`known in the art with typical formulations consisting of the use of an epinephrine
`
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`Petition for Inter Partes Review of U.S. Patent No. 9,283,197
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`base, sodium metabisulfite, sodium chloride, and water for injection. (Ex. 1005,
`
`971–973). Numerous studies address the potential drug stabilizing effects of
`
`formulation variables as well as optimized conditions of the preparation and
`
`package of epinephrine solutions. (Id.; Ex. 1006; Ex. 1007; Ex. 1011). These
`
`studies indicate that the use of sodium metabisulfite as an antioxidant, removal of
`
`oxygen, and keeping the pH, a desired range (for example, 3.0–3.8) effectively
`
`prevents drug inactivation. (Ex. 1005, 977).
`
`Epinephrine solutions are generally sterilized by filtration or by heating.
`
`(Ex. 1012, 445). Additionally, tonicity agents may be used to adjust isotonicity
`
`and increase stability. (Id). Epinephrine injections must comply with governing
`
`standards from United States Pharmacopeia (“USP”), which outlines requirements
`
`for identity, potency, purity, and performance of pharmaceutical compounds. (Ex.
`
`1002, ¶25; Ex. 1013; Ex. 1014; Ex. 1015).
`
`The first modern epinephrine autoinjector, the EpiPen, was invented in the
`
`mid-1970s and approved for marketing by the FDA in 1987. (Ex. 1002, ¶28).
`
`Epinephrine injections, compliant with USP, consisting of sterile 1 mg/ml
`
`epinephrine solution in water for injections with the use of a tonicity agent have
`
`been commercially available since at least the 1990s. (Id.; see also, e.g., Ex.
`
`1018).
`
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`Petition for Inter Partes Review of U.S. Patent No. 9,283,197
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`C. Racemization and Oxidation Processes
`Epinephrine is subject to racemization and oxidation, both of which reduce
`
`the pharmacological efficacy of epinephrine. (Ex. 1005, 977–978; Ex. 1002, ¶29).
`
`Both reactions should be minimized in pharmaceutical formulations in order to
`
`maximize the amount of active l-epinephrine delivered to the patient. (Ex. 1002,
`
`¶29).
`
`Racemization is the enantiomeric conversion of l-epinephrine into its less
`
`biologically active dextrorotatory isoform, d-epinephrine. (Ex. 1005, 970). L-
`
`epinephrine is known in the art to be at least ten times more potent than d-
`
`epinephrine. (Ex. 1022, 483). The degradation chemistry in sulfite-free aqueous
`
`media is shown below:
`
`
`
`(Ex. 1002, ¶30).
`
`D-epinephrine has less pharmacological activity than l-epinephrine. (Ex.
`
`1005, 969). Thus, in creating epinephrine for pharmaceutical use, it is desirable to
`
`maximize the content of l-epinephrine in solution and decrease the likelihood of
`
`racemization. (Ex. 1002, ¶31).
`
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`Petition for Inter Partes Review of U.S. Patent No. 9,283,197
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`In addition to degradation through racemization, epinephrine is also easily
`
`subject to oxidation, which results in a colored solution. (Ex. 1012, 439). The
`
`final product of oxidation is adrenolutin as shown in the figure below:
`
`
`
`(Ex. 1002, ¶32; Ex. 1012, 440; Ex. 1008).
`
`The pH level is known to impact both the rate of racemization and oxidation
`
`in epinephrine injections. (Ex. 1002, ¶34). In particular, the rate of oxidation
`
`increases with a higher pH, while the rate of racemization decreases with a higher
`
`pH. (Ex. 1012, 441; Ex. 1007, 361). Accordingly, there is an optimum pH, which
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`racemization and oxidation can be balanced to minimize loss of potency. (Ex.
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`1002, ¶¶34, 51, 139). Most studies demonstrate that optimal stability is achieved
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`by maintaining the pH between 2.8 and 4.0. (Ex. 1012, 441 (optimum pH of 3.0 to
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`3.8); Ex. 1006, [0014] (optimum pH of 3.0 to 4.0); Ex. 1010, 2:55–57 (optimum
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`pH of 2.8 to 3.5); Ex. 1005, 977 (optimum pH of 3 to 3.8); Ex. 1009 at 55
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`(optimum pH range of 2.8–3.6). A pH between 2.8 and 4.0 is consistent with the
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`permissible pH range for an epinephrine injection as stated in USP—between 2.2
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`and 5.0. (Ex. 1014, 2261; Ex. 1002, ¶35).
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`D. Adrenalone and Other Impurities
`In compounding an epinephrine formulation it is also desirable to limit by-
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`product impurities in the starting drug substance (raw material). (Ex. 1002, ¶36;
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`Ex. 1011, 1). One such impurity is adrenalone and the limits of adrenalone
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`permissible in epinephrine raw material are laid out in USP. (Ex. 1014, 2260). In
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`particular, under the “Limit of Adrenalone,” USP states:
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`Its absorptivity (see Spectrophotometry and Light-scattering <851>),
`310 nm, determined in a solution in dilute hydrochloric acid (1 in 200)
`containing 2 mg per mL, is not more than 0.2.
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`(Id.).
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`This represents a molar percentage of 0.5% adrenalone. (Ex. 1002, ¶ 37-41).
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`It was also known in the art to measure and reduce the amount of adrenalone
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`present in epinephrine injections. (Ex. 1011). For example, commercially
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`available epinephrine injections, such as EpiPen, were found to comprise 0.071%
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`adrenalone. (Id., 16).
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`Petition for Inter Partes Review of U.S. Patent No. 9,283,197
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`III. U.S. PATENT NO. 9,283,197
`The application leading to the ‘197 Patent was filed on August 15, 2014.
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`(Ex 1001).
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`‘197 Patent Overview
`
`A.
`The ‘197 Patent is directed to an allegedly novel formulation of epinephrine
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`and method of medical use. (Ex. 1001). As the specification describes,
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`epinephrine has a long history of pharmaceutical use that spans many decades
`
`since it was first synthesized at the turn of the twentieth century. (Id., 1:15–18).
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`The background of the ‘197 Patent acknowledges that epinephrine
`
`formulations are plagued by the two major problems discussed above, racemization
`
`and oxidation. (Id., 1:55–58). The ‘197 Patent asserts that “[i]nadvertently,
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`increasing the in-process pH to 2.8–3.3, unexpectedly reduced the racemization of
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`l-epinephrine to d-epinephrine at release by approximately two-thirds, from 14% to
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`5%, respectively….This discovery led to new methods of manufacturing sulfite-
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`free, l-epinephrine solution with an in-process pH of 2.8 to 3.3, approximately 3.0,
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`which was a nonobvious solution to the problem of racemization.” (Ex. 1001,
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`4:48–58).
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`The Challenged Claims, however, do not require a preservative-free, sulfite-
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`free formulation. Instead, the Challenged Claims merely recite an injectable liquid
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`Petition for Inter Partes Review of U.S. Patent No. 9,283,197
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`pharmaceutical formulation in accordance with known USP epinephrine standards.
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`(Ex. 1002, ¶¶43–52).
`
`Claim 6 of the ‘197 Patent is reproduced below.
`
`l-
`formulation of
`liquid pharmaceutical
`injectable
`An
`epinephrine sterile solution; said
`liquid pharmaceutical
`formulation having a pH between 2.8 and 3.3; said injectable
`liquid pharmaceutical formulation compounded in an aqueous
`solution as 1.0 to 1.06 mg/mL l-epinephrine, and further
`including a
`tonicity agent; said
`liquid pharmaceutical
`formulation including no more than about 6% d-epinephrine
`and no more than about 0.5% adrenalone at release, and no
`more than about 12% d-epinephrine and no more than about
`0.5% adrenalone over a shelf-life of at least 12 months.
`
`Claim 7 further requires that the formulation has a concentration of 1 mg per
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`mL l-epinephrine.
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`Prosecution History of the ‘197 Patent
`
`B.
`During prosecution of the ‘197 Patent, Patent Owner argued the prior art did
`
`not disclose “Applicant’s pH range of 2.8 to 3.3, which was unexpectedly found to
`
`be critical by the Applicant to reduce the racemization of l-epinephrine.” (Ex.
`
`1004, 21). This assertion is incorrect. Numerous references not cited to or
`
`considered by the Patent Office disclose a pH range of 2.8 to 3.3. (See, e.g., Ex.
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`1010, 2:57–58 (disclosing a “most preferable” pH range of 2.8 to 3.5); Ex. 1006,
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`Petition for Inter Partes Review of U.S. Patent No. 9,283,197
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`[0014] (pH range of 3–4); Ex. 1005, 977 (pH range of 3–3.8); Ex. 1007 at 355 (pH
`
`range above 2.4 (3–3.5); Ex. 1009 at 55 (pH range of 2.8–3.6)).
`
`Further in this regard, during prosecution, Patent Owner stressed the
`
`importance of the sulfite-free formulation by arguing that a formulation of
`
`“preservative-free and sulfite-free, had never been accomplished before.” (Ex.
`
`1004, 19). Again, this assertion is incorrect. Sulfite-free epinephrine formulations
`
`have been in use since at least 1989. (Ex. 1010, Abstract). Moreover, the
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`Challenged Claims do not require the formulation to be preservative- and sulfite-
`
`free.
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`Nonetheless, the Examiner allowed the application stating: “nothing in the
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`prior art that would teach or suggest the instantly claimed pH range of between 2.8
`
`and 3.3 would result in the limited racemization and impurities as instantly
`
`claimed.” (Ex. 1004, 10). The Examiner did not have the benefit of the present art
`
`in front of it.
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`As discussed in detail below, the ‘197 Patent merely identifies a known
`
`solution to a known problem—optimizing pH to minimize racemization and
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`oxidation. The claimed pH range existed in the prior art. Moreover, the resulting
`
`claimed levels of d-epinephrine and adrenalone were known in the prior art. (Ex.
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`1002, ¶¶41, 52, 71).
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