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
`
`DECLARATION OF BARRETT RABINOW
`
`
`
`
`
`Eton Ex. 1003
`1 of 154
`
`

`

`TABLE OF CONTENTS
`
`I. INTRODUCTION ................................................................................................ 1
`
`II. SUMMARY OF OPINIONS ............................................................................... 1
`
`III. BACKGROUND/QUALIFICATIONS ............................................................... 3
`
`IV. DOCUMENTS AND MATERIALS CONSIDERED ......................................... 5
`
`V. LEGAL PRINCIPLES ......................................................................................... 6
`
`VI. PERSON OF ORDINARY SKILL IN THE ART ............................................... 8
`
`VII. THE SCOPE & CONTENT OF THE PRIOR ART .......................................10
`
`A. L-Cysteine and Aluminum Toxicity........................................................10
`
`B. The Sandoz Label ....................................................................................14
`
`C. Regulatory and Market Demand For Reducing Aluminum ....................18
`
`D. L-Cysteine’s Known Oxygen Sensitivity ................................................25
`
`E. Other Impurities Including Heavy Metals ...............................................36
`
`F. Optimizing the Sandoz L-Cysteine Product ............................................37
`
`G. The Sandoz Label Provides The Motivation for Combining the
`Sandoz and Hospira Labels .....................................................................55
`
`H. The POSITA Would Have Understood That The Product Disclosed
`By The Sandoz Label Could Also Be Used As Taught By Federal
`Register and The Hospira 7.25% Cysteine HCl Package Insert .............55
`
`VIII. THE ’155 PATENT .........................................................................................58
`
`A. Summary ..................................................................................................58
`
`B. Prosecution History .................................................................................62
`
`IX. CLAIM CONSTRUCTION ...............................................................................73
`
`i
`
`Eton Ex. 1003
`2 of 154
`
`

`

`X. CLAIMS 1-30 ARE UNPATENTABLE UNDER § 103 ..................................73
`
`A. Claim 1 ....................................................................................................74
`
`B. Claim 2 ....................................................................................................83
`
`C. Claim 3 ....................................................................................................84
`
`D. Claim 4 ....................................................................................................86
`
`E. Claim 5 ....................................................................................................86
`
`F. Claim 6 ....................................................................................................87
`
`G. Claim 7 ....................................................................................................88
`
`H. Claim 8 ....................................................................................................89
`
`I. Claim 9 ....................................................................................................90
`
`J. Claim 10 ..................................................................................................91
`
`K. Claim 11 ..................................................................................................94
`
`L. Claim 12 ..................................................................................................96
`
`M. Claim 13 ..................................................................................................98
`
`N. Claim 14 ................................................................................................100
`
`O. Claim 15 ................................................................................................101
`
`P. Claim 16 ................................................................................................105
`
`Q. Claim 17 ................................................................................................108
`
`R. Claim 18 ................................................................................................110
`
`S. Claim 19 ................................................................................................111
`
`T. Claim 20 ................................................................................................112
`
`ii
`
`Eton Ex. 1003
`3 of 154
`
`

`

`U. Claim 21 ................................................................................................114
`
`V. Claim 22 ................................................................................................115
`
`W. Claim 23 ................................................................................................119
`
`X. Claim 24 ................................................................................................120
`
`Y. Claim 25 ................................................................................................121
`
`Z. Claim 26 ................................................................................................123
`
`AA. Claim 27 ................................................................................................124
`
`BB. Claim 28 ................................................................................................129
`
`CC. Claim 29 ................................................................................................135
`
`DD. Claim 30 ................................................................................................136
`
`XI. SECONDARY CONSIDERATIONS ..............................................................137
`
`XII. CONCLUSION ..............................................................................................137
`
`
`
`iii
`
`Eton Ex. 1003
`4 of 154
`
`

`

`I.
`
`INTRODUCTION
`
`1. My name is Barrett Rabinow. My findings, as set forth herein, are
`
`based on my education and background in the fields discussed below.
`
`2.
`
`I have been retained by, and submit this Declaration on behalf of, Eton
`
`Pharmaceuticals, Inc. (“Eton” or “Petitioner”), which I understand is challenging the
`
`validity of claims 1-30 of U.S. Patent No. 10,583,155 (“’155 patent”) in a petition
`
`for post grant review (“PGR”). I have been asked to offer opinions generally
`
`regarding the prior art, the understandings of the person of ordinary skill in the art,
`
`and whether claims 1-30 would have been obvious to the person of ordinary skill in
`
`the art. I reserve the right to supplement this Declaration in response to additional
`
`evidence that may come to light or that I am asked to consider.
`
`3.
`
`I am being compensated for my time in connection with this PGR at my
`
`standard consulting rate of $350 per hour. My compensation is not affected by the
`
`substance of my opinions or the outcome of this matter.
`
`II. SUMMARY OF OPINIONS
`
`4.
`
`The ’155 patent issued with thirty claims. Claims 1-27 are generally
`
`directed to a method of treating a subject having an adverse health condition that is
`
`responsive to L-Cysteine administration, comprising parenterally administering a
`
`parenteral composition comprising a mixture of one or more amino acids,
`
`intravenous fluid, and a stable L-Cysteine composition wherein the L-Cysteine
`
`1
`
`Eton Ex. 1003
`5 of 154
`
`

`

`composition has a therapeutically effective amount of L-Cysteine (or its
`
`pharmaceutically acceptable salt or hydrate thereof) and specified amounts of known
`
`impurities Aluminum, L-Cystine and pyruvic acid. Claims 28-30 are directed to a
`
`total parenteral nutritional composition comprising a mixture of a stable L-Cysteine
`
`composition and one or amino acids selected from a recited group and wherein the
`
`L-Cysteine composition has a therapeutically effective amount of L-Cysteine (or its
`
`pharmaceutically acceptable salt or hydrate thereof) and specified amounts of known
`
`impurities Aluminum, L-Cystine and pyruvic acid. the composition.
`
`5.
`
`Claims 1-30 are obvious in view of the combination of the prior art
`
`Sandoz and Hospira Labels, in view of the knowledge of the person of ordinary skill
`
`in the art. The Sandoz Label discloses a L-Cysteine composition for parenteral
`
`administration and teaches mixing that composition with a dextrose solution and a
`
`crystalline amino acid injection to meet the intravenous amino acid nutritional
`
`requirements of infants receiving total parenteral nutrition (“TPN”). The Hospira
`
`Label discloses a crystalline amino acid composition for injection comprising the
`
`claimed amino acids. The claimed aluminum, L-cystine, and pyruvic acid levels are
`
`the reasonably expected result of optimizing the Sandoz product by eliminating
`
`aluminum in response to regulatory and market demand and preventing oxidation of
`
`L-Cysteine (a known oxygen sensitive drug) and the formation of its known
`
`oxidative degradation impurities, L-cystine and pyruvic acid, using art-recognized
`
`2
`
`Eton Ex. 1003
`6 of 154
`
`

`

`techniques. Moreover, the claimed adverse health conditions that are responsive to
`
`L-Cysteine were known in the art and thus do not patentably distinguish the claims
`
`from the combination of the Sandoz and Hospira Labels.
`
`III. BACKGROUND/QUALIFICATIONS
`
`6.
`
`I have over 39 years of industrial experience in pharmaceutical research
`
`and development (“R&D”) and sterile drug development and consider myself an
`
`expert.
`
`7. My current work is consulting for the pharmaceutical industry,
`
`involving R&D, manufacturing, regulatory, quality, and patent issues, with an
`
`emphasis on sterile injectable dosage forms, and issues concerning chemical
`
`reactions, formulations, stability, reaction rates, leaching, gas transmission through
`
`plastic, closure/container technology, impurities, and generally characterization and
`
`analysis of pharmaceutical products.
`
`8. My relevant past professional activities have included: committee
`
`member of the Aluminum Methodology for the Parenteral Drug Association,
`
`consultant and point presenter to the U.S. Food and Drug Administration (“FDA”)
`
`on issues of aluminum methodology, toxicology, and formulations for large volume
`
`parenteral solutions, osmolarity and stability storage issues, consultant for the
`
`Association for the Advancement of Medical Instrumentation on aluminum
`
`methodology and the appropriate levels in dialysis solutions, and reviewer for the
`
`3
`
`Eton Ex. 1003
`7 of 154
`
`

`

`Journal of Pharmaceutical Sciences.
`
`9. My academic career concentrated on chemistry and clinical chemistry.
`
`I received a Bachelor of Arts / atrium baccalaureus (AB), cum laude, in Chemistry
`
`from Cornell University in 1968.
`
`10.
`
`In 1969, I earned a Master of Science (MS) in Organic Chemistry from
`
`the University of Chicago, where my concentration was on synthesis, kinetics and
`
`mechanism.
`
`11.
`
`In 1968, I started my doctoral work at the University of Chicago, where
`
`I focused on fast reaction kinetics and mechanisms. In 1974, I completed my Ph.D.
`
`in Physical Organic Chemistry. I then did post-doctoral work in electrochemistry at
`
`the University of Chicago.
`
`12.
`
`I also received a Postdoctoral Fellowship in Clinical Chemistry funded
`
`by the National Institutes of Health (“NIH”), at the former Michael Reese Medical
`
`Center in Chicago. Subsequently, I was Director, Chemistry at Norwegian
`
`American Hospital in Chicago, until I joined Baxter Healthcare in 1977. At Baxter,
`
`I led corporate troubleshooting teams and task forces of industry-wide organizations
`
`for the most serious chemical problems of high commercial impact, developing
`
`novel methods and leading-edge techniques to solve critical research and
`
`manufacturing problems. I also negotiated favorable outcomes for the company and
`
`industry with the FDA.
`
`4
`
`Eton Ex. 1003
`8 of 154
`
`

`

`13.
`
`I also was responsible for global technical vision for new product /
`
`process design, incorporating multiple disciplines. In this context, I led a research
`
`team to develop a nanoparticle drug delivery platform currently in use for long-term
`
`(e.g., 1-month) injections for treatment of HIV.
`
`14. Other details concerning my background, academic work, and
`
`professional history are set forth in my curriculum vitae, which is attached as
`
`Exhibit A to this declaration.
`
`IV. DOCUMENTS AND MATERIALS CONSIDERED
`
`15. To form the opinions included in this Declaration, I reviewed the ’155
`
`patent, the prosecution history of the ’155 patent, the materials cited in this
`
`Declaration, and various prior art references. In forming my opinions, I have also
`
`relied on my experience and education.
`
`16. Certain references cited in my Declaration are drug product package
`
`display panels and package inserts (which I refer to collectively and individually as
`
`drug product labels) for commercially marketed drugs. The drug product labels are
`
`publicly available from a variety of sources, including online (e.g., the FDA website,
`
`the manufacturers’ website, or DrugsDB.eu) and in print (e.g., Physicians’ Desk
`
`Reference (“PDR”) or accompanying the drug product). Those skilled in the art
`
`would have understood that each of these sources were publicly available and could
`
`be accessed to obtain reliable information about drug products, including the Sandoz
`
`5
`
`Eton Ex. 1003
`9 of 154
`
`

`

`L-Cysteine Product and other drug products specifically addressed in this
`
`Declaration.
`
`V. LEGAL PRINCIPLES
`
`17.
`
`I am not an attorney, and I will offer no opinions on the law. I am,
`
`however, informed on several principles concerning patent validity which I have
`
`used in arriving at my opinions.
`
`18.
`
`I am advised that if each and every element or step of a claim is found
`
`in a prior art publication or was in public use, on sale or otherwise available to the
`
`public before the effective filing date of the claimed invention then the claim is
`
`“anticipated” by the prior art publication or public use because the claimed invention
`
`is not considered new or novel. I also understand that a claim may also be invalid
`
`as “obvious” if the claimed subject matter would have been obvious to the
`
`hypothetical person having ordinary skill in the art (“POSITA”) in view of the prior
`
`art publications or public uses combined with other publications or knowledge
`
`possessed by the POSITA as of the claimed invention’s effective filing date. I
`
`further understand that the POSITA is assumed to know about and to have access to
`
`all relevant prior art in the field of endeavor covered by the patent and all analogous
`
`prior art.
`
`19.
`
`I am advised that a claim may be rendered obvious by a single prior-art
`
`reference or from a combination of two or more prior art references.
`
`6
`
`Eton Ex. 1003
`10 of 154
`
`

`

`20.
`
`I understand that the effective filing date for the claims of the ’155
`
`patent is January 15, 2019. Thus, prior art to the ’155 patent includes patents, printed
`
`publications, public uses and disclosures (with certain limited exception I am
`
`advised are not applicable here), and the knowledge possessed by the POSITA as of
`
`January 15, 2019.
`
`21.
`
`I also understand
`
`that an obviousness analysis requires an
`
`understanding of the scope and content of the prior art, any differences between the
`
`claimed invention and the prior art, and the level of ordinary skill in evaluating the
`
`pertinent art.
`
`22.
`
`I further understand that certain factors may support or rebut the
`
`obviousness of a claim, which are referred to as secondary considerations. I
`
`understand that such secondary considerations include, among other things,
`
`commercial success of the patented invention, skepticism of those having ordinary
`
`skill in the art at the time of the alleged invention, unexpected results of the alleged
`
`invention, any long-felt but unsolved need in the art that was satisfied by the alleged
`
`invention, the failure of others to make the alleged invention, praise of the alleged
`
`invention by those having ordinary skill in the art, and copying of the alleged
`
`invention by others in the field. I understand that there must be a nexus—a
`
`connection—between any such secondary considerations and the claimed invention.
`
`I also understand that contemporaneous and independent invention by others is a
`
`7
`
`Eton Ex. 1003
`11 of 154
`
`

`

`secondary consideration tending to show obviousness.
`
`23.
`
`I further understand that a claim is obvious if it unites old elements with
`
`no change to their respective functions or alters prior art by mere substitution of one
`
`element for another known in the field, and that combination yields predictable
`
`results. While it may be helpful to identify a reason for this combination, common
`
`sense should guide, and no rigid requirement of finding a teaching, suggestion, or
`
`motivation to combine is required. When a product is available, design incentives
`
`and other market forces can prompt variations of it, either in the same field or
`
`different one. If a POSITA can implement a predictable variation, obviousness
`
`likely bars its patentability. For the same reason, if a technique has been used to
`
`improve one device or product, and a POSITA would recognize that it would
`
`improve similar devices or products in the same way, then using the technique is
`
`obvious. I understand that a claim may be obvious if common sense directs one to
`
`combine multiple prior art references or add missing features to reproduce the
`
`alleged invention recited in the claims.
`
`24.
`
`I am also informed that one should be cautious of using hindsight in
`
`evaluating whether a claimed invention would have been obvious.
`
`VI. PERSON OF ORDINARY SKILL IN THE ART
`
`25.
`
`I have been advised that there are multiple factors relevant to
`
`determining the level of ordinary skill in the pertinent art, including the educational
`
`8
`
`Eton Ex. 1003
`12 of 154
`
`

`

`level of active workers in the field at the time of the alleged invention, the
`
`sophistication of the technology, the type of problems encountered in the art, and the
`
`prior-art solutions to those problems.
`
`26. The ’155 patent generally relates to an L-Cysteine parenteral
`
`composition and methods of treatment comprising administering the same. In my
`
`experience, a POSITA at the time of the alleged invention would have had at least a
`
`Ph.D. degree in chemistry or biochemistry and at least 2 years of experience (or less
`
`education but more years of experience, i.e., an M.S. with at least 3-5 years of
`
`experience, or a B.S. with a minimum of 6 years of experience) with pharmaceutical
`
`drug product
`
`formulation, analysis, and development, optimization, and
`
`manufacture, including experience with processes and techniques for minimizing
`
`impurities in and improving the stability of, pharmaceutical drug products during
`
`manufacture and storage.
`
`27. For purposes of this Declaration, unless otherwise noted, my statements
`
`and opinions, such as those regarding my experience and the understanding of a
`
`POSITA generally (and specifically related to the references identified herein)
`
`reflect the knowledge that existed as of and prior to January 2019, at the very latest.
`
`As of and prior to January 2019, I would have qualified as a POSITA according to
`
`the above definition.
`
`9
`
`Eton Ex. 1003
`13 of 154
`
`

`

`VII. THE SCOPE & CONTENT OF THE PRIOR ART
`
`A. L-Cysteine and Aluminum Toxicity
`
`28. According to the “Background” of the ’155 patent, L-Cysteine is
`
`generally classified as a “non-essential” or “semi-essential” amino acid because it
`
`can be synthesized in small amounts by the human body.1 Nevertheless, the ’155
`
`patent notes that some adults can benefit from L-Cysteine supplementation.2 With
`
`respect to pre-term infants, the ’155 patent reports that L-Cysteine supplementation
`
`can be beneficial due to their biochemical immaturity of the enzyme cystathionase,
`
`which is involved in L-Cysteine synthesis.3
`
`29. Long before January 2019, L-Cysteine was (and still is) typically
`
`provided as an L-Cysteine Hydrochloride Injection solution which, after
`
`combination with an Amino Acid Injection solution, is administered parenterally to
`
`meet the amino acid requirements of patients receiving total parenteral nutrition.4 In
`
`
`1 Ex. 1001 at 13 (’155 patent, 1:27-29.)
`
`2 Ex. 1001 at 13 (’155 patent, 1:29-31.)
`
`3 Ex. 1001 at 13 (’155 patent, 1:31-35.)
`
`4 Ex. 1005 at 1, 6; see also Ex. 1004 at 5, 11. Exhibits 1005 and 1004 include two
`
`captures from the Internet Archive with the Sandoz Label, one dated April 3, 2017,
`
`and the other dated August 24, 2016. Both versions contain the same language and
`
`
`
`10
`
`Eton Ex. 1003
`14 of 154
`
`

`

`fact, in 1986, the FDA approved Hospira’s NDA for a 7.25% Cysteine
`
`Hydrochloride Injection (NDA 19-523) that, according to the Hospira 7.25%
`
`Cysteine HCl Label, was “indicated for use as an additive to amino acid solutions to
`
`meet nutritional requirements of newborn infants requiring total parenteral nutrition
`
`(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 acids
`
`solutions to provide a more complete profile of amino acids for protein synthesis.”5
`
`
`pre-date the ’155 patent’s January 2019 effective filing date by at least 2 years. For
`
`the sake of completeness, parallel cites to the 2017 and 2016 captures are provided
`
`herein.
`
`5 Ex. 1092 at 1, 10 (Attachment 3 to May 8, 2018 Citizen Petition regarding Cysteine
`
`Hydrochloride Injection 5%). In 2005, Hospira voluntarily asked FDA that the NDA
`
`19-523 be withdrawn, and in 2010, FDA announced that Hospira’s 7.25% Product
`
`“not withdrawn for reasons of safety or effectiveness.” Ex. 1091 at 2 (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).) Years
`
`later, on May 8, 2018, Lachman Consultant Services, Inc. submitted a Citizen
`
`Petition, “requesting the Commissioner of the [FDA] to declare that Cysteine
`
`Hydrochloride Injection 5% containing 34.6 mg/mL of Cysteine base are suitable
`
`
`
`11
`
`Eton Ex. 1003
`15 of 154
`
`

`

`30.
`
`I understand that Petitioner requested a copy of the file for Hospira’s
`
`NDA 19-523 for 7.25% Cysteine HCl on July 11, 2017, and that Petitioner received
`
`the requested materials on or about July 28, 2017.6
`
`31. Aluminum was (and still is) a known toxic impurity in parenteral
`
`nutritional compositions.7 As such, the FDA amended the labeling requirements for
`
`
`for consideration in an abbreviated new drug application (ANDA).” Ex. 1092 at 1.
`
`Attachment 3 to Lachman’s Citizen Petition is the “Approved labeling for reference-
`
`listed drug, Cysteine Hydrochloride Injection 7.25%” (“Hospira Package Insert”).
`
`Ex. 1092 at 3, 7-11.
`
`6 Ex. 1093 at 2-3, ¶¶4-7 (Chilakuri Decl.)
`
`7 E.g., Ex. 1006 at 1 (A Hernández-Sánchez et al., Aluminum in Parenteral Nutrition:
`
`A Systematic Review, 67 EUR. J. CLINICAL NUTRITION 230 (2013) (“Aluminum
`
`([“]Al[”]) toxicity in parenteral nutrition solutions ([“]PNS[”]) has been a problem
`
`for decades and is still unresolved.”); Ex. 1007 at 1-2 (Robert L. Poole et al.,
`
`Aluminum in Pediatric Parenteral Nutrition Products: Measured Versus Labeled
`
`Content, 16 J. PEDIATRIC PHARMACOLOGY & THERAPEUTICS 92 (2011) (“Parenteral
`
`nutrition ([“]PN[”]) has long been implicated as a major source of aluminum
`
`exposure as a result of contamination of the component ingredients.”); Ex. 1008 at
`
`1 (Denise Bohrer et al., Influence of the Glass Packing on the Contamination of
`
`
`
`12
`
`Eton Ex. 1003
`16 of 154
`
`

`

`parenteral drug products to address the “evidence linking the use of parenteral drug
`
`products containing aluminum to morbidity and mortality among patients on TPN
`
`therapy, especially among premature neonates and patients with impaired kidney
`
`function.”8
`
`32. Those amendments were codified at 21 C.F.R. § 201.323, which also
`
`requires manufacturers to include the following warning statement in connection
`
`
`Pharmaceutical Products by Aluminum. Part II: Amino Acids for Parenteral
`
`Nutrition, 15 J. TRACE ELEMENTS MED. & BIOLOGY 103 (2001) (“Bohrer II”) (“The
`
`presence of [Al] as contaminant in parenteral nutrition ([“]PN[”]) solutions is well-
`
`known and has been very [sic] discussed in the literature in least years (1-5).”); Ex.
`
`1064 at 1 (Mary S. Fewtrell et al., Symposium 2: Micronutrients Under the
`
`Microscopt Aluminum Exposure From Parenteral Nutrition in Preterm Infants and
`
`Later Health Outcomes During Childhood and Adolescensce, 70 PROCEEDINGS
`
`NUTRITION SOC. 299 (2011) (“Parenteral nutrition (PN) solutions are liable to
`
`contamination with aluminum, particularly from acidic solutions in glass vials,
`
`notably calcium gluconate.”).)
`
`8 Ex. 1054 at 1 (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. pt. 201);
`
`Ex. 1035 at 2 (same).)
`
`
`
`13
`
`Eton Ex. 1003
`17 of 154
`
`

`

`with large volume parenteral (“LVP’s”), small volume parenteral (“SVP’s”), and
`
`pharmacy bulk packaging (“PBP’s”) products used in total parenteral nutrition
`
`(“TPN”):
`
`WARNING: This product contains aluminum that may be toxic.
`
`Aluminum may reach
`
`toxic
`
`levels with prolonged parenteral
`
`administration if kidney function is impaired. Premature neonates are
`
`particularly at risk because their kidneys are immature, and they require
`
`large amounts of calcium and phosphate solutions, which contain
`
`aluminum.
`
`Research indicates that patients with impaired kidney function,
`
`including premature neonates, who receive parenteral levels of
`
`aluminum at greater than 4 to 5 [micro]g/kg/day accumulate aluminum
`
`at levels associated with central nervous system and bone toxicity.
`
`Tissue loading may occur at even lower rates of administration.9
`
`B. The Sandoz Label
`
`33. Years before the ’155 patent’s effective filing date, Sandoz Inc.
`
`(“Sandoz”) marketed L-Cysteine Hydrochloride Injection, 50 mg/mL (“Sandoz L-
`
`Cysteine Product”) in the United States.10 According to the Label and Prescribing
`
`
`9 Ex. 1068 at 1-2 (21 C.F.R. § 201.323(e).)
`
`10 Ex. 1022 at 3, ¶¶8-9 (Johnson Decl.); Ex. 1005 at 5, 11; Ex. 1004 at 9, 14; see also
`
`Ex. 1016 at 2 (Cysteine, DRUGBANK, https://www.drugbank.ca/drugs/DB00151 (last
`
`
`
`14
`
`Eton Ex. 1003
`18 of 154
`
`

`

`Information (“the Sandoz Label”), the Sandoz L-Cysteine Product was indicated
`
`“for use only after dilution as an additive to Crystalline Amino Acid Injections to
`
`meet the intravenous amino acid nutritional requirements of infants receiving total
`
`parenteral nutrition.”11 The Sandoz Label further provides that “[e]ach mL [of the
`
`Sandoz L-Cysteine Product] contains: 50 mg of L-Cysteine Hydrochloride
`
`Monohydrate USP; Water for Injection, USP q.s.; Air replaced with Nitrogen. pH
`
`1.0-2.5.”12 Because, as discussed below, L-Cysteine is oxygen sensitive and subject
`
`to oxidative degradation in the presence of oxygen, a POSITA would have
`
`understood that air was replaced with nitrogen in the Sandoz L-Cysteine Product to
`
`stabilize and prevent the oxidative degradation of L-Cysteine. In addition, based
`
`upon their absence from the list of ingredients on the Sandoz Label, the POSITA
`
`would have interpreted the Sandoz Label as teaching that the product packaged
`
`therein is free of antioxidants.13
`
`34. The Sandoz Label advises that the Sandoz L-Cysteine Product
`
`
`visited May 7, 2020).)
`
`11 Ex. 1005 at 2, 7; Ex. 1004 at 6, 11.
`
`12 Ex. 1005 at 1, 6; Ex. 1004 at 5, 11.
`
`13 See Ex. 1005 at 5, 11; Ex. 1004 at 8, 14.
`
`
`
`15
`
`Eton Ex. 1003
`19 of 154
`
`

`

`“[c]ontains no more than 5,000 mcg/L [i.e., 5,000 ppb] of aluminum,”14 which the
`
`POSITA would have understood to mean aluminum in an amount falling somewhere
`
`within the range of 0 ppb to 5,000 ppb, and includes the following warning:
`
`WARNING: This product contains aluminum that may be toxic. Aluminum
`
`may reach toxic levels with prolonged parenteral administration if kidney
`
`function is impaired. Premature neonates are particularly at risk because their
`
`kidneys are immature, and they require large amounts of calcium and
`
`phosphate solutions, which contain aluminum.
`
`Research indicates that patients with impaired kidney function, including
`
`premature neonates, who receive parenteral levels of aluminum at greater than
`
`4 to 5 mcg/kg/day accumulate aluminum at levels associated with central
`
`nervous system and bone toxicity. Tissue loading may occur at even lower
`
`rates of administration.15
`
`35.
`
`I understand that Allergy Laboratories, Inc. (“Allergy”) manufactured
`
`the Sandoz L-Cysteine Product.16 The aluminum levels measured in the Sandoz L-
`
`Cysteine Product were at the very low end of the no more than (“NMT”) 5,000 ppb
`
`range stated on the Sandoz Label.17 I understand that the aluminum levels were
`
`
`14 Ex. 1005 at 5, 10; Ex. 1004 at 8, 13.
`
`15 Ex. 1005 at 2, 8; Ex. 1004 at 6, 12.
`
`16 Ex. 1022 at 3, ¶¶8-9 (Johnson Decl.)
`
`17 Ex. 1022 at 6-7, ¶15 (Johnson Decl.); see Ex. 1005 at 5, 10; Ex. 1004 at 8, 13.
`
`
`
`16
`
`Eton Ex. 1003
`20 of 154
`
`

`

`typically first measured less than a month after manufacture and were typically
`
`below about 100 ppb.18 I understand that the aluminum levels were analyzed by
`
`Metrics Inc.19 I have reviewed and understand the Metrics aluminum data and
`
`supporting notebook pages, which confirm that at least sample lots #2100115,
`
`2081915, 2012114, and 2072115 contained less than 100 ppb aluminum. I also
`
`understand that the aluminum levels would gradually increase (typically to several
`
`hundred ppb) from 1-24 months after manufacture.20 The POSITA would have
`
`understood that a likely source of the aluminum (as initially observed and over time)
`
`was the glass vial in which the Sandoz L-Cysteine drug product was packaged. Glass
`
`vials were known to leach aluminum.21 Nevertheless, I understand that the amount
`
`
`18 Ex. 1022 at 6-7, ¶15 (Johnson Decl.)
`
`19 Ex. 1022 at 5, ¶12 (Johnson Decl.); Ex. 1078 at 1 (Metrics Decl.)
`
`20 Ex. 1022 at 6-7, ¶15 (Johnson Decl.)
`
`21 Ex. 1014 at 8 (Michael J Akers, Parenteral Preparations, in REMINGTON: THE
`
`SCIENCE AND PRACTICE OF PHARMACY 810 (David B. Troy et al. eds., 21st ed. 2006)
`
`(“with respect to glass leachables,” minor extractables include aluminum); see also
`
`Ex. 1008 at 2 (Bohrer II) (“The presence of aluminum in PN solutions could be
`
`related to an interaction of these solutions with the aluminum present in the glass
`
`container.”); Ex. 1054 at 1 (63 Fed. Reg. 176) (“Aluminum also leaches from glass
`
`
`
`17
`
`Eton Ex. 1003
`21 of 154
`
`

`

`of aluminum that leached into the Sandoz L-Cysteine drug product over the
`
`product’s projected shelf life was well-below the NMT 5,000 ppb limit set forth in
`
`the Sandoz Label.22
`
`C. Regulatory and Market Demand For Reducing Aluminum
`
`36. As noted by A Hernández-Sánchez et al. in 2013, the market had been
`
`slow to “universally embrace[]” and address the “Al problem” and recommended
`
`that manufacturers improve manufacturing techniques in order to provide a wide
`
`range of low aluminum content products, that “healthcare providers should ensure
`
`[parenteral nutrition solution] ingredients with the lowest amount of Al are used in
`
`the preparation of PNS,” and noted “[b]y choosing products with the least amount
`
`of Al contamination, Al exposure and the potential for Al toxicity can be reduced.”23
`
`By around 2017, FDA appeared to have picked-up on this call for action. For
`
`
`containers
`.
`.
`.
`”); Ex.
`
`1055
`
`at
`
`4
`
`(W. Mihatsch
`
`et
`
`al.,
`
`ESPGHAN/ESPEN/ESPR/ESPEN Guidelines on Pediatric Parenteral Nutrition:
`
`Calcium, Phosphorus and Magnesium, 37 CLINICAL NUTRITION 236