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. 10,653,719
`
`PGR2020-00086
`
`PETITION FOR POST GRANT REVIEW
`
`

`

`Petition for Post Grant Review of U.S. Patent No. 10,653,719
`
`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`II. MANDATORY NOTICES ............................................................................. 2
`A. Real Party-in-Interest ................................................................................. 2
`B. Related Matters .......................................................................................... 2
`C. Lead and Back-up Counsel and Service Information ............................... 4
`D. Service Information ................................................................................... 4
`
`III.
`
`PAYMENT OF FEES ..................................................................................... 4
`
`IV. CERTIFICATION OF STANDING ............................................................... 5
`
`V. OVERVIEW OF CHALLENGE AND RELIEF REQUESTED .................... 5
`A. Petitioner Requests Cancellation of the Challenged Claims ..................... 5
`B. The Sandoz Label is Publicly Available Prior Art .................................... 7
`C. Additional References Cited to Establish the Knowledge of a
`POSITA are Publicly Available Prior Art ............................................. 8
`D. Sections 325(d) and 314(a) Do Not Impede Institution .......................... 16
`
`VI. OVERVIEW OF U.S. PATENT 10,653,719 ................................................ 17
`A. Summary of Specification ....................................................................... 17
`B. Summary of the Challenged Claims ........................................................ 17
`C. Summary of the Prosecution History ...................................................... 19
`D. Level of Ordinary Skill in the Art ........................................................... 23
`
`VII. CLAIM CONSTRUCTION .......................................................................... 24
`
`VIII. THE CHALLENGED CLAIMS ARE UNPATENTABLE .......................... 25
`A. Statement of the Relevant Law ............................................................... 25
`B. Overview of Prior Art Cited in the Grounds ........................................... 26
`1.
`Sandoz Label (Ex. 1005) ........................................................... 26
`C. Additional Knowledge of the POSITA as of the Effective Filing
`Date ...................................................................................................... 30
`1.
`The Motivation For Lowering Aluminum Levels .................... 30
`2.
`The Sources of Aluminum Contamination Were Well-
`Known and Easily Rectified ..................................................... 32
`L-Cysteine’s Oxygen Sensitivity Was Well-Known And
`Easily Addressed ....................................................................... 33
`D. Lack of Visually Detectable Particulate Matter in Injections Was
`Well Known ........................................................................................ 35
`E. Claims 1-30 Are Unpatentable ................................................................ 37
`
`3.
`
`i
`
`

`

`Petition for Post Grant Review of U.S. Patent No. 10,653,719
`
`1.
`
`Ground 1: Claims 1-27 Are Obvious Over the
`Combination of the Sandoz Label in view of the
`Knowledge of a POSITA .......................................................... 41
`
`IX. ABSENCE OF SECONDARY CONSIDERATIONS .................................. 55
`
`X.
`
`CONCLUSION .............................................................................................. 55
`
`XI. CERTIFICATE OF WORD COUNT ........................................................... 56
`
`
`ii
`
`

`

`Petition for Post Grant Review of U.S. Patent No. 10,653,719
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`
`Apple Inc. v. Fintiv, Inc.,
`IPR2020-00019, Paper 11 (PTAB March 20, 2020) .................................... 16, 17
`
`Celltrion, Inc. v. Biogen, Inc.,
`IPR2017-01095, Paper 60 (PTAB Oct. 4, 2018) .................................................. 9
`
`ClearValue, Inc. v. Pearl River Polymers, Inc.,
`668 F.3d 1340 (Fed. Cir. 2012) .......................................................................... 42
`
`In re Copaxone Consol. Cases,
`906 F.3d 1013 (Fed. Cir. 2018) .......................................................................... 26
`
`General Plastic Industrial Co., Ltd. v. Canon Kabushiki Kaisha,
`IPR2016-01357, Paper 19 (PTAB Sept. 6, 2017) ............................................... 16
`
`Grünenthal GmbH v. Antecip Bioventures II LLC,
`PGR2018-00092, Paper 25 (PTAB Feb. 25, 2020) .............................................. 9
`
`Hulu, LLC v. Sound View Innovations, LLC,
`IPR2018-01039, Paper 29 (PTAB Dec. 20, 2019) ........................................... 7, 9
`
`Koninklijke Philips N.V. v. Google LLC,
`948 F.3d 1330 (Fed. Cir. 2020) .......................................................................... 25
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 25, 26
`
`NHK Spring Co. v. Intri-Plex Techs, Inc.,
`IPR2018-00752, Paper 8 (PTAB Sept. 12, 2018) ............................................... 16
`
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) .......................................................................... 42
`
`Philips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) .......................................................................... 24
`
`Randall Mfg. v. Rea,
`733 F.3d 1355 (Fed. Cir. 2013) ............................................................................ 6
`
`iii
`
`

`

`Petition for Post Grant Review of U.S. Patent No. 10,653,719
`
`Realtime Data, LLC v. Iancu,
`912 F.3d 1368 (Fed. Cir. 2019) .......................................................................... 26
`
`Yeda Research v. Mylan Pharms. Inc.,
`906 F.3d 1031 (Fed. Cir. 2018) .......................................................................... 26
`
`Statutes
`
`35 U.S.C. § 103 .................................................................................................passim
`
`35 U.S.C. § 112(a) ................................................................................................... 19
`
`Other Authorities
`
`37 C.F.R. §42.10(b) ................................................................................................... 4
`
`37 C.F.R. § 42.15(b) .................................................................................................. 4
`
`37 C.F.R. § 42.200 ................................................................................................... 24
`
`iv
`
`

`

`Petition for Post Grant Review of U.S. Patent No. 10,653,719
`
`PETITIONER’S EXHIBIT LIST
`
`Exhibit Description
`
`1001 U.S. Patent No. 10,583,155
`
`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
`
`1006 A Hernández-Sánchez et al., Aluminum in Parenteral Nutrition: A
`Systematic Review, 67 EUR. J. CLINICAL NUTRITION 230 (2013)
`
`1007 Robert L. Poole et al., Aluminum in Pediatric Parenteral Nutrition
`Products: Measured Versus Labeled Content, 16 J. PEDIATRIC
`PHARMACOLOGY & THERAPEUTICS 92 (2011)
`
`1008 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”)
`
`1009 Number Not Used
`
`1010 Number Not Used
`
`1011 Kavita Pilaniya et al., Recent Trends in the Impurity Profile of
`Pharmaceuticals, 3 J. ADVANCED PHARMACEUTICAL TECH. & RES. 302
`
`v
`
`

`

`Petition for Post Grant Review of U.S. Patent No. 10,653,719
`
`(2010)
`
`1012 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 Michael J Akers, Parenteral Preparations, in REMINGTON: THE
`SCIENCE AND PRACTICE OF PHARMACY 810 (David B. Troy et al. eds.,
`21st ed. 2006)
`
`1015 Winston W.K. Koo et al., Aluminum in Parenteral Nutrition
`Solution— Sources and Possible Alternatives, 10 J. PARENTERAL &
`ENTERAL NUTRITION 591 (1986)
`
`1016 Cysteine, DRUGBANK, https://www.drugbank.ca/drugs/DB00151 (last
`visited May 7, 2020)
`
`1017 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)
`
`1018
`
`FDA GUIDANCE FOR INDUSTRY Q8(R2) PHARMACEUTICAL
`DEVELOPMENT, U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
`FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION
`AND RESEARCH (CDER) CENTER FOR BIOLOGICS EVALUATION AND
`RESEARCH (CBER) (Nov. 2009)
`
`1019 August 4, 2017 Letter from Donna Griebel, M.D., Director of Division
`of Gastroenterology and Inborn Errors Products, CDER, to Patent
`Owner
`
`1020 Loyd V. Allen, L-Cysteine Hydrochloride 50 mg/mL Injection, 36 U.S.
`PHARMACIST 41 (Sept. 20, 2011)
`
`1021 ESSENTIALS OF PHARMACEUTICAL CHEMISTRY (Donald Cairns ed., 4th
`ed. 2012)
`
`vi
`
`

`

`Petition for Post Grant Review of U.S. Patent No. 10,653,719
`
`1022 Declaration of Harry “Warren” Johnson, dated May 15, 2020
`
`1023 M.X. Sullivan et al., The Effect of Pyruvic Acid on the Estimation of
`Cystine and Cysteine, 122 J. BIOL. CHEM. 11 (1937)
`
`1024 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)
`
`1025
`
`Soji Rokushika et al., Radiolysis of Cystine in Aqueous Solution by
`Gamma Irradiation, 7-2 J. RADIATION RES. 47 (1966)
`
`1026 Ben H. Nicolet, Biochemistry by Analogy: The Sulfur of Cystine, 28 J.
`WASH. ACADS. SCI. 84 (1938)
`
`1027 Kenneth C. Waterman et al., Stabilization of Pharmaceuticals to
`Oxidative Degradation, 7 PHARMACEUTICAL DEV. & TECH. 1 (2002).
`
`1028 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
`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
`
`Jalpa Patel et al., Stability Considerations for Biopharmaceuticals,
`Part 1: Overview of Protein and Peptide Degradation Pathways, 2011
`BIOPROCESS INT’L 20
`
`1032 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)
`
`vii
`
`

`

`Petition for Post Grant Review of U.S. Patent No. 10,653,719
`
`1033 Gaozhong Zhu et al., Formulation of Protein- and Peptide-Based
`Parental Products, in PHARMACEUTICAL DOSAGE FORMS (Sandeep
`Nema et al. eds. 2010)
`
`1034 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)
`
`1035 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)
`
`1036 G.J. Schuringa et al., The Reaction of Combined Cystine of Wool with
`Sodium Bisulfite, 21 TEXTILE RES. J. 281 (1951)
`
`1037 Lawrence X. Yu et al., Understanding Pharmaceutical Quality by
`Design, 16 AM. ASSOC. PHARM. SCIENTISTS J. 771 (2014
`
`1038 Victoria Lima-Rogel et al., Aluminum Contamination in Parenteral
`Nutrition Admixtures for Low-Birth-Weight Preterm Infants in Mexico,
`40 J. PARENTERAL AND ENTERAL NUTRITION 1014 (2016).
`
`1039 Number Not Used
`
`1040 Number Not Used
`
`1041 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 UCSF CHILDREN’S HOSPITAL INTENSIVE CARE NURSERY HOUSE STAFF
`MANUAL (2004-2006)
`
`viii
`
`

`

`Petition for Post Grant Review of U.S. Patent No. 10,653,719
`
`1046 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 Number Not Used
`
`1050
`
` Number Not Used
`
`1051
`
` Number Not Used
`
`1052 Number Not Used
`
`1053 August 2017 Important Drug Warning Letter from Patent Owner to
`Health Care Provider
`
`1054 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)
`
`1055 W. Mihatsch, et al., ESPGHAN/ESPEN/ESPR/ESPEN Guidelines on
`Pediatric Parenteral Nutrition: Calcium, Phosphorus and Magnesium,
`37 CLINICAL NUTRITION (2018)
`
`1056 Dayong Luo et al., Kinetics and Mechanism of the Reaction of
`Cysteine and Hydrogen Peroxide in Aqueous Solution, 94 J. PHARM.
`SCI. 304 (2005)
`
`1057 CDER – NON-CLINICAL REVIEW(S), APP. NO. 210906ORIG1S000
`(signed 09/28/2018)
`
`1058 Arika Hanaki, et al., Manometric Study of the Copper-Catalyzed
`Oxidation of Cysteine, 19 CHEM. PHARM. BULL. 1006 (1971)
`
`
`ix
`
`

`

`Petition for Post Grant Review of U.S. Patent No. 10,653,719
`
`1059 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 Number Not Used.
`
`1061 Len Okabe, Studies on the Solubility of Cystine Under Various
`Conditions, and On A New Method of Cystine Preparation, 8
`BIOCHEM. J. 441 (1927)
`
`1062 QUALITY BY DESIGN (QBD) APPROACHES FOR ORALLY INHALED AND
`NASAL DRUG PRODUCTS (OINDPS) IN THE USA, RDD EUROPE (2007)
`
`1063 Number Not Used.
`
`1064 Number Not Used.
`
`1065 Number Not Used.
`
`1066 Number Not Used.
`
`1067 Number Not Used.
`
`1068
`
`21 C.F.R. § 201.323
`
`1069 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)
`
`1070 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
`(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 Number Not Used.
`
`x
`
`

`

`Petition for Post Grant Review of U.S. Patent No. 10,653,719
`
`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 August 11, 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
`
`SIGMA ALDRICH PRODUCT INFORMATION, L-CYSTEINE
`HYDROCHLORIDE MONOHYDRATE (05/06)
`
`1080 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
`Comparison of Four Common Techniques, 41 TALANTA 211 (1994)
`
`1083 Number Not Used.
`
`1084 Number Not Used.
`
`1085 Number Not Used.
`
`1086 Number Not Used.
`
`1087 Number Not Used.
`
`1088 Number Not Used.
`
`xi
`
`

`

`Petition for Post Grant Review of U.S. Patent No. 10,653,719
`
`1089 Number Not Used.
`
`1090 Number Not Used.
`
`1091 Number Not Used.
`
`1092 Number Not Used.
`
`1093 Number Not Used.
`
`1094 BENTLEY’S TEXTBOOK OF PHARMACEUTICALS: AN ADAPTATION
`(Sanjay K. Jain eds. et al., 2012)
`
`1095 Number Not Used.
`
`1096 Number Not Used.
`
`1097 Number Not Used.
`
`1098 Number Not Used.
`
`1099 Number Not Used.
`
`1100 Number Not Used.
`
`1101 U.S. Patent No. 10,478,453
`
`1102 Number Not Used.
`
`1103 Number Not Used.
`
`1104 Number Not Used.
`
`1105 Number Not Used.
`
`1106 U.S. Patent No. 10,654,719
`
`1107 U.S. Patent No. 10,654,719 File History
`
`1108
`
`Stephen E. Langille, Particulate Matter in Injectable Drug Products,
`
`xii
`
`

`

`Petition for Post Grant Review of U.S. Patent No. 10,653,719
`
`PDA J. PHARM. SCI. & TECH. 186, 186, 188 (2013)
`
`1109 Michael J. Akers, STERILE DRUG PRODUCTS: FORMULATION,
`PACKAGING, MANUFACTURING, AND QUALITY 434-36 (2010)
`
`1110 USP 32/NF 27 (The U.S. Pharmacopeial Convention, 2009)
`
`1111
`
`Salvatore J. Turco, Intravenous Admixtures, in REMINGTON: THE
`SCIENCE AND PRACTICE OF PHARMACY 810 (David B. Troy et al. eds.,
`21st ed. 2006)
`
`1112 Andy Rignall, ICHQ1A(R2) Stability Testing of New Drug Substance
`and Product and ICHQ1C Stability Testing of New Dosage Forms, in
`ICH QUALITY GUIDELINES: AN IMPLEMENTATION GUIDE 37 (Andrew
`Teasdale et al. eds., 2018)
`
`1113
`
`International Conference on Harmonisation; Guidance on Q6A
`Specifications: Test Procedures and Acceptance Criteria for New
`Drug Substances and New Drug Products: Chemical Substances, 65
`Fed. Reg. 83,041 (Dec. 29, 2000)
`
`1114
`
`FDA Warning Letter to Mr. Ian Reed, Pfizer, dated February 14, 2017
`
`1115
`
`Stability Studies, in HANDBOOK OF MODERN PHARMACEUTICAL
`ANALYSIS 466 (Satinder Ahuja eds. 2001)
`
`1116 Declaration of Harry “Warren” Johnson, dated August 24, 2020
`
`1117 Q1A(R2) STABILITY TESTING OF NEW DRUG SUBSTANCES AND
`PRODUCTS
`
`1118 August 26, 2020 Scheduling Order in Exela Pharma Sciences, LLC v.
`Eton Pharmaceuticals, Inc., No. 20-00365-MN (D. Del., filed March
`16, 2020)
`
`1119 THE MERCK INDEX: AN ENCYCLOPEDIA OF CHEMICALS, DRUGS, AND
`BIOLOGICALS (2006)
`
`1120 U.S. Patent No. 9,220,700
`
`xiii
`
`

`

`Petition for Post Grant Review of U.S. Patent No. 10,653,719
`
`1121
`
`July 23, 2020 Office Action in Application No. 16/746,028
`
`1122
`
`July 23, 2020 Office Action in Application No. 16/773,641
`
`1123 U.S. Patent No. 4,385,086
`
`xiv
`
`

`

`Petition for Post Grant Review of U.S. Patent No. 10,653,719
`
`
`
`Petitioner Eton Pharmaceuticals, Inc. (“Petitioner” or “Eton”) requests post
`
`grant review (“PGR”) of claims 1-27 (“Challenged Claims”) of U.S. Patent No.
`
`10,653,719 (“’719 patent”) (Ex. 1106), purportedly owned by Exela Pharma
`
`Sciences, LLC (“Patent Owner”). Petitioner seeks a determination that the
`
`Challenged Claims are unpatentable.
`
`I.
`
`INTRODUCTION
`
`The Challenged Claims are generally directed to L-Cysteine Hydrochloride
`
`solutions that, inter alia, contain less than about 150 ppb of aluminum, are
`
`substantially free of visually detectable particulate matter and intended for use as an
`
`additive in a parenteral nutrition composition. The ’719 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 Hydrochloride Solution 500 mg/10 mL (50 mg/mL). Ex.
`
`1073 at 2-3. According to the Orange Book, Patent Owner is the Applicant Holder
`
`for ELCYS®. Ex. 1073 at 1.
`
`The Challenged Claims are unpatentable under 35 U.S.C. § 103 over the
`
`combination of the Sandoz Label and the knowledge possessed by the person of
`
`ordinary skill in the art (“POSITA”). The Sandoz Label discloses, among other
`
`things, an L-Cysteine Hydrochloride Injection (50 mg/mL) solution that is intended
`
`for use as an additive in a parenteral nutrition composition. As discussed herein, the
`
`
`
`1
`
`

`

`Petition for Post Grant Review of U.S. Patent No. 10,653,719
`
`POSITA could have and would have been motivated, before the effective filing date
`
`of the ’719 patent, i.e., January 15, 2019, to optimize the product that is the subject
`
`of the Sandoz Label to contain less than 150 ppb aluminum (a known toxin), to be
`
`substantially free of visually detectable particulate matter (a known requirement of
`
`injectables solutions such as the product that is the subject of the Sandoz Label) and
`
`to have the other limitations required of the Challenged Claims. As a result, the
`
`Challenged Claims are not patentable. Had the Examiner been fully apprised of the
`
`full scope and content of the prior art, the 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 ’719 patent is unpatentable, and thus a PGR trial should be instituted, and the
`
`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 ’719 patent is subject to Exela Pharma Sciences, LLC v. Eton Pharms.,
`
`Inc., Case No. 1:20-cv-00365-MN (D. Del., filed March 16, 2020) (“District Court
`
`Action”). On July 28, 2020, Patent Owner filed an Amended Complaint in the
`
`
`
`2
`
`

`

`Petition for Post Grant Review of U.S. Patent No. 10,653,719
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`District Court Action to assert the ’719 patent against Petitioner. Petitioner filed its
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`Answer and Affirmative Defenses to Patent Owner’s Amended Complaint on
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`August 11, 2020. Ex. 1077 at 1-29. The District Court issued a Scheduling Order
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`on August 26, 2020. Ex. 1118 at 1-13.
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`In addition to the ’719 patent, Petitioner is aware of two other issued patents
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`and five pending patent applications that are in the same family and which claim
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`priority to the same application as the ’719 patent, namely, Application Nos.
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`16/248,460 (“the ’460 application”) and 16/665,702 (“the ’702 application”). The
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`’460 application, which issued as U.S. Patent No. 10,478,453, is the subject of a
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`Petition for Post-Grant Review filed by Petitioner on May 19, 2020 (PGR2020-
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`00064), and the ’702 application, which issued as U.S. Patent No. 10,583,155, is the
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`subject of a Petition for Post-Grant Review filed by Petitioner on June 8, 2020
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`(PGR2020-00068). The issued patents and pending applications in the family of the
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`’719 patent are as follows:
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`U.S. Patent / U.S. Patent Appl. Nos.
`U.S. Patent No. 10,478,453
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`Purported Filing Date
`January 15, 2019
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`U.S. Patent No. 10,583,155
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`October 28, 2019
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`U.S. Patent Appl. No. 16/746,028
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`January 17, 2020
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`U.S. Patent Appl. No.16/773,641
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`January 27, 2020
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`U.S. Patent Appl. No.16/850,726
`U.S. Patent Appl. No.16/850,962
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`April 16, 2020
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`3
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`Petition for Post Grant Review of U.S. Patent No. 10,653,719
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`U.S. Patent Appl. No.16/850,973
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`
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`C. Lead and Back-up Counsel and Service Information
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`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).
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`D. Service Information
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`Please address all correspondence to lead and back-up counsel. Petitioner
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`consents to electronic service.
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`III. PAYMENT OF FEES
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`The undersigned authorizes the Office to charge the fee set forth in 37 C.F.R.
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`
`
`4
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`

`Petition for Post Grant Review of U.S. Patent No. 10,653,719
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`§ 42.15(b) for this Petition to Deposit Account No. 08-1394. The undersigned
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`further authorizes payment for any additional fees that may be due in connection
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`with this Petition to be charged to the above-referenced deposit account.
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`IV. CERTIFICATION OF STANDING
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`The PGR provisions apply to any patent containing a claim with an effective
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`filing date after March 16, 2013. See AIA §§ 3(n)(1) and 6(f)(2)(A). The ’719 patent
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`issued from U.S. Patent Appl. No. 16/773,563 (“’563 application”), filed on January
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`27, 2020. Ex. 1106 at 1. The ’563 application claims priority to a parent application,
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`the ’460 application (now U.S Patent No. 10,478,453), which was filed on January
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`15, 2019. Ex. 1101 at 1. Accordingly, the effective filing date of the ’719 patent is
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`no earlier than January 15, 2019 (the January 15, 2019 effective filing date is
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`assumed for purposes of this PGR), years after March 16, 2013, meaning that the
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`’719 patent is available for PGR.
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`Petitioner is filing this Petition within nine months of the issue date of the
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`’719 patent, May 19, 2020. Ex. 1106 at 1. Petitioner further certifies that it is not
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`barred or estopped from requesting PGR of the Challenged Claims on the grounds
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`identified in this Petition.
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`V. OVERVIEW OF CHALLENGE AND RELIEF REQUESTED
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`A. Petitioner Requests Cancellation of the Challenged Claims
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`Petitioner requests institution of a PGR trial and cancellation of the
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`
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`5
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`Petition for Post Grant Review of U.S. Patent No. 10,653,719
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`Challenged Claims based on the grounds set forth below,1 which is supported by,
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`among other things, the Declaration of Barrett Rabinow, Ph.D. (Ex. 1003):
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`Ground Basis Challenged Claims
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`Asserted Reference(s)
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`1
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`§ 103
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`1-27
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`The Sandoz Label in view of the
`Knowledge of a POSITA
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`
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`The public availability and prior art status of the Sandoz Label are established
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`below in Part V.B. An obviousness analysis must “read[] the prior art in context,
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`taking account of ‘demands known to the design community’, ‘the background
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`knowledge possessed by a person having ordinary skill in the art,’ and ‘the
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`inferences and creative steps that a person of ordinary skill in the art would
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`employ.’” Randall Mfg. v. Rea, 733 F.3d 1355, 1362 (Fed. Cir. 2013) (quoting KSR
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`Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007)).
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`Eton demonstrates the knowledge of a POSITA by Dr. Rabinow’s Declaration
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`and the various prior art references cited and discussed therein. These additional
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`references are identified to establish what a POSITA would have known at the
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`relevant time, and not to supplement the disclosure of the prior art references cited
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`in the Grounds. The public availability and prior art status of Eton’s additional
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`1 For purposes of this Petition only, Petitioner does not challenge the Challenged
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`Claims under § 112. Petitioner reserves the right to raise any and all applicable
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`challenges, including any/all § 112 defenses, in the District Court Action.
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`
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`6
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`Petition for Post Grant Review of U.S. Patent No. 10,653,719
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`references are established below in Part V.C.
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`A more detailed discussion of the substance of the Sandoz Label and Eton’s
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`additional references that are reflective of the knowledge possessed by the POSITA
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`is presented below in Parts VIII.B and VIII.C, respectively.
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`B. The Sandoz Label is Publicly Available Prior Art
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`The Sandoz Label (Ex. 1005), revised in 2010, was publicly available no later
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`than August 24, 2016, on http://www.drugsDB.eu (“DrugsDB.eu”). Ex. 1005 at 1,
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`6; Ex. 1004 at 1-2, 10-11. DrugsDB.eu states that the Sandoz Label was reproduced
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`“with permission of U.S. National Library of Medicine.” Ex. 1005 at 1, 5, 6, 11; Ex.
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`1004 at 5, 9, 11, 14.
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`PTAB precedent provides guidance for establishing pharmaceutical labels as
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`prior art. In Sandoz Inc. v. AbbVie Biotechnology Ltd., the Board found that a
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`Wayback Machine screenshot, an accompanying Internet Archive affidavit
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`regarding the site, and expert testimony on how a POSITA “exercising reasonable
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`diligence could have located” the label was sufficient to establish the label as prior
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`art for institution. IPR2018-00156, Paper 11, at 10-13 (PTAB June 5, 2018)
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`(precedential); see also Hulu, LLC v. Sound View Innovations, LLC, IPR2018-
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`01039, Paper 29, at 18 (PTAB Dec. 20, 2019) (precedential) (confirming that a
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`screenshot of a website from the Wayback Machine, a declaration from the Internet
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`Archive including the site’s archival records, and expert testimony asserting its
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`
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`7
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`Petition for Post Grant Review of U.S. Patent No. 10,653,719
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`public accessibility was “strong indicia that an asserted reference was publicly
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`accessible”). The same evidence is presented here.
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`Petitioner submits Wayback Machine screen shots of DrugsDB.eu,
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`accompanying Internet Archive affidavits, and expert testimony demonstrating the
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`public accessibility of DrugsDB.eu. Ex. 1005 at 1, 6; Ex. 1004 at 1-2, 4-5, 10-11;
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`Ex. 1003, ¶15. Dr. Rabinow confirms that drug product labels (e.g., the Sandoz
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`Label) was publicly accessible from a variety of sources, including DrugsDB.eu, and
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`were electronically available online and in printed materials accompanying the
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`commercial drug products. Ex. 1003, ¶15. Information regarding the Sandoz Label
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`was also publicly available in the 2015 edition of Drug Facts and Comparisons, a
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`publication bearing a copyright date of 2014 that “has served the drug information
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`needs of pharmacists and other health care professionals since its inception in 1946.”
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`Ex. 1074 at 8, 22-23; Ex. 1075 at 1. Accordingly, the Sandoz Label qualifies as AIA
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`§ 102(a) prior art. See Sandoz, IPR2018-00156, Paper 11, at 9-13.
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`C. Additional References Cited to Establish the Knowledge of a
`POSITA are Publicly Available Prior Art
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`Public accessibility is the touchstone for determining whether a reference
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`constitutes a printed publication. Public availability of journal articles can be
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`established by showing:
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`1)
`
`2)
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`“the name of the journal”;
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`“citation information reflecting the date, the volume number, and the
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`
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`8
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`Petition for Post Grant Review of U.S. Patent No. 10,653,719
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`3)
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`4)
`
`5)
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`pertinent page numbers of the journal”;
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`“the dates the article was available to the public”;
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`“the publisher of the journal”; and
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`“where readers interested in learning more about the topic of [the
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`article] can make inquiries.”
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`Grünenthal GmbH v. Antecip Bioventures II LLC, PGR2018-00092, Paper 25 at 17-
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`18 (PTAB Feb. 25, 2020); Celltrion, Inc. v. Biogen, Inc., IPR2017-01095, Paper 60
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`at 24 n.17 (PTAB Oct. 4, 2018) (“We note that, in many cases, a party may establish
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`that a journal article which is circulated . . . in a routine manner may be presumed to
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`have been publicly accessible on the publication date contained in the article.”).
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`Similarly, for books, “the indicia on the face of a reference, such as printed dates
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`and stamps, are considered as part of the totality of the evidence.” Hulu, LLC,
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`IPR2018-01039, Paper 29 at 17-18.
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`Eton provides the following information to establish the public availability
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`and prior art status of its additional references2:
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`