( 12 ) United States Patent
`Maloney et al .
`
`US 10,912,795 B1
`( 10 ) Patent No .:
`( 45 ) Date of Patent :
`* Feb . 9 , 2021
`
`US010912795B1
`
`( 54 ) STABLE , HIGHLY PURE L - CYSTEINE
`COMPOSITIONS FOR INJECTION AND
`METHODS OF USE
`( 71 ) Applicant : Exela Pharma Sciences , LLC , Lenoir ,
`NC ( US )
`( 72 ) Inventors : John Maloney , Salisbury , NC ( US ) ;
`Aruna Koganti , Lenoir , NC ( US ) ;
`Phanesh Koneru , Waxhaw , NC ( US )
`( 73 ) Assignee : Exela Pharma Sciences , LLC , Lenoir ,
`NC ( US )
`Subject to any disclaimer , the term of this
`patent is extended or adjusted under 35
`U.S.C. 154 ( b ) by 0 days .
`This patent is subject to a terminal dis
`claimer .
`( 21 ) Appl . No .: 16 / 850,726
`Apr. 16 , 2020
`( 22 ) Filed :
`
`( * ) Notice :
`
`( 63 )
`
`Related U.S. Application Data
`Continuation of application No. 16 / 773,563 , filed on
`Jan. 27 , 2020 , now Pat . No. 10,653,719 , and a
`( Continued )
`
`( 51 ) Int . Cl .
`A61K 33/06
`A61K 31/095
`
`( 52 ) U.S. CI .
`CPC
`
`( 2006.01 )
`( 2006.01 )
`( Continued )
`A61K 33/06 ( 2013.01 ) ; A23L 33/16
`( 2016.08 ) ; A23L 33/175 ( 2016.08 ) ;
`( Continued )
`
`( 56 )
`
`( 58 ) Field of Classification Search
`A61K 33/06
`CPC
`See application file for complete search history .
`References Cited
`U.S. PATENT DOCUMENTS
`5/1983 Nakayama
`4,385,086 A *
`6,051,567 A
`4/2000 Abrahamson et al .
`( Continued )
`
`CO9D 4/00
`427/387
`
`OTHER PUBLICATIONS
`U.S. Appl . No. 16 / 773,641 , filed Jan. 27 , 2020 , Pending .
`( Continued )
`Primary Examiner Benjamin J Packard
`( 74 ) Attorney , Agent , or Firm — Alston Bird LLP
`( 57 )
`ABSTRACT
`The subject matter described herein is directed to stable
`L - cysteine compositions for injection , comprising : L - cyste
`ine or a pharmaceutically acceptable salt thereof and / or
`hydrate thereof in an amount from about 10 mg / mL to about
`100 mg / mL ; Aluminum in an amount from about 1.0 parts
`per billion ( ppb ) to about 250 ppb ; cystine in an amount
`from about 0.01 wt % to about 2 wt % relative to L - cysteine ;
`pyruvic acid in an amount from about 0.01 wt % to about 2
`wt % relative to L - cysteine ; a pharmaceutically acceptable
`carrier , comprising water ; headspace 02 that is less than
`1.0 % ; dissolved oxygen present in the carrier in an amount
`from about 0.01 parts per million ( ppm ) to about 1 ppm ,
`wherein the composition is enclosed in a single - use con
`tainer having a volume of from 10 mL to 100 mL . Also
`described are compositions for a total parenteral nutrition
`regimen and methods for their use .
`29 Claims , 5 Drawing Sheets
`
`Dissolved Oxygen Levels per Tray
`
`14.0
`
`12.0
`
`10.0
`
`DO ( ppm ) 8.0
`
`6.0
`
`4.0
`
`2.0
`
`Final Dissolved
`Oxygen Compounding
`
`Post Filling -Pre HSR
`
`Post Filling . During Post HSR -Capping
`Loading of Lyo
`Filled Vials
`
`**
`
`w
`
`Tray 1
`Tray 2
`Tray 3
`Tray 4
`Tray 17
`Tray 18
`www.Tray 19
`w ... Tray 20
`Tray 21
`wwwxTray 22
`Tray 23
`Tray 24
`Tray 37
`Tray 38
`Tray 39
`Tray 40
`
`W
`
`Nexus Ex. 1018
`Page 1 of 45
`
`

`

`US 10,912,795 B1
`Page 2
`
`Related U.S. Application Data
`continuation - in - part of application No. 16 / 773,641 ,
`filed on Jan. 27 , 2020 , which is a continuation of
`application No. 16 / 746,028 , filed on Jan. 17 , 2020 ,
`which is a continuation of application No. 16/746 ,
`028 , filed on Jan. 17 , 2020 , which is a continuation of
`application No. 16 / 665,702 , filed on Oct. 28 , 2019 ,
`now Pat . No. 10,583,155 , which is a continuation of
`application No. 16 / 248,460 , filed on Jan. 15 , 2019 ,
`now Pat . No. 10,478,453 .
`( 51 ) Int . Ci .
`A61K 31401
`A61K 31/405
`A61K 47/02
`A61K 33/241
`A61K 9/00
`A61K 33/36
`A61K 33/00
`A23L 33/175
`A61K 33/28
`A23L 33/16
`A61K 31/198
`A61K 31/4172
`A61K 31/191
`A61 ) 1/14
`( 52 ) U.S. CI .
`CPC
`
`( 2006.01 )
`( 2006.01 )
`( 2006.01 )
`( 2019.01 )
`( 2006.01 )
`( 2006.01 )
`( 2006.01 )
`( 2016.01 )
`( 2006.01 )
`( 2016.01 )
`( 2006.01 )
`( 2006.01 )
`( 2006.01 )
`( 2006.01 )
`
`A61K 9/0029 ( 2013.01 ) ; A61K 31/095
`( 2013.01 ) ; A61K 31/191 ( 2013.01 ) ; A61K
`31/198 ( 2013.01 ) ; A61K 31/401 ( 2013.01 ) ;
`A61K 31/405 ( 2013.01 ) ; A61K 31/4172
`( 2013.01 ) ; A61K 33/00 ( 2013.01 ) ; A61K
`33/241 ( 2019.01 ) ; A61K 33/28 ( 2013.01 ) ;
`A61K 33/36 ( 2013.01 ) ; A61K 47/02 ( 2013.01 ) ;
`A23V 2002/00 ( 2013.01 ) ; A61J 1/1412
`( 2013.01 )
`
`( 56 )
`
`References Cited
`U.S. PATENT DOCUMENTS
`6,382,442 B1
`5/2002 Thibault et al .
`6,992,218 B2
`1/2006 Dietlin et al .
`1/2008 Driscoll et al .
`7,323,206 B1
`8,415,337 B1
`4/2013 Krishna
`9,220,700 B2
`12/2015 Savarese et al .
`12/2019 Sutterer et al .
`10,493,051 B1
`10,543,186 B1
`1/2020 Sutterer et al .
`2019/0233153 A1
`8/2019 Hofstetter
`2019/0247307 A1
`8/2019 Hofstetter
`
`OTHER PUBLICATIONS
`U.S. Appl . No. 16 / 773,563 , filed Jan. 27 , 2020 , U.S. Pat . No.
`10,653,719 , Issued , May 2020 , Maloney , et al .
`U.S. Appl . No. 16 / 746,028 , filed Jan. 17 , 2020 , Pending .
`U.S. Appl . No. 16 / 665,702 , filed Oct. 28 , 2019 , U.S. Pat . No.
`10,583,155 , Issued , Mar. 2020 , Maloney , et al .
`U.S. Appl . No. 16 / 248,460 , filed Jan. 15 , 2019 , U.S. Pat . No.
`10,478,453 , Issued , Nov. 2019 , Maloney , et al .
`Petition for Post Grant Review of U.S. Pat . No. 10,583,155 , Eton
`Pharmaceuticals , Inc. v . Exela Pharma Sciences , LLC , PGR2020
`00068 , ( PTAB Jun . 8 , 2020 ) .
`Van Goudoever et al . , “ ESPGHAN / ESPEN / ESPR / CSPEN guide
`lines on pediatric parenteral nutrion : Amino acids , ” Clinical Nutri
`tion , 37 : 2315-2323 , ( 2018 ) .
`Healthcare Professional Letter from Baxter Healthcare Corporation ,
`" Temporary importation of intravenous drug products to address
`
`drug shortages , ” 8 pages , ( 2017 ) , retrieved from Exhibit 1087 ,
`Petition for Post Grant Review of U.S. Pat . No. 10,583,155 , Eton
`Pharmaceuticals , Inc. v . Exela Pharma Sciences , LLC , PGR2020
`00068 , ( PTAB Jun . 8 , 2020 ) .
`Ziegler , Ekhard E. , “ Parenteral Nutrition , ” Iowa Neonatology Hand
`book : Feeding , ( 2006 ) .
`Worthington et al . ,
`“ When is Parenteral Nutrition Appropriate ?, "
`Journal of Parenteral and Enteral Nutrition , 41 ( 3 ) : 324-377 , ( 2017 ) .
`Gasser et al . , “ Parenteral Nutrition : Macronutrient Composition and
`Requirements , ” Support Line , 27 ( 6 ) : 6-12 , ( 2005 ) .
`Citizen Petition , Lachman Consultant Services , Inc. , 12 pages ,
`( 2018 ) , retrieved from Exhibit 1092 , Petition for Post Grant Review
`of U.S. Pat . No. 10,583,155 , Eton Pharmaceuticals , Inc. v . Exela
`Pharma Sciences , LLC , PGR2020-00068 , ( PTAB Jun . 8 , 2020 ) .
`Declaration of Madan Chilakuri , ( 2020 ) , Exhibit 1093 , Petition for
`Post Grant Review of U.S. Pat . No. 10,583,155 , Eton Pharmaceu
`ticals , Inc. V. Exela Pharma Sciences , LLC , PGR2020-00068 ,
`( PTAB Jun . 8 , 2020 ) .
`Excerpt from “ Parenteral Formulations ( Chapter 30 ] ” , Bentley's
`Textbook of Pharmaceutics : An Adaptation , Eds . Sanjay K. Jain et
`al . , pp . 410-415 , ( 2012 ) .
`Ahola et al . , “ N - Acetylcysteine does not Prevent Bronchopulmonary
`Dysplasia in Immature Infants : A Randomized Controlled Trial , ” J
`Pediatr , 143 : 713-719 , ( 2003 ) .
`“ Guidance for Industry : E11 Clinical Investigation of Medicinal
`Products in the Pediatric Population , ” U.S. Dept. of Health and
`Human Services , FDA , CDER , CBER , 17 pages , ( 2000 ) .
`USPXXI , The United States Pharmacopeia , Twenty - First Revision , The
`U.S. Pharmacopeial Convention , Inc. , pp . 19-20 , 268-269 , and
`1375 , ( 1985 ) .
`Boullata , Joseph I. , “ Nutrients and Associated Substances , ” Remington :
`The Science and Practice of Pharmacy , 21 Ed . , Ed . David B. Troy ,
`Philadelphia : Lippincott Williams & Wilkins , pp . 1688-1693 , ( 2005 ) .
`Yesil et al . , “ Evaluation of the Children with Acute Acetaminophen
`Overdose and Intravenous N - Acetylcysteine Treatment , ” Pak J Med
`Sci . , 34 ( 3 ) : 590-594 , ( 2018 ) .
`Lee et al . , “ Intravenous N - Acetylcysteine Improves Transplant Free
`Survival in Early Stage Non - Acetaminophen Acute Liver Failure , ”
`Gastroenterology , 137 ( 3 ) : 856-864 , ( 2009 ) .
`Declaration of Judy K. He , ( 2020 ) , Exhibit 1105 , Petition for Post
`Grant Review of U.S. Pat . No. 10,583,155 , Eton Pharmaceuticals ,
`Inc. v . Exela Pharma Sciences , LLC , PGR2020-00068 , ( PTAB Jun .
`8 , 2020 ) .
`Declaration of Barrett Rabinow , ( 2020 ) , Exhibit 1003 , Petition for
`Post Grant Review of U.S. Pat . No. 10,583,155 , Eton Pharmaceu
`ticals , Inc. V. Exela Pharma Sciences , LLC , PGR2020-00068 ,
`( PTAB Jun . 8 , 2020 ) .
`“ Guidelines for the Use of Parenteral and Enteral Nutrition in Adult
`and Pediatric Patients , ” ASPEN Board of Directors and the Clinical
`Guidelines Task Force , Journal of Parenteral and Enteral Nutrition ,
`26 ( 1 Suppl . ) : 1SA - 138SA , ( 2002 ) .
`“ ACETADOTE ( acetylcysteine ) injection , for intravenous use : Pre
`scribing Information [ package insert ] , ” Cumberland Pharmaceuti
`cals Inc. , 12 pages , ( 2017 ) .
`" Aluminum in Large and Small Volume Parenterals Used in Total
`Parenteral Nutrition , ” Federal Register , 65 ( 17 ) : 4103-4111 , ( 2000 ) .
`" Aluminum in Large and Small Volume Parenterals Used in Total
`Parenteral Nutrition ; Delay of Effective Date , ” Federal Register ,
`66 ( 18 ) : 7864-7865 , ( 2001 ) .
`“ AMINOSYN ( prescribing information and label ] , ” Hospira , Inc. ,
`19 pages , ( 2012 ) .
`“ AMINOSYN ( prescribing information and label ] , ” Hospira , Inc. ,
`28 pages , ( 2019 ) .
`" ASHP Guidelines on the Safe Use of Automated Compounding
`Devices for the Preparation of Parenteral Nutrition Admixtures , "
`Automation and Information Technology Guidelines , 63-67 , ( 2000 ) .
`" Chapter 18 : Preparation of Parenteral Nutrition , ” Aseptic Process
`ing Manual , NHS Technical Specialist Education and Training
`Group , 24 pages , ( 2018 ) .
`“ Cysteine Hydrochloride [ FDA package insert ] , ” Hospira , Inc. , 7
`pages , ( 2007 ) .
`" Cysteine Hydrochloride Injection [ Material Safety Data Sheet ] , ”
`Hospira Inc. , 6 pages , ( 2011 ) .
`
`Nexus Ex. 1018
`Page 2 of 45
`
`

`

`US 10,912,795 B1
`Page 3
`
`( 56 )
`
`References Cited
`OTHER PUBLICATIONS
`" Cysteine Hydrochloride Injection ( prescribing information ] , ” Hospira ,
`Inc. , 4 pages , ( 2004 ) . [ Retrieved from the Internet Dec. 28 , 2016 :
`< URL : https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo .
`cfm ? archiveid = 113819 > ] .
`" Cysteine , ” TOXNET : Toxicology Data Network , National Library
`of Medicine HSDB Database , 20 pages , ( 2016 ) . [ Retrieved from the
`Internet Jun . 27 , 2017 : < URL : https://toxnet.nlm.nih.gov/cgi-bin/
`sis / search / a ? dbs + hsdb : @ term + @ DOCNO + 2109 > ] .
`" Cysteine : Pediatric drug information , ” Lexicomp , Inc. , 4 pages ,
`( 1978 ) .
`“ Determination That Cysteine Hydrochloride Injection , USP , 7.25 % ,
`Was Not Withdrawn From Sale for Reasons of Safety or Effective
`ness , " Federal Register , 75 ( 107 ) : 31790-31791 , ( 2010 ) .
`“ Effect of L - Cysteine ( Acetium® Capsules ) in Restoration of the
`Structure and Function of Gastric Mucosa After H. pylori Eradica
`tion in Patients with Atrophic Gastritis . A randomized , controlled
`trial . , ” Study Protocol , BIOHIT Healthcare , 45 pages , ( 2016 ) .
`“ Guideline on the Use of Parenteral Nutrition in Neonatal and
`Paediatric Units , ” Clinical Practice Guideline , Royal College of
`Physicians in Ireland , 46 pages , ( 2016 ) .
`“ L - Cysteine [ product information ] , ” Sigma - Aldrich , Inc. , 2 pages ,
`( 2003 ) .
`“ L - Cysteine Hydrochloride [ prescribing information and label ] ” ,
`Sandoz Inc. , 6 pages , ( 2010 ) .
`“ L - Cysteine Hydrochloride Injection , USP ( prescribing informa
`tion ] , ” American Regent , Inc. , 2 pages , ( 2009 ) .
`“ L - Cysteine Hydrochloride Injection , solution [ drug label informa
`tion ] ” , Sandoz Inc . , ( 2018 ) .
`“ L - Cysteine Hydrochloride Monohydrate [ product information ] , "
`Sigma - Aldrich , Inc. , 1 page , ( 2006 ) .
`“ PROSOL [ prescribing information and label ] , ” Baxter Healthcare
`Corporation , 14 pages , ( 2014 ) .
`" Safe Practices for Parenteral Nutrition Formulations , ” National
`Advisory Group on Standards and Practice Guidelines for Parenteral
`Nutrition , Journal of Parenteral and Enteral Nutrition , 22 ( 2 ) : 49-66 ,
`( 1998 ) . [ Retrieved from the Internet Mar. 12 , 2015 : < URL : https : //
`onlinelibrary.wiley.com/doi/10.1177/014860719802200249 > ] .
`“ Scientific Opinion on the safety and efficacy of L - cysteine hydro
`chloride monohydrate as a flavouring additive for pets , ” European
`Food Safety Authority Journal , 11 ( 10 ) : 3437 , 13 pages , ( 2013 ) .
`“ The Provision of Parenteral Nutrition within Neonatal Ser
`vices A Framework for Practice , " British Association of Perinatal
`Medicine , 27 pages , ( 2016 ) .
`“ Total Parenteral Nutrition ( TPN ) -Administration in Adult Ward
`Areas and Intensive Care of St. George Hospital Only , ” St. George /
`Sutherland Hospitals and Health Services , NSW Government Health
`South Eastern Sydney Local Health Network , 10 pages , ( 2013 ) .
`[ Retrieved from the Internet May 11 , 2020 : < URL : https : // www .
`aci.health.nsw.gov.au/_data/assets/pdf_file/0006/306438/stgeorge Total
`Parenteral_Nutrition_ICU_Adult_Wards_SGSHHS_CLIN089 .
`pdf > ] .
`“ TRAVASOL ( prescribing information and label ] , ” Baxter Health
`care Corporation , 19 pages , ( 2017 ) .
`“ TROPHAMINE [ prescribing information and label ] , ” B. Braun
`Medical Inc. , 21 pages , ( 2014 ) .
`“ TROPHAMINE® ( Amino Acid Injections ) ( package insert ] , ” B.
`Braun Medical Inc. , pp . 5-16 , ( 2003 ) .
`Abdulrazik et al . , “ Formulation for Slow Release of Oral Radiation
`Protection Drugs , ” Int . J. Nucl . Med . Biol . , 11 ( 1 ) : 53-54 , ( 1984 ) .
`Advenier et al . , " Aluminum Contamination of Parenteral Nutrition
`and Aluminum Loading in Children on Long - Term Parenteral
`Nutrition , ” Journal of Pediatric Gastroenterology and Nutrition ,
`36 ( 4 ) : 448-453 , ( 2003 ) . [ Retrieved from the Internet Jun . 6 , 2018 :
`< URL : https://journals.lww.com/jpgn Fulltext / 2003 / 04000 / Aluminum_
`Contamination_of_Parenteral_Nutrition_and.5.aspx # pdf - link > ] .
`Allen , Jr. , Loyd V. , “ L - Cysteine Hydrochloride 50 mg / mL Injec
`tion , ” U.S. Pharmacist , 36 ( 9 ) : 41-42 , ( 2011 ) . [ Retrieved from the
`Internet May 26 , 2016 : < URL : https : //www.uspharmacist.com/article/
`1cysteinehydrochloride50mgmlinjection > ] .
`
`Allen , Loyd V. , “ Chapter 1 : Guidelines for Compounding Prac
`tices , ” The Art , Science , and Technology of Pharmaceutical Com
`pounding , 4th Ed.:1-18 , ( 2012 ) .
`Allwood et al . , “ Compatibility and Stability of Additives in Parenteral
`Nutrition Admixtures , ” Nutrition , 14 ( 9 ) : 697-706 , ( 1998 ) .
`Anderson et al . ,
`“ Physical Compatibility of Calcium Chloride and
`Sodium Glycerophosphate in Pediatric Parenteral Nutrition Solu
`tions , ” Journal of Parenteral and Enteral Nutrition , 40 ( 8 ) : 1166
`1169 , ( 2016 , Epub . 2015 ) . [ Retrieved from the Internet Oct. 24 ,
`2015 : < URL : https://onlinelibrary.wiley.com/doi/epdf/10.1177/
`0148607115592673 > ] .
`Ayers et al . ,
`“ A.S.P.E.N. Parenteral Nutrition Safety Consensus
`Recommendations , ” Scholarship and Professional Work — COPHS ,
`Butler University , 66 pages , ( 2014 ) .
`Baines et al . , “ The Association Between Cysteine , Bone Turnover ,
`and Low Bone Mass , ” Calcif Tissue Int , 81 ( 6 ) : 450-454 , ( 2007 ) .
`Balogh , Judit Kovácsné , “ Preparation and examination of TPN
`systems for the individual clinical therapy , ” ( Ph.D. Thesis ) , Sem
`melweis University , Hungary , 116 pages , ( 2007 ) .
`Bengoa et al . , “ Amino acid - induced hypercalciuria in patients on
`total parenteral nutrition , ” The American Journal of Clinical Nutri
`tion , 38 ( 2 ) : 264-269 , ( 1983 ) . [ Retrieved from the Internet Dec. 14 ,
`2017 : < URL : https://academic.oup.com/ajcn/article-abstract/38/2/
`264/4690894 > ] .
`Bettner et al . , “ Effects of pH , Temperature , Concentration , and Time
`on Particle Counts in Lipid - Containing Total Parenteral Nutrition
`Admixtures , ” Journal of Parenteral and Enteral Nutrition , 10 ( 4 ) : 375
`380 , ( 1986 ) . [ Retrieved from the Internet Mar. 10 , 2015 : < URL :
`https://onlinelibrary.wiley.com/doi/epdf/10.1177/
`0148607186010004375 > ] .
`Bishop et al . , “ Aluminum Neurotoxicity in Preterm Infants Receiv
`ing Intravenous - Feeding Solutions , ” The New England Journal of
`Medicine , 336 ( 22 ) : 1557-1561 , ( 1997 ) . [ Retrieved from the Internet
`Jun . 5 , 2018 : < URL : https://www.nejm.org/doi/full/10.1056/
`NEJM199705293362203 > ] .
`Bistrian , Bruce R. , “ Brief History of Parenteral and Enteral Nutri
`tion in the Hospital in the USA , " Nestlé Nutr Inst Workshop Ser
`Perform Program , 12 : 127-136 , ( 2009 ) .
`Bjelton et al . , “ Availability of Cysteine and of L - 2 - Oxo - Thiazolidine
`4 - Carboxylic Acid as a Source of Cysteine in Intravenous Nutri
`tion , ” Journal of Parenteral and Enternal Nutrition , 14 ( 2 ) : 177-182 ,
`( 1990 ) .
`Bohrer et al . , Aluminum Loading in Preterm Neonates Revisited ,
`JPGN , 51 ( 2 ) : 237-241 , ( 2010 ) .
`Bohrer et al . , “ Influence of the glass packing on the contamination
`of pharmaceutical products by aluminum . Part II : Amino acids for
`parenteral nutrition , ” J. Trace Elem . Med . Biol . , 15 ( 2-3 ) : 103-108 ,
`( 2001 ) .
`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 , ” J. Trace
`Elem . Med . Biol . , 17 ( 2 ) : 107-115 , ( 2003 ) .
`Borges - Santos et al . , “ Plasma glutathione of HIV + patients responded
`positively and differently to dietary supplementation with cysteine
`or glutamine , ” Nutrition , 28 ( 7-8 ) : 753-756 , ( 2012 ) .
`Boullata et al . , “ A.S.P.E.N. Clinical Guidelines : Parenteral Nutrition
`Ordering , Order Review , Compounding , Labeling , and Dispens
`ing , ” Journal of Parenteral and Enteral Nutrition , 38 ( 3 ) : 334-377 ,
`( 2014 ) .
`Brigham et al . , “ The Concentrations of Cysteine and Cystine in
`Human Blood Plasma , ” J Clin Invest . , 39 ( 11 ) : 1633-1638 , ( 1960 ) .
`Brown et al . , “ Potential Aluminum Exposure from Parenteral Nutri
`tion in Patients with Acute Kidney Injury , " The Annals of
`Pharmacotherapy , 42 ( 10 ) : 1410-1415 , ( 2008 ) .
`Bulbul et al . ,
`“ Letter to the Editor : Nutritional support in preterm
`infants , ” Pediatrics and Neonatology , 58 ( 6 ) : 562 , ( 2017 ) .
`Bullock et al . ,
`“ Emulsion Stability in Total Nutrient Admixtures
`Containing a Pediatric Amino Acid Formulation , ” Journal of Parenteral
`and Enteral Nutrition , 16 ( 1 ) : 64-68 , ( 1992 ) . [ Retrieved from the
`Internet Feb. 10 , 2015 : < URL : https://onlinelibrary.wiley.com/doi/
`pdf / 10.1177 / 014860719201600164 > ] .
`Calkins et al . , “ Effect of High - Dose Cysteine Supplementation on
`Erythrocyte Glutathione : a Double - Blinded , Randomized Placebo
`
`Nexus Ex. 1018
`Page 3 of 45
`
`

`

`US 10,912,795 B1
`Page 4
`
`22
`
`( 56 )
`
`References Cited
`OTHER PUBLICATIONS
`Controlled Pilot Study in Critically Ill Neonates , " JPEN J Parenter
`Enteral Nutr . , 40 ( 2 ) : 226-234 , ( 2016 ) .
`Carlson et al . , “ Neonatal Parenteral and Enteral Nutrition : A Resource
`Guide for the Student and Novice Neonatal Nurse Practitioner , "
`National Association of Neonatal Nurse Practitioners , 23 pages ,
`( 2010 ) .
`Clemens et al . ,
`“ Twice Daily Dosing of Dabigatran for Stroke
`Prevention in Atrial Fibrillation : A Pharmacokinetic Justification , "
`Curr Med Res Opin , 28 ( 2 ) : 195-201 , ( 2012 ) .
`Complaint with Request for Temporary Restraining Order , Prelimi
`nary and Permanent Injunctions , Exela Pharma Sciences , LLC
`V.Sandoz , Inc. , No. 1 : 19 - cv - 318 , ( W.D.N.C. , Nov. 6 , 2019 ) .
`Connelly et al . , “ Congenital Hypothyroidism Caused by Excess
`Prenatal Maternal Iodine Ingestion , ” The Journal of Pediatrics ,
`161 ( 4 ) : 760-762 , ( 2012 ) .
`Courtney - Martin et al . , “ Plasma Aluminum Concentrations in Pedi
`atric Patients Receiving Long - Term Parenteral Nutrition , ” Journal
`of Parenteral and Enteral Nutrition , 39 ( 5 ) : 578-585 , ( 2014 ) .
`Courtney - Martin et al . , “ The Addition of Cysteine to the Total
`Sulphur Amino Acid Requirement as Methionine Does Not Increase
`Erythrocytes Glutathione Synthesis in the Parenterally Fed Human
`Neonate , ” Pediatric Research , 67 ( 3 ) : 320-324 , ( 2010 ) .
`Darkwa et al . , “ Antioxidant Chemistry : Oxidation of L - Cysteine
`and Its Metabolites by Chlorite and Chlorine Dioxide , ” J. Phys .
`Chem . A. , 108 ( 26 ) : 5576-5587 , ( 2004 ) .
`De Cloet et al . , “ Physicochemical stable standard all - in - one parenteral
`nutrition admixtures for infants and children in accordance with the
`ESPGHAN / ESPEN guidelines , ” Nutrition , 49 : 41-47 , ( 2018 ) .
`Declaration of John Geissler , Exhibit 1 , Response in Opposition to
`Plaintiff's Motion for Preliminary Injunction , Exela Pharma Sci
`ences , LLC v.Sandoz , Inc. , No. 1 : 19 - cv - 318 , ( W.D.N.C. , Dec. 6 ,
`2019 ) .
`Delange , F. , " Optimal Iodine Nutrition during Pregnancy , Lactation
`and the Neonatal Period , ” Int J Endocrinol Metab , 2 ( 1 ) : 1-12 ,
`( 2004 ) .
`Delange , Francois , “ Iodine deficiency in Europe and its conse
`quences : an update , ” Eur J Nucl Med , 29 ( Suppl . 2 ) : S404 - S416 ,
`( 2002 ) .
`Delange , Francois , “ Iodine requirements during pregnancy , lacta
`tion and the neonatal period and indicators of optimal iodine
`nutrition , ” Public Health Nutrition : 10 ( 12A ) : 1571-1580 , ( 2007 ) .
`Dietary Reference Intakes for Energy , Carbohydrate , Fiber , Fat ,
`Fatty Acids , Cholesterol , Protein , and Amino Acids , The National
`Academies Press , 1358 pages , ( 2002 ) . [ Retrieved from the Internet
`Dec. 12 , 2017 : < URL : http://www.nap.edu/10490 > ] .
`Dietary Reference Intakes for Vitamin A , Vitamin K , Arsenic ,
`Boron , Chromium , Copper , Iodine , Iron , Manganese , Molybdenum ,
`Nickel , Silicon , Vanadium , and Zinc , National Academy Press , 800
`pages , ( 2000 ) . [ Retrieved from the Internet Dec. 16 , 2018 : < URL :
`http://www.nap.edu/catalog/10026.html > ] .
`Dilger et al . ,
`“ Excess Dietary L - Cysteine , but Not L - Cystine , Is
`Lethal for Chicks but Not for Rats or Pigs , ” The Journal of
`Nutrition , 137 ( 2 ) : 331-338 , ( 2007 ) . [ Retrieved from the Internet Jun .
`28 , 2017 : < URL : https : //academic.oup.com/in/article/137/2/331/
`4664534 > ] .
`Domingo et al . , “ Risks of aluminium exposure during pregnancy , "
`Contributions to Science , 1 ( 4 ) : 479-487 , ( 2000 ) .
`Dumortier et al . ,
`“ Development of a Thermogelling Ophthalmic
`Formulation of Cysteine , ” Drug Development and Industrial Phar
`macy , 32 ( 1 ) : 63-72 , ( 2006 ) . [ Retrieved from the Internet May 12 ,
`2015 : < URL : https://www.tandfonline.com/doi/full/10.1080/
`03639040500390934 > ] .
`El - Shenawy et al . , “ Nephrotoxicity of sodium valproate and pro
`tective role of L - cysteine in rats at biochemical and histological
`levels , ” J Basic Clin Physiol Pharmacol , 27 ( 5 ) : 497-504 , ( 2016 ) .
`[ Retrieved from the Internet May 4 , 2016 : < URL : https : // www .
`degruyter.com/view/j/jbcpp.2016.27.issue-5/jbcpp-2015-0106/jbcpp
`2015-0106.xml > ] .
`
`“ Aluminium exposure from parenteral nutrition in
`Fewtrell et al . ,
`preterm infants and later health outcomes during childhood and
`adolescence , ” Symposium 2 : Micronutrients under the Microscope ,
`Proceedings of the Nutrition Society , 70 ( 3 ) : 299-304 , ( 2011 ) . [ Retrieved
`from the Internet Jun . 4 , 2018 : < URL : https://www.cambridge.org
`core / journals / proceedings - of - the - nutrition - society / article / aluminium
`exposure - from - parenteral - nutrition - in - preterm - infants - and - later
`health - outcomes - during - childhood - and - adolescence /
`F5D0A6109616E8C9D7F8C2C707213860 / core - reader > ] .
`Flora et al . , “ Chelation in Metal Intoxication , ” Int . J. Environ . Res .
`Public Health , 7 ( 7 ) : 2745-2788 , ( 2010 ) .
`Fortenberry et al . , “ Evaluating Differences in Aluminum Exposure
`through Parenteral Nutrition in Neonatal Morbidities , ” Nutrients ,
`9 ( 11 ) : E1249 , 6 pages , ( 2017 ) .
`Frey et al . , “ Confirming the Causative Role of Acetaminophen in
`Indeterminate Acute Liver Failure Using Acetaminophen - Cysteine
`Adducts , ” J. Med . Toxicol . , 11 ( 2 ) : 218-222 , ( 2015 ) .
`Friedmann et al . , “ Reactions of Pyruvic Acid with Thiolacetic Acid
`and Cysteine , ” Biochem J , 30 ( 10 ) : 1886-1891 , ( 1936 ) .
`Fürst et al . , “ Parenteral nutrition by a solution of crystalline amino
`acids , ” Acta Med Scand Suppl . , 472 : 283-293 , ( 1967 ) .
`Fusch et al . , “ Neonatology / Paediatrics Guidelines on Parenteral
`Nutrition , Chapter 13 , " GMS German Medical Science , 7 ( Doc15 ) : 23
`pages , ( 2009 ) .
`Ghirri et al . , “ Iodine Supplementation in the Newborn , ” Nutrients ,
`6 ( 1 ) : 382-390 , ( 2014 ) .
`Gura et al . , “ Aluminum contamination in products used in parenteral
`nutrition : Has anything changed ?, ” Nutrition , 26 ( 6 ) : 585-594 , ( 2010 ) .
`Gura et al . , “ Recent developments in aluminium contamination of
`products used in parenteral nutrition , ” Curr Opin Clin Nutr Metab
`Care , 9 ( 3 ) : 239-246 , ( 2006 ) .
`Gura , Kathleen M. , “ Aluminum contamination in parenteral prod
`ucts , ” Current Opinions in Clinical Nutrition and Metabolic Care ,
`17 ( 6 ) : 551-557 , ( 2014 ) .
`Hardy et al . , “ Formulation , Stability , and Administration of Parenteral
`Nutrition With New Lipid Emulsions , ” Nutrition in Clinical Prac
`tice , 24 ( 5 ) : 616-625 , ( 2009 ) .
`Hardy et al . , “ P.83 : Stability of aqueous cysteine solutions for TPN
`[ Abstract ] , ” Clinical Nutrition , 12 ( Suppl 2 ) : 61 , ( 1993 ) .
`Harman et al . , “ Free Radical Metabolites of L - Cysteine Oxidation , ”
`The Journal of Biological Chemistry , 259 ( 9 ) : 5606-5611 , ( 1984 ) .
`[ Retrieved from the Internet Feb. 6 , 2017 : < URL : http : //www.jbc .
`org / content / 259 / 9 / 5606.full.pdf > ] .
`Heird et al . , “ Pediatric Parenteral Amino Acid Mixture in Low Birth
`Weight Infants , ” Pediatrics , 81 ( 1 ) : 41-50 , ( 1988 ) . [ Retrieved from
`the Internet Dec. 8 , 2017 : < URL : http : //pediatrics.aappublications .
`org / content / 81 / 1 / 41 > ] .
`Hellström et al . , “ Sal863 . L - Cysteine Slow - Release Capsule For
`mulation in Prevention of Gastric Carcinogenesis Associated With
`Atrophic Gastritis , " AGA Abstracts , 146 ( 5 , Suppl 1 ) : S - 315 , ( 2014 ) .
`Helms et al . , “ Cysteine supplementation results in normalization of
`plasma taurine concentrations in children receiving home parenteral
`nutrition , ” J Pediatr , 134 ( 3 ) : 358-361 , ( 1999 ) .
`Hernández - Sánchez et al . , “ Aluminum in parenteral nutrition : a
`systematic review , ” European Journal of Clinical Nutrition , 67 ( 3 ) : 230
`238 , ( 2013 ) .
`Heyman et al . , “ Aluminum Does Not Accumulate in Teenagers and
`Adults on Prolonged Parenteral Nutrition Containing Free Amino
`Acids , " Journal of Parenteral and Enteral Nutrition , 10 ( 1 ) : 86-87 ,
`( 1986 ) .
`Hintz et al . , “ Aluminum Exposure From Pediatric Parenteral Nutri
`tion : Meeting the New FDA Regulation , ” JPEN J Parenter Enteral
`Nutr , 32 : 242-246 , ( 2008 ) .
`Ho et al . ,
`“ Trend of Nutritional Support in Preterm Infants , "
`Pediatrics and Neonatology , 57 ( 5 ) : 365-370 , ( 2016 ) .
`Hu et al . ,
`“ Efficacy and safety of acetylcysteine in “ non
`acetaminophen ” acute liver failure : A meta - analysis of prospective
`clinical trials , ” Clin Res Hepatol Gastroenterol , 39 ( 5 ) : 594-599 ,
`( 2015 ) .
`Hulst , Jessie ,
`“ Principles of feeding the preterm infant , ” 36th
`ESPEN Congress , Geneva , 44 pages , ( 2014 ) .
`
`Nexus Ex. 1018
`Page 4 of 45
`
`

`

`US 10,912,795 B1
`Page 5
`
`( 56 )
`
`References Cited
`OTHER PUBLICATIONS
`“ Calcium Chloride in Neonatal Parenteral Nutrition
`Huston et al . ,
`Solutions with and without Added Cysteine : Compatibility Studies
`Using Laser and Micro - Flow Imaging Methodology , ” PLoS One ,
`10 ( 8 ) : e0136894 , ( 2015 ) .
`Huston et al . , “ Calcium chloride in neonatal parenteral nutrition : A
`15 year experience , ” Journal of Neonatal - Perinatal Medicine , 10 ( 1 ) : 33
`38 , ( 2017 )
`Huston et al . , “ Calcium Chloride in Neonatal Parenteral Nutrition :
`Compatibility Studies Using Laser Methodology , ” PLoS One ,
`9 ( 9 ) : e106825 , ( 2014 ) .
`Ishii et al . , “ A case of drug - induced ductopenia resulting in fatal
`biliarv cirrhosis , ” Liver , 13 ( 4 ) : 227-231 , ( 1993 ) .
`Ishii et al . , " Cystathionine y - Lyase - deficient Mice Require Dietary
`Cysteine to Protect against Acute Lethal Myopathy and Oxidative
`Injury , ” The Journal of Biological Chemistry , 285 ( 34 ) : 26358
`26368 , ( 2010 ) .
`Jadhav et al . ,
`“ Parenteral Amino Acid and Metabolic Acidosis in
`Premature Infants , ” JPEN J Parenter Enteral Nutr . , 31 ( 4 ) : 278-283 ,
`( 2007 ) .
`Jalilehvand et al . , " Lead ( II ) Complex Formulation with L - Cysteine
`in Aqueous Solution , ” Inorganic Chemistry , 54 : 2160-2170 , ( 2015 ) .
`Janáky et al . , “ Mechanisms of L - Cysteine Neurotoxicity , " Neurochemi
`cal Research , 25 ( 9/10 ) : 1397-1405 ( 2000 ) .
`Ji et al . , “ Excessive L - cysteine induces vacuole - like cell death by
`activating endoplasmic reticulum stress and mitogen - activated pro
`tein kinase signaling in intestinal porcine epithelial cells , ” Amino
`Acids , 48 ( 1 ) : 149-156 , ( 2015 ) .
`John et al . ,
`“ Total parenteral nutrition usage trends in the United
`States , ” Journal of Critical Care , 40 : 312-313 , ( 2017 ) .
`Kartal et al . , “ Compatibility of chewing gum excipients with the
`amino acid L - cysteine and stability of the active substance in
`directly compressed chewing gum formulation , ” Journal of Phar
`macy and Pharmacology , 60 ( 9 ) : 1131-1138 , ( 2008 ) .
`Kartal et al . , “ Formulation and in - vivo evaluation of L - cysteine
`chewing gums for binding carcinogenic acetaldehyde in the saliva
`during smoking , ” Journal of Pharmacy and Pharmacology , 59 ( 10 ) : 1353
`1358 , ( 2007 ) .
`Kartal - Hodzic , Alma ,
`" Formulation studies for eliminating saliva
`carcinogenic acetaldehyde with L - cysteine containing chewing gum , "
`( Academic Disseration ) , Division of Biopharmaceutics and
`Pharmacokinetics , University of Helsinki , Finland , 60 pages , ( 2012 ) .
`Klein et al . , “ Hypocalcemia Complicating Deferoxamine Therapy
`in an Infant with Parenteral Nutrition - Associated Aluminum Over
`load : Evidence for a Role of Aluminum in the Bone Disease of
`Infants , ” Journal of Pediatric Gastroenterology and Nutrition , 9 ( 3 ) : 400
`403 , ( 1989 ) . [ Retrieved from the Internet Jun . 5 , 2018 : < URL :
`https://journals.lww.com/jpgn/Abstract/1989/10000/Hypocalcemia
`Complicating_Deferoxamine_Therapy_in.24.aspx > ] .
`Klein , Catherine J. ,
`“ Nutrient Requirements for Preterm Infant
`Formulas , ” The Journal of Nutrition , 132 ( 6 Suppl 1 ) : 13955-1577S ,
`( 2002 ) . [ Retrieved from the Internet Dec. 6 , 2017 : < URL : http : //
`jn.nutrition.org > ] .
`Kolaric et al . , “ Solutions Preparing for Total Parenteral Nutrition for
`Children , ” Proceedings of the 7th WSEAS International Conference
`on Mathematics & Computers in Biology & Chemistry , Cavtat ,
`Croatia , 6 pages , ( 2006 ) .
`Koletzko et al . ,
`“ Guidelines on Paediatric Parenteral Nutrition : 3 .
`Amino Acids , " J. Pediatr . Gastroenterol . Nutr . , 41 ( Suppl . 2 ) : S12
`S18 , ( 2005 ) .
`Komura et al . , “ Increased Incidence of Cholestasis during Total
`Parenteral Nutrition in Children , ” The Kurume Medical Journal ,
`40 ( 1 ) : 7-11 , ( 1993 ) .
`Koo et al . , “ Response to aluminum in parenteral nutrition during
`infancy , ” The Journal of Pediatrics , 109 ( 5 ) : 877-883 , ( 1986 ) .
`Laine et al . , " Cysteine usage increases the need for acetate in
`neonates who receive total parenteral nutrition , ” The American
`Journal of Clinical Nutrition , 54 ( 3 ) : 565-567 , ( 1991 ) .
`[ Retrieved
`from the Internet Apr. 14 , 2015 : < URL : https://academic.oup.com/
`ajcn / article - abstract / 54 / 3 / 565 / 4694399 > ] .
`
`Lapillonne et al . , “ Quality of newborn care : adherence to guidelines
`for parenteral nutrition in preterm infants in four European coun
`tries , ” BMJ Open , 3 ( 9 ) : E003478 , 8 pages , ( 2013 ) . [ Retrieved from
`the Internet Jun . 6 , 2018 : < URL : https://bmjopen.bmj.com/content/
`3 / 9 / e003478 > ] .
`Larchet et al . ,
`“ Aluminium Loading in Children Receiving Long
`term Parenteral Nutrition , ” Clinical Nutrition , 9 (