UNITED STATES PATENT AND TRADEMARK OFFICE
`
`———————
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`
`———————
`
`ETON PHARMACEUTICALS, INC.,
`
`Petitioner
`
`v.
`
`EXELA PHARMA SCIENCES, LLC,
`
`Patent Owner
`
`———————
`
`U.S. PATENT NO. 10,583,155
`
`PGR2020-00068
`
`
`
`PETITION FOR POST GRANT REVIEW
`
`
`1
`
`EXELA 2016
`Eton Pharmaceuticals v. Exela Pharma Sciences
`PGR2020-00086
`
`

`

`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION ................................................................................................ 1
`
`II. MANDATORY NOTICES .................................................................................. 3
`
`A. Real Party-in-Interest................................................................................. 3
`
`B. Related Matters .......................................................................................... 3
`
`C. Lead and Back-up Counsel and Service Information ............................... 5
`
`D. Service Information ................................................................................... 5
`
`III. PAYMENT OF FEES .......................................................................................... 6
`
`IV. CERTIFICATION OF STANDING .................................................................... 6
`
`V. OVERVIEW OF CHALLENGE AND RELIEF REQUESTED ........................ 7
`
`A. Petitioner Requests Cancellation of the Challenged Claims ..................... 7
`
`B. The Sandoz Label, the Hospira Label, and the Hospira 7.25%
`Cysteine HCl Package Insert (and associated Federal Register
`Publication) are Publicly Available Prior Art ........................................... 8
`
`C. Additional References Cited to Establish the Knowledge of a
`POSITA are Publicly Available Prior Art ...............................................12
`
`D. Sections 325(d) and 314(a) Do Not Impede Institution ..........................21
`
`VI. OVERVIEW OF U.S. PATENT 10,478,155 .....................................................22
`
`A. Summary of Specification .......................................................................22
`
`B. Summary of the Challenged Claims ........................................................23
`
`C. Summary of the Prosecution History ......................................................25
`
`D. Level of Ordinary Skill in the Art ...........................................................29
`
`VII. CLAIM CONSTRUCTION.............................................................................29
`
`2
`
`

`

`VIII. THE CHALLENGED CLAIMS ARE UNPATENTABLE ............................30
`
`A. Statement of the Relevant Law ...............................................................30
`
`B. Overview of Prior Art Cited in the Grounds ...........................................31
`
`1.
`
`Sandoz Label (Ex. 1005) .................................................................31
`
`2. Hospira Label - Aminosyn® 5% (amino acids) (Ex. 1009) .............34
`
`3. Hospira 7.25% Cysteine HCl Package Insert (Ex. 1093 and Ex.
`1092) ................................................................................................35
`
`4.
`
`75 Fed. Reg. 31,790-791 (June 4, 2010) (Exhibit 1091) ................36
`
`C. Additional Knowledge of the POSITA As of The Effective Filing
`Date ..........................................................................................................36
`
`1. The Motivation For Lowering Aluminum Levels ..........................36
`
`2. The Sources of Aluminum Contamination Were Well-Known
`and Easily Rectified ........................................................................39
`
`3. L-Cysteine’s Oxygen Sensitivity Was Well-Known And Easily
`Addressed ........................................................................................40
`
`D. Claims 1-30 Are Unpatentable ................................................................42
`
`1. Ground 1: Claims 1-16, 18, 23-24, and 26-30 Are Obvious
`Over the Combination of the Sandoz Label and the Hospira
`Label, In View of the Knowledge of a POSITA .............................45
`
`2. Ground 2: Claims 17, 19-22, and 25 Are Obvious Over the
`Combination of the Sandoz Label and the Hospira Label, In
`Further View of the Hospira 7.25% Cysteine HCl Package
`Insert (or 75 Fed. Reg. 31,790-791 (June 4, 2010)) and the
`Knowledge of a POSITA ................................................................69
`
`IX. ABSENCE OF SECONDARY CONSIDERATIONS ......................................73
`
`X. CONCLUSION ..................................................................................................73
`
`3
`
`

`

`XI. CERTIFICATE OF WORD COUNT ................................................................74
`
`
`
`
`
`4
`
`

`

`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`
`Apple Inc. v. Fintiv, Inc.,
`IPR2020-00019, Paper 11 (PTAB March 20, 2020) .......................................... 22
`
`Celltrion, Inc. v. Biogen, Inc.,
`IPR2017-01095, Paper 60 (PTAB Oct. 4, 2018) ................................................ 12
`
`ClearValue, Inc. v. Pearl River Polymers, Inc.,
`668 F.3d 1340 (Fed. Cir. 2012) .......................................................................... 50
`
`In re Copaxone Consol. Cases,
`906 F.3d 1013 (Fed. Cir. 2018) .......................................................................... 31
`
`General Plastic Industrial Co., Ltd. v. Canon Kabushiki Kaisha,
`IPR2016-01357, Paper 19 (PTAB Sept. 6, 2017) ............................................... 21
`
`Grünenthal GmbH v. Antecip Bioventures II LLC,
`PGR2018-00092, Paper 25 (PTAB Feb. 25, 2020) ............................................ 12
`
`Hulu, LLC v. Sound View Innovations, LLC,
`IPR2018-01039, Paper 29 (PTAB Dec. 20, 2019) ................................... 9, 12, 13
`
`Koninklijke Philips N.V. v. Google LLC,
`948 F.3d 1330 (Fed. Cir. 2020) .......................................................................... 30
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 30, 31
`
`NHK Spring Co. v. Intri-Plex Techs, Inc.,
`IPR2018-00752, Paper 8 (PTAB Sept. 12, 2018) ............................................... 22
`
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) .......................................................................... 50
`
`Philips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) .......................................................................... 29
`
`Randall Mfg. v. Rea,
`733 F.3d 1355 (Fed. Cir. 2013) ............................................................................ 8
`
`5
`
`

`

`Realtime Data, LLC v. Iancu,
`912 F.3d 1368 (Fed. Cir. 2019) .......................................................................... 31
`
`Yeda Research v. Mylan Pharms. Inc.,
`906 F.3d 1031 (Fed. Cir. 2018) .......................................................................... 31
`
`Statutes
`
`35 U.S.C. § 103 .............................................................................................. 7, 25, 27
`
`35 U.S.C. § 112(a) ................................................................................................... 25
`
`Other Authorities
`
`37 C.F.R. §42.10(b) ................................................................................................... 5
`
`37 C.F.R. § 42.15(b) .................................................................................................. 6
`
`37 C.F.R. §42.24 ...................................................................................................... 74
`
`37 C.F.R. § 42.200 ................................................................................................... 29
`
`6
`
`

`

`PETITIONER’S EXHIBIT LIST
`
`Exhibit Description
`
`1001
`
`U.S. Patent No. 10,583,155 (“’155 patent”)
`
`1002
`
`U.S. Patent No. 10,478,453 File History
`
`1003
`
`Declaration of Barrett Rabinow, Ph.D.
`
`1004
`
`Affidavit of Christopher Butler
`
`1005
`
`Way Back Machine Screenshots of
`
`https://web.archive.org/web/20170403170533/http:/drugsdb.eu/drug.p
`hp?d=L-
`cysteine%20Hydrochloride&m=Sandoz%20Inc&id=083366d6-0437-
`4ee0-90d4-440a5b5d03b5.xml and
`
`https://web.archive.org/web/20160824090050/http:/drugsdb.eu/drug.p
`hp?d=L-
`cysteine%20Hydrochloride&m=Sandoz%20Inc&id=083366d6-0437-
`4ee0-90d4-440a5b5d03b5.xml
`
`A Hernández-Sánchez et al., Aluminum in Parenteral Nutrition: A
`Systematic Review, 67 EUR. J. CLINICAL NUTRITION 230 (2013)
`
`Robert L. Poole et al., Aluminum in Pediatric Parenteral Nutrition
`Products: Measured Versus Labeled Content, 16 J. PEDIATRIC
`PHARMACOLOGY & THERAPEUTICS 92 (2011)
`
`Denise Bohrer et al., Influence of the Glass Packing on the
`Contamination of Pharmaceutical Products by Aluminum. Part II:
`Amino Acids for Parenteral Nutrition, 15 J. TRACE ELEMENTS MED. &
`BIOLOGY 103 (2001) (“Bohrer II”)
`
`1006
`
`1007
`
`1008
`
`7
`
`

`

`1009
`
`Way Back Machine Screenshots of
`
`https://web.archive.org/web/20130831172706/http:/www.drugsdb.eu/d
`rug.php?d=Aminosyn&m=Hospira,%20Inc.&id=2A72A8B8-A77C-
`49C6-3C8D-43B03672D802.xml
`
`1010
`
`Affidavit of Christopher Butler
`
`1011
`
`1012
`
`Kavita Pilaniya et al., Recent Trends in the Impurity Profile of
`Pharmaceuticals, 3 J. ADVANCED PHARMACEUTICAL TECH. & RES. 302
`(2010)
`
`Denise Bohrer et al., Influence of the Glass Packing on the
`Contamination of Pharmaceutical Products by Aluminum. Part III:
`Interaction Container-Chemicals During the Heating for Sterilisation,
`17 J. TRACE ELEMENTS MED. & BIOLOGY 107 (2003) (“Bohrer III”)
`
`1013
`
`Q3D ELEMENTAL IMPURITIES: GUIDANCE FOR INDUSTRY (Sept. 2015)
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`Michael J Akers, Parenteral Preparations, in REMINGTON: THE
`SCIENCE AND PRACTICE OF PHARMACY 810 (David B. Troy et al. eds.,
`21st ed. 2006)
`
`Winston W.K. Koo et al., Aluminum in Parenteral Nutrition
`Solution— Sources and Possible Alternatives, 10 J. PARENTERAL &
`ENTERAL NUTRITION 591 (1986)
`
`Cysteine, DRUGBANK, https://www.drugbank.ca/drugs/DB00151 (last
`visited May 7, 2020)
`
`Barrett E. Rabinow et al., Plastic Packaging Materials, in
`REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 1047 (David
`B. Troy et al. eds., 21st ed. 2006)
`
`FDA GUIDANCE FOR INDUSTRY Q8(R2) PHARMACEUTICAL
`DEVELOPMENT, U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
`FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION
`
`8
`
`

`

`AND RESEARCH (CDER) CENTER FOR BIOLOGICS EVALUATION AND
`RESEARCH (CBER) (Nov. 2009)
`
`1019
`
`1020
`
`1021
`
`August 4, 2017 Letter from Donna Griebel, M.D., Director of Division
`of Gastroenterology and Inborn Errors Products, CDER, to Patent
`Owner
`
`Loyd V. Allen, L-Cysteine Hydrochloride 50 mg/mL Injection, 36 U.S.
`PHARMACIST 41 (Sept. 20, 2011)
`
`ESSENTIALS OF PHARMACEUTICAL CHEMISTRY (Donald Cairns ed., 4th
`ed. 2012)
`
`1022
`
`Declaration of Harry “Warren” Johnson
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`M.X. Sullivan et al., The Effect of Pyruvic Acid on the Estimation of
`Cystine and Cysteine, 122 J. BIOL. CHEM. 11 (1937)
`
`R.S. Asquith et al., The Photochemical Degradation of Cystine in
`Aqueous Solution in the Presence of Air, 184 BIOCHIMICA ET
`BIOPHYSICA ACTA (BBA) – GENERAL SUBJECTS 345 (1969)
`
`Soji Rokushika et al., Radiolysis of Cystine in Aqueous Solution by
`Gamma Irradiation, 7-2 J. RADIATION RES. 47 (1966)
`
`Ben H. Nicolet, Biochemistry by Analogy: The Sulfur of Cystine, 28 J.
`WASH. ACADS. SCI. 84 (1938)
`
`Kenneth C. Waterman et al., Stabilization of Pharmaceuticals to
`Oxidative Degradation, 7 PHARMACEUTICAL DEV. & TECH. 1 (2002).
`
`Henri J. R. Maget, Use of an Oxygen Extractor to Minimize Oxidation
`of Compounded Preparations, 3 INT’L J. PHARM. COMPOUNDING 493
`(1999)
`
`1029
`
`Alpaslan Yaman, Engineering Considerations in Sterile Powder
`Processes, in STERILE PHARMACEUTICAL PRODUCTS: PROCESS
`
`9
`
`

`

`ENGINEERING APPLICATIONS 297 (Kenneth E. Avis ed. 1995)
`
`1030
`
`Copyright Registration Number for Alpaslan Yaman, Engineering
`Considerations in Sterile Powder Processes, in STERILE
`PHARMACEUTICAL PRODUCTS: PROCESS ENGINEERING APPLICATIONS
`297 (Kenneth E. Avis ed. 1995)
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`
`Jalpa Patel et al., Stability Considerations for Biopharmaceuticals,
`Part 1: Overview of Protein and Peptide Degradation Pathways, 2011
`BIOPROCESS INT’L 20
`
`Henry L. Avallone et al., Food and Drug Administration Inspection
`and Licensing of Manufacturing Facilities, in DRUG BIOTECHNOLOGY
`REGULATION: SCIENTIFIC BASIS AND PRACTICES 322-23 (Yuan-yuan H.
`Chiu et al. eds. 1991)
`
`Gaozhong Zhu et al., Formulation of Protein- and Peptide-Based
`Parental Products, in PHARMACEUTICAL DOSAGE FORMS (Sandeep
`Nema et al. eds. 2010)
`
`Andrew Teasdale et al., Impurities in New Drug Substances and New
`Drug Products: ICH Q3A/B: Key Guidelines in the General Impurity
`Management Process, in ICH QUALITY GUIDELINES: AN
`IMPLEMENTATION GUIDE (Andrew Teasdale et al. eds. 2018)
`
`Aluminum in Large and Small Volume Parenterals Used in Total
`Parenteral Nutrition, 65 Fed. Reg. 4103 (Jan. 26, 2000) (codified at 21
`C.F.R. pt. 201)
`
`G.J. Schuringa et al., The Reaction of Combined Cystine of Wool with
`Sodium Bisulfite, 21 TEXTILE RES. J. 281 (1951)
`
`Lawrence X. Yu et al., Understanding Pharmaceutical Quality by
`Design, 16 AM. ASSOC. PHARM. SCIENTISTS J. 771 (2014
`
`Victoria Lima-Rogel et al., Aluminum Contamination in Parenteral
`Nutrition Admixtures for Low-Birth-Weight Preterm Infants in Mexico,
`
`10
`
`

`

`1039
`
`1040
`
`1041
`
`40 J. PARENTERAL AND ENTERAL NUTRITION 1014 (2016).
`
`Ulrich Reichert et al., Metal Residue: How Much is Too Much?,
`PHARMA MANUFACTURING (Aug. 19, 2013)
`
`Diane L. Tribble et al., Hypercysteinemia and Delayed Sulfur
`Excretion in Cirrhotics After Oral Cysteine Loads, 50 Am. Soc.
`Clinical Nutrition 1401 (1989)
`
`David Connaughton, Argon or Nitrogen: Which is Best for Your
`Application?, PARKER (Sept. 15, 2016), http://blog.parker.com/argon-
`or-nitrogen-which-is-best-for-your-application
`
`1042
`
`Prescribing Information for Selenious Acid Injection (revised
`04/2019)
`
`1043
`
`July 10, 2019 Press Release regarding Selenious Acid Injection
`
`1044
`
`Prescribing Information for Zinc Sulfate Injection (revised 07/2019)
`
`1045
`
`1046
`
`UCSF CHILDREN’S HOSPITAL INTENSIVE CARE NURSERY HOUSE STAFF
`MANUAL (2004-2006)
`
`Reese H. Clark et al., Effects of Two Different Doses of Amino Acid
`Supplementation on Growth and Blood Amino Acid Levels in
`Premature Neonates Admitted to the Neonatal Intensive Care Unit: A
`Randomized, Controlled Trial, 129 PEDIATRICS 1286 (2007)
`
`1047
`
`E. Friedmann et al., CCLXV, Reactions of Pyruvic Acid with
`Thiolacetic Acid and Cysteine, 30 BIOCHEM. J. 1886 (1936)
`
`1048
`
`U.S. Patent No. 8,415,337 (“’337 patent”)
`
`1049
`
`Maaike A. Riedijk et al., Cysteine: A Conditionally Essential Amino
`Acid In Low-Birth-Weight Preterm Infants?, 86 AM. J. CLIN.
`NUTRITION 1120 (2007)
`
`11
`
`

`

`1050
`
`1051
`
`A. D. Patrick, The Degradative Metabolism of L-Cysteine and L-
`Cystine In Vitro By Liver in Cystinosis, 83 BIOCHEM. J. 248 (1962)
`
`Soghier LM et al., CYSTEINE, CYSTINE OR N-ACETYLCYSTEINE
`SUPPLEMENTATION IN PARENTERALLY FED NEONATES (REVIEW),
`COCHRANE DATABASE OF SYSTEMATIC REVIEWS (2010).
`
`1052
`
`Screenshot of https://www.rxlist.com/aminosyn-sulfite-free-drug.htm
`
`1053
`
`1054
`
`1055
`
`1056
`
`1057
`
`1058
`
`1059
`
`August 2017 Important Drug Warning Letter from Patent Owner to
`Health Care Provider
`
`Aluminum in Large and Small Volume Parenterals Used in Total
`Parenteral Nutrition, 63 Fed. Reg. 176 (Jan. 5, 1998) (codified at 21
`C.F.R. 201)
`
`W. Mihatsch, et al., ESPGHAN/ESPEN/ESPR/ESPEN Guidelines on
`Pediatric Parenteral Nutrition: Calcium, Phosphorus and Magnesium,
`37 CLINICAL NUTRITION (2018)
`
`Dayong Luo et al., Kinetics and Mechanism of the Reaction of
`Cysteine and Hydrogen Peroxide in Aqueous Solution, 94 J. PHARM.
`SCI. 304 (2005)
`
`CDER – NON-CLINICAL REVIEW(S), APP. NO. 210906ORIG1S000
`(signed 09/28/2018)
`
`Arika Hanaki, et al., Manometric Study of the Copper-Catalyzed
`Oxidation of Cysteine, 19 CHEM. PHARM. BULL. 1006 (1971)
`
`
`E. S. Guzman Barron, Thiol Groups of Biological Importance, in
`Advances in Enzymology and Related Subjects of Biochemistry 203-
`207 (F. F. Nord ed., 1951)
`
`1060
`
`Daniel Rudman et al., Hypotyrosinemia, Hypocystinemia, and Failure
`to Retain Nitrogen During Total Parenteral Nutrition of Cirrhotic
`
`12
`
`

`

`1061
`
`1062
`
`1063
`
`1064
`
`Patients, 81 GASTROENTEROLOGY 1025 (1981)
`
`Len Okabe, Studies on the Solubility of Cystine Under Various
`Conditions, and On A New Method of Cystine Preparation, 8
`BIOCHEM. J. 441 (1927)
`
`QUALITY BY DESIGN (QBD) APPROACHES FOR ORALLY INHALED AND
`NASAL DRUG PRODUCTS (OINDPS) IN THE USA, RDD EUROPE (2007)
`
`Walter D. Block et al., Methionine, Cysteine, Cystine, and Taurine
`Interrelationships in Human Plasma, 22 AM. J. CLINICAL NUTRITION
`33 (1969)
`
`Mary Fewtrell et al., Symposium 2: Micronutrients Under the
`Microscope Aluminium Exposure From Parenteral Nutrition in
`Preterm Infants and Later Health Outcomes During Childhood and
`Adolescence, 70 PROCEEDINGS OF THE NUTRITION SOC. 299 (2011)
`
`1065
`
`Charles J. J. Fox, On the Coefficients of Absorption of Nitrogen and
`Oxygen in Distilled Water and Sea-Water and of Atmospheric
`Carbonic Acid in Sea-Water, 5 TRANS. FARAD. SOC., 68 (1909)
`
`1066
`
`STANDARD METHODS FOR THE EXAMINATION OF WATER AND SEWAGE,
`APHA (2d ed. 1915)
`
`1067
`
`U.S. Patent No. 6,382,442 (“’442 patent”)
`
`1068
`
`21 C.F.R. § 201.323
`
`1069
`
`1070
`
`Kasra Kasaraian et al., Developing an Injectable Formula Containing
`an Oxygen-Sensitive Drug: A Case Study of Danofloxacin Injectable, 4
`PHARM. DEV. & TECH. 475 (1999)
`
`Michael L. McHalsky, et al., Reduction of Aluminum Levels in
`Dialysis Fluids Through the Development and Use of Accurate and
`Sensitive Analytical Methodology, 41 J. PARENTERAL SCI. & TECH. 67
`
`13
`
`

`

`(1987)
`
`1071
`
`Barrett E. Rabinow et al., Aluminum in Parenteral Products: Analysis,
`Reduction and Implications for Pediatric TPN, 43 J. PARENTERAL SCI.
`& TECH. (1989)
`
`1072
`
`George C. Whipple et al., Solubility of Oxygen in Sea Water, 33 J. AM.
`CHEM. SOC. 362 (1911)
`
`1073
`
`Orange Book Screenshot for Elcys
`
`1074
`
`DRUG FACTS AND COMPARISONS (2015)
`
`1075
`
`Copyright Registration Number for DRUG FACTS AND COMPARISONS
`(2015)
`
`1076
`
`USP 32/NF 18, The U.S. Pharmacopeial Convention (1995)
`
`1077
`
`Eton Pharmaceuticals, Inc.’s May 6, 2020 Answer and Affirmative
`Defenses to Complaint in Exela Pharma Sciences, LLC v. Eton
`Pharmaceuticals, Inc., No. 20-00365-MN (D. Del., filed March 16,
`2020)
`
`1078
`
`Declaration of Daniel Ingles
`
`1079
`
`1080
`
`SIGMA ALDRICH PRODUCT INFORMATION, L-CYSTEINE
`HYDROCHLORIDE MONOHYDRATE (05/06)
`
`R.C. Whiting et al., Effect of Headspace Oxygen Concentration on
`Growth and Toxin Production by Proteolytic Strains of Clostridium
`Botulinum, 55 J. FOOD PROTECTION 23 (1992)
`
`1081
`
`Farideh Jalilehvand et al., Lead(II) Complex Formation with L-
`Cysteine in Aqueous Solution, 54 INORG. CHEM. 2160 (2015)
`
`1082
`
`Ian B. Butler et al., Removal of Dissolved Oxygen From Water: A
`
`14
`
`

`

`Comparison of Four Common Techniques, 41 TALANTA 211 (1994)
`
`1083
`
`U.S. Patent No. 10,583,155 File History
`
`1084
`
`1085
`
`1086
`
`1087
`
`1088
`
`1089
`
`1090
`
`1091
`
`Jay Mirtallo et. al., Safe Practices for Parenteral Nutrition, 28 J.
`PARENTERAL & ENTERAL NUTRITION S39 (2004)
`
`Michael C. Storm et al., Cysteine Supplementation Normalizes Plasma
`Taurine Concentrations in Low Birth Weight Premature Infants
`Requiring Parenteral Nutrition Support, 27 NUTRITION WEEK 2003
`ABSTRACTS S4
`
`Johannes B. van Goudoever et al., ESPGHAN/ESPEN/ESPR/CSPEN
`Guidelines on Pediatric Parenteral Nutrition: Amino Acids, 37
`CLINICAL NUTRITION 2315 (2018)
`
`Letter from Baxter Healthcare Corp. to Healthcare Professional, dated
`November 30, 2017
`
`Ekhard E. Zeigler, Parenteral Nutrition¸ in IOWA NEONATOLOGY
`HANDBOOK (2006)
`
`Patricia Worthington et al., When is Parenteral Nutrition
`Appropriate?, 41 J. PARENTERAL & ENTERAL NUTRITION 324 (2017)
`
`Emily Gasser et al., Parenteral Nutrition: Macronutrient Composition
`and Requirements, 27 SUPPORT LINE 6 (2005)
`
`Determination that Cysteine Hydrochloride Injection, USP, 7.25%,
`Was Not Withdrawn From Sale for Reasons of Safety or Effectiveness,
`75 Fed. Reg. 31,790 (June 4, 2010)
`
`1092
`
`May 8, 2018 Citizen Petition regarding Cysteine Hydrochloride
`Injection 5% and Attachments (including Hospira Package Insert)
`
`1093
`
`Declaration of Madan Chilakuri
`
`15
`
`

`

`1094
`
`1095
`
`1096
`
`1097
`
`1098
`
`1099
`
`1100
`
`BENTLEY’S TEXTBOOK OF PHARMACEUTICALS: AN ADAPTATION
`(Sanjay K. Jain eds. et al., 2012)
`
`Michael H. Malloy et al., Total Parenteral Nutrition in Sick Preterm
`Infants: Effects of Cysteine Supplementation with Nitrogen Intakes of
`240 and 400 mg/kg/day, 3 J. PEDIATRIC GASTROENTEROLOGY &
`NUTRITION 239 (1984)
`
`Terhi Ahola et al., N-Acetylcysteine Does Not Prevent
`Bronchopulmonary Dysplasia in Immature Infants: A Randomized
`Control Trial, 143 J. PEDIATRICS 713 (2003)
`
`Stanley H. Zlotkin, et al., Cysteine Supplementation to Cysteine-free
`Intravenous Feeding Regimens in Newborn Infants, 34 AM. J.
`CLINICAL NUTRITION 914 (1981)
`
`GUIDANCE FOR INDUSTRY: E11 CLINICAL INVESTIGATION
`OF MEDICINAL PRODUCTS IN THE PEDIATRIC POPULATION
`(Dec. 2000)
`
`THE UNITED STATES PHARMACOPEIA – THE NATIONAL FORMULARY,
`(1985)
`
`Joseph Boullata, Nutrients and Associated Substances, in REMINGTON:
`THE SCIENCE AND PRACTICE OF PHARMACY 1688 (David B. Troy et al.
`eds., 21st ed. 2006)
`
`1101
`
`U.S. Patent No. 10,478,453 (“’453 patent”)
`
`1102
`
`1103
`
`Yakup Yesil et al., Evaluation of the Children with Acute
`Acetaminophen Overdose and Intravenous N-Acetylcysteine
`Treatment, 34 PAK J. MED. SCI. 590 (2018)
`
`WM Lee et al., Intravenous N-Acetylcysteine Improves Transplant-
`Free Survival in Early Stage Non-Acetaminophen Acute Liver Failure,
`137 GASTROENTEROLOGY 856 (2009)
`
`16
`
`

`

`1104
`
`Shadi S. Yarandi et al., Amino Acid Composition in Parenteral
`Nutrition: What is the Evidence?, 14 CURRENT OPINION IN CLINICAL
`NUTRITION & METABOLIC CARE, 75 (2011)
`
`1105
`
`Declaration of Judy He
`
`
`
`17
`
`

`

`
`
`Petitioner Eton Pharmaceuticals, Inc. (“Petitioner” or “Eton”) requests post
`
`grant review (“PGR”) of claims 1-30 (“Challenged Claims”) of U.S. Patent No.
`
`10,583,155 (“’155 patent”) (Ex. 1001), purportedly owned by Exela Pharma
`
`Sciences, LLC (“Patent Owner”). Petitioner seeks a determination that the
`
`Challenged Claims are unpatentable.
`
`I.
`
`INTRODUCTION
`
`The ’155 patent’s claims are generally directed to a method of treating a
`
`subject having an adverse health condition responsive to L-Cysteine administration,
`
`and a total parenteral composition comprising a stable L-Cysteine composition
`
`having specified levels of aluminum, L-cystine and pyruvic acid, which were known
`
`impurities. The ’155 patent is listed in the U.S. Food and Drug Administration’s
`
`(“FDA”) electronic version of Approved Drug Products with Therapeutic
`
`Equivalence Evaluations (“Orange Book”) as covering ELCYS®, an Cysteine
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`Hydrochloride Solution 500 mg/10 mL (50 mg/mL). Ex. 1073 at 1-2. According to
`
`the Orange Book, Patent Owner is the Applicant Holder for ELCYS®. Ex. 1073 at
`
`3.
`
`Claims 1-16, 18, 23-24, and 26-30 are unpatentable under 35 U.S.C. § 103
`
`over the combination of the Sandoz Label and the Hospira Label, in view of the
`
`knowledge possessed by the person of ordinary skill in the art (“POSITA”), and
`
`claims 17, 19-22, and 25 are unpatentable over the combination of the Sandoz Label,
`
`18
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`

`

`the Hospira Label in further view of the Hospira 7.5% Cysteine Hydrochloride
`
`(“HCl”) Package Insert (and/or its associated Federal Register publication), in view
`
`of the knowledge possessed by the POSITA.
`
`The Sandoz Label discloses, among other
`
`things, an L-Cysteine
`
`Hydrochloride Injection (50 mg/mL) composition and is indicated for use as an
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`additive to crystalline amino acid injections to meet the intravenous amino acid
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`nutritional requirements of infants in need of total parenteral nutrition (“TPN”),
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`which is a claimed “adverse health condition.” The Hospira Label discloses, among
`
`other things, crystalline amino acid solutions for injection of the type taught by the
`
`Sandoz Label.
`
`The Hospira 7.5% Cysteine HCl Package Insert (and its associated Federal
`
`Register publication) discloses an FDA-approved L-Cysteine Hydrochloride
`
`injection solution indicated for use as an additive to amino acids solutions to treat a
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`variety of adverse health conditions, including to meet the nutritional requirements
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`of newborn infants in need of TPN and of adult and pediatric patients with severe
`
`liver disease who may have impaired enzymatic processes and require TPN. It can
`
`also be added to amino acid solutions to provide a more complete profile of amino
`
`acids for protein synthesis.
`
`The POSITA could have and would have been motivated, before the effective
`
`filing date of the ’155 patent, i.e., January 15, 2019, to optimize the product that is
`
`19
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`

`

`the subject of the Sandoz Label for use in the claimed methods of treatments as
`
`taught by the Sandoz Label and the Hospira 7.5% Cysteine HCl Package Insert with
`
`a reasonable expectation of success. And, even if there had been no such motivation
`
`to optimize the Sandoz Label product (and there most certainly was), the Challenged
`
`Claims merely recite known compositions with known impurities at known levels
`
`for use in known methods of treatment. The claims are not patentable. Had the
`
`Examiner been fully apprised of the full scope and content of the prior art, the
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`Challenged Claims would not have issued.
`
`Accordingly, this Petition, and its supporting evidence, including the
`
`Declaration of Dr. Barrett Rabinow (Ex. 1003) and the prior art discussed herein,
`
`demonstrates that it is more likely than not that at least one of the Challenged Claims
`
`of the ’155 patent is unpatentable, and thus a PGR trial should be instituted, and the
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`Challenged Claims found unpatentable.
`
`II. MANDATORY NOTICES
`
`A. Real Party-in-Interest
`
` The following are real parties in interest: Eton Pharmaceuticals, Inc.
`
`B. Related Matters
`
`The ’155 patent is subject to the following civil actions:
`
`•
`
`Exela Pharma Sciences, LLC v. Eton Pharms., Inc., Case No. 1:20-cv-
`
`00365-MN (D. Del., filed March 16, 2020) (“District Court Action”);
`
`20
`
`

`

`•
`
`Exela Pharma Sciences LLC v. Sandoz Inc., Case No. 1:20-cv-00645-
`
`MN (D. Del., filed May 14, 2020); and
`
`•
`
`Exela Pharma Sciences LLC v. Sandoz Inc., Case No. 1:20-cv-01393
`
`(D. Colo., filed May 15, 2020).
`
`As noted above, Patent Owner filed the District Court Action against
`
`Petitioner on March 16, 2020. Petitioner filed its Answer and Affirmative Defenses
`
`to Patent Owner’s Complaint on May 6, 2020. Ex. 1077 at 1-24. The District Court
`
`has not yet issued a Scheduling Order.
`
`In addition to the ’155 patent, Petitioner is aware of two other issued patents
`
`and five pending patent applications that are in the same family and which claim
`
`priority to the same application as the ’155 patent, namely, Application No.
`
`16/248,460 (“the ’460 application”). The ’460 application issued as U.S. Patent No.
`
`10,478,453 and is the subject of a Petition for Post-Grant Review filed by Petitioner
`
`on May 19, 2020 (PGR2020-00064). The issued patents and pending applications
`
`in the family of the ’155 patent are as follows:
`
`U.S. Patent / U.S. Patent Appl. Nos.
`U.S. Patent No. 10,478,453
`
`Purported Filing Date
`January 15, 2019
`
`U.S. Patent Appl. No. 16/746,028
`
`January 17, 2020
`
`U.S. Patent No. 10,653,719
`U.S. Patent Appl. No.16/773,641
`
`January 27, 2020
`
`21
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`

`

`U.S. Patent Appl. No.16/850,726
`U.S. Patent Appl. No.16/850,962
`U.S. Patent Appl. No.16/850,973
`
`April 16, 2020
`
`
`
`C. Lead and Back-up Counsel and Service Information
`
`Lead Counsel
`Ralph J. Gabric (Reg. No. 34,167)
`ralph.gabric.ipr@haynesboone.com
`HAYNES AND BOONE LLP
`2323 Victory Ave. Suite 700
`Dallas, TX 75219
`Tel.: (312) 216-1620
`
`
`
`
`
`Back-Up Counsel
`Eugene Goryunov (Reg. No. 61,579)
`eugene.goryunov.ipr@haynesboone.com
`HAYNES AND BOONE LLP
`2323 Victory Ave. Suite 700
`Dallas, TX 75219
`Tel.: (312) 216-1620
`
`Judy K. He (Reg. No. 75,173)
`judy.he.ipr@haynesboone.com
`HAYNES AND BOONE LLP
`2323 Victory Ave. Suite 700
`Dallas, TX 75219
`Tel.: (312) 216-1620
`
`Jeff Wolfson (Reg. No. 42,234)
`jeff.wolfson.ipr@haynesboone.com
`HAYNES AND BOONE LLP
`2323 Victory Ave. Suite 700
`Dallas, TX 75219
`Tel.: (312) 216-1620
`
`
`Petitioner concurrently submits a Power of Attorney. 37 C.F.R. §42.10(b).
`
`D. Service Information
`
`Please address all correspondence to lead and back-up counsel. Petitioner
`
`consents to electronic service.
`
`22
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`

`

`III. PAYMENT OF FEES
`
`The undersigned authorizes the Office to charge the fee set forth in 37 C.F.R.
`
`§ 42.15(b) for this Petition to Deposit Account No. 08-1394. The undersigned
`
`further authorizes payment for any additional fees that may be due in connection
`
`with this Petition to be charged to the above-referenced deposit account.
`
`IV. CERTIFICATION OF STANDING
`
`The PGR provisions apply to any patent containing a claim with an effective
`
`filing date after March 16, 2013. See AIA §§ 3(n)(1) and 6(f)(2)(A). The ’155 patent
`
`issued from U.S. Patent Appl. No. 16/665,702 (“’702 application”), filed on October
`
`28, 2019. Ex. 1083 at 2-124. The ’702 application claims priority to a parent
`
`application, the ’460 application (now U.S Patent No. 10,478,453), which was filed
`
`on January 15, 2019. Ex. 1001 at 1. Accordingly, the effective filing date of the
`
`’155 patent is no earlier than January 15, 2019 (the January 15, 2019 effective filing
`
`date is assumed for purposes of this PGR), years after March 16, 2013, meaning that
`
`the ’155 patent is available for PGR.
`
`Petitioner is filing this Petition within nine months of the issue date of the
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`’155 patent, March 10, 2020. Ex. 1001 at 1. Petitioner further certifies that it is not
`
`barred or estopped from requesting PGR of the Challenged Claims on the grounds
`
`identified in this Petition.
`
`23
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`

`

`V. OVERVIEW OF CHALLENGE AND RELIEF REQUESTED
`
`A. Petitioner Requests Cancellation of the Challenged Claims
`
`Petitioner requests institution of a PGR trial and cancellation of the
`
`Challenged Claims based on the grounds set forth below,1 which is supported by,
`
`among other things, the Declaration of Barrett Rabinow, Ph.D. (Ex. 1003):
`
`Ground Basis Challenged Claims
`
`Asserted Reference(s)
`
`1
`
`§ 103 1-16, 18, 23-24, and
`26-30
`
`2
`
`§ 103
`
`17, 19-22, 25
`
`The Sandoz Label and the Hospira
`Label, in view of the Knowledge of a
`POSITA
`
`The Combination of the Sandoz Label
`and the Hospira Label, in further view
`of the Hospira 7.25% Cysteine HCl
`Package Insert (and/or 75 Fed. Reg.
`31,790-791 (June 2010)), in view of the
`Knowledge of a POSITA
`
`
`
`The public availability and prior art status of the Sandoz Label, the Hospira
`
`Label, and the Hospira 7.25% Cysteine HCl Package Insert (and associated Federal
`
`Register publication) are established below in Part V.B. An obviousness analysis
`
`must “read[] the prior art in context, taking account of ‘demands known to the design
`
`community’, ‘the background knowledge possessed by a person having ordinary
`
`1 For purposes of this Petition only, Petitioner does not challenge the Challenged
`
`Claims under § 112. Petitioner reserves the right to raise any and all applicable
`
`challenges, including any/all § 112 defenses, in the District Court Action.
`
`24
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`

`

`skill in the art,’ and ‘the inferences and creative steps that a person of ordinary skill
`
`in the art would employ.’” Randall Mfg. v. Rea, 733 F.3d 1355, 1362 (Fed. Cir.
`
`2013) (quoting KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007)).
`
`Eton demonstrates the knowledge of a POSITA in Dr. Rabinow’s Declaration
`
`and various additional prior art references. These additional references are identified
`
`to establish what a POSITA would have known at the relevant time, and not to
`
`supplement the disclosure of the prior art references cited in the Grounds. The public
`
`availability and prior art status of Eton’s additional references are established below
`
`in Part V.C.
`
`A more detailed discussion of the substance of the Sandoz Label, the Hospira
`
`Label, the Hospira 7.25% Cysteine HCl Package Insert (and associated Federal
`
`Register publication) and Eton’s additional references that are reflective of the
`
`knowledge possessed by the POSITA is presented below in Parts VIII.B and VIII.C,
`
`respectively.
`
`B. The Sandoz Label, the Hospira Label, and the Hospira 7.25%
`Cysteine HCl Package Insert (and