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
`
`DECLARATION OF BARRETT RABINOW
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`TABLE OF CONTENTS
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`I.
`
`INTRODUCTION................................................................................................1
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`II. SUMMARY OF OPINIONS ...............................................................................1
`
`III. BACKGROUND/QUALIFICATIONS ...............................................................2
`
`IV. DOCUMENTS AND MATERIALS CONSIDERED.........................................4
`
`V. LEGAL PRINCIPLES .........................................................................................5
`
`VI. PERSON OF ORDINARY SKILL IN THE ART...............................................8
`
`VII. The Scope & Content of the Prior Art...............................................................9
`
`VIII. THE ’719 PATENT.........................................................................................59
`
`A. Summary..................................................................................................59
`
`B. Prosecution History .................................................................................64
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`IX. CLAIM CONSTRUCTION...............................................................................74
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`X. CLAIMS 1-27 ARE UNPATENTABLE UNDER § 103..................................75
`
`A. Claim 1 ....................................................................................................76
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`[Preamble] “A solution of L-cysteine comprising:” ...............................76
`
`[a] “a pharmaceutically acceptable carrier,” ...........................................76
`
`[b] “about 50 mg/mL of L-cysteine hydrochloride monohydrate, or
`equivalent amount of a pharmaceutically acceptable L-cysteine or a
`salt or hydrate thereof,” ...........................................................................77
`
`[c] “less than about 150 ppb of aluminum,”............................................77
`
`[d] “a pH from about 1.0 to about 2.5, and”............................................78
`
`[e] “wherein the solution is substantially free of visually detectable
`particulate matter and” ............................................................................78
`
`i
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`7.
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`[f] “suitable for use as an additive in a parenteral nutrition
`composition for administration to an individual.” ..................................79
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`B. Claim 2 ....................................................................................................79
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`C. Claim 3 ....................................................................................................80
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`D. Claim 4 ....................................................................................................80
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`E. Claim 5 ....................................................................................................81
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`F. Claim 6 ....................................................................................................82
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`G. Claim 7 ....................................................................................................83
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`H. Claim 8 ....................................................................................................85
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`I. Claim 9 ....................................................................................................85
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`J. Claim 10 ..................................................................................................87
`
`K. Claim 11 ..................................................................................................88
`
`L. Claim 12 ..................................................................................................88
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`[Preamble] “A solution of L-cysteine comprising:” ...............................88
`
`[a] “a pharmaceutically acceptable carrier,” ...........................................88
`
`[b] “about 50 mg/mL of L-cysteine hydrochloride monohydrate, or
`equivalent amount of a pharmaceutically acceptable L-cysteine or a
`salt or hydrate thereof,” ...........................................................................89
`
`[c] “less than about 150 ppb of aluminum,”............................................89
`
`[d] “a pH from about 1.0 to about 2.5, and”............................................90
`
`[e] “wherein the solution is substantially free of visually detectable
`particulate matter for at least 6 months from the time of manufacture
`of the solution and” .................................................................................90
`
`7.
`
`[f] “is suitable for use as an additive in a parenteral nutrition
`
`ii
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`composition for administration to a neonate or infant.” .........................91
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`M. Claim 13 ..................................................................................................91
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`N. Claim 14 ..................................................................................................92
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`O. Claim 15 ..................................................................................................93
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`P. Claim 16 ..................................................................................................94
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`Q. Claim 17 ..................................................................................................95
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`[Preamble] “A solution of L-cysteine comprising:” ...............................95
`
`[a] “a pharmaceutically acceptable carrier,” ...........................................95
`
`[b] “about 50 mg/mL of L-cysteine hydrochloride monohydrate, or
`equivalent amount of a pharmaceutically acceptable L-cysteine or a
`salt or hydrate thereof, in a low oxygen environment”...........................95
`
`[c] “less than about 150 ppb of aluminum, and”.....................................96
`
`[d] “a pH from about 1.0 to about 2.5,” ..................................................97
`
`[e] “wherein the solution is substantially free of visually detectable
`particulate matter and” ............................................................................97
`
`[f] “is suitable for use as an additive in a parenteral nutrition
`composition for administration to a neonate or infant.” .........................98
`
`R. Claim 18 ..................................................................................................98
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`S. Claim 19 ..................................................................................................99
`
`T. Claim 20 ................................................................................................100
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`U. Claim 21 ................................................................................................101
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`V. Claim 22 ................................................................................................102
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`W. Claim 23 ................................................................................................103
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`iii
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`X. Claim 24 ................................................................................................104
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`Y. Claim 25 ................................................................................................105
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`Z. Claim 26 ................................................................................................106
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`AA. Claim 27 ................................................................................................106
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`XI. SECONDARY CONSIDERATIONS..............................................................107
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`XII. CONCLUSION..............................................................................................108
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`I.
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`INTRODUCTION
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`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 1-27 of U.S. Patent No. 10,653,719 (“’719 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 1-27 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 ’719 patent issued with twenty-seven claims. Claims 1-27 are
`
`generally directed to L-Cysteine hydrochloride monohydrate solutions substantially
`
`free of visually detectable particulate matter that are suitable for use as an additive
`
`in a parenteral nutrition composition. Claims 1-27 are obvious in view of the prior
`
`art Sandoz Label which discloses a L-Cysteine hydrochloride monohydrate solution
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`1
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`that is intended for use as an additive to Crystalline Amino Acid injections to meet
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`the intravenous amino acid nutritional requirements of infants receiving total
`
`parenteral nutrition. In short, claims 1-27 are the reasonably expected result of
`
`optimizing the product disclosed by the Sandoz Label using well-known techniques
`
`to minimize aluminum (a known toxic impurity) in response to regulatory and
`
`market demand, while also preventing oxidative degradation of L-Cysteine (which
`
`was known to be oxygen sensitive) and the formation of L-Cystine precipitates (an
`
`oxidative degradation product of L-Cysteine) and other visually detectable
`
`particulate matter using art-recognized techniques.
`
`III. BACKGROUND/QUALIFICATIONS
`
`5.
`
`I have over 39 years of industrial experience in pharmaceutical research
`
`and development (“R&D”) and sterile drug development and consider myself an
`
`expert in pharmaceutical R&D.
`
`6.
`
`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.
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`7.
`
`My relevant past professional activities have included: committee
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`2
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`member of the Aluminum Methodology for the Parenteral Drug Association,
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`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
`
`Journal of Pharmaceutical Sciences.
`
`8.
`
`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.
`
`9.
`
`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.
`
`10.
`
`In 1969, 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.
`
`11.
`
`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
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`American Hospital in Chicago, until I joined Baxter Healthcare in 1977. At Baxter,
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`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.
`
`12.
`
`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.
`
`13. 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
`
`14.
`
`To form the opinions included in this Declaration, I reviewed the ’719
`
`patent, the prosecution history of the ’719 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.
`
`15. Certain references cited in my Declaration are drug product package
`
`display panels and package inserts (which I refer to collectively and individually as
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`drug product labels) for commercially marketed drugs. The drug product labels are
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`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
`
`L-Cysteine Product and other drug products specifically addressed in this
`
`Declaration.
`
`V. LEGAL PRINCIPLES
`
`16.
`
`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.
`
`17.
`
`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
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`possessed by the POSITA as of the claimed invention’s effective filing date. I
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`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.
`
`18.
`
`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.
`
`19.
`
`I have assumed that the effective filing date for the claims of the ’719
`
`patent is January 15, 2019. Thus, prior art to the ’719 patent includes patents, printed
`
`publications, public uses and disclosures (with certain limited exceptions I am
`
`advised are not applicable here), and the knowledge possessed by the POSITA as of
`
`January 15, 2019.
`
`20.
`
`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.
`
`21.
`
`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
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`invention, any long-felt but unsolved need in the art that was satisfied by the alleged
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`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
`
`secondary consideration tending to show obviousness.
`
`22.
`
`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
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`alleged invention recited in the claims.
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`23.
`
`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
`
`24.
`
`I have been advised that there are multiple factors relevant to
`
`determining the level of ordinary skill in the pertinent art, including the educational
`
`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.
`
`25.
`
`The ’719 patent generally relates to solutions of L-Cysteine, which may
`
`be administered as part of a total parenteral nutritional composition. 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, 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.
`
`26.
`
`For purposes of this Declaration, unless otherwise noted, my statements
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`and opinions, such as those regarding my experience and the understanding of a
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`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.
`
`VII. THE SCOPE & CONTENT OF THE PRIOR ART
`
`A.
`
`L-Cysteine and Aluminum Toxicity
`
`27. According to the “Background” of the ’719 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 ’719
`
`patent notes that some adults can benefit from L-Cysteine supplementation.2 With
`
`respect to pre-term infants, the ’719 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
`
`28.
`
`Long before January 2019, L-Cysteine was (and still is) typically
`
`provided as an L-Cysteine Hydrochloride Monohydrate Injection solution which,
`
`
`1 Ex. 1106 at 13 (’719 patent, 1:32-34.)
`
`2 Ex. 1106 at 13 (’719 patent, 1:34-36.)
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`3 Ex. 1106 at 13 (’719 patent, 1:37-40.)
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`after combination with an Amino Acid Injection solution,
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`is administered
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`parenterally to meet the amino acid requirements of patients receiving total
`
`parenteral nutrition.4
`
`29. Aluminum was (and still is) a known toxic impurity in parenteral
`
`nutritional compositions.5 As such, the FDA amended the labeling requirements for
`
`
`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
`
`pre-date the ’719 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 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
`
`10
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`parenteral drug products to address the “evidence linking the use of parenteral drug
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`products containing aluminum to morbidity and mortality among patients on TPN
`
`therapy, especially among premature neonates and patients with impaired kidney
`
`function.”6
`
`30.
`
`Those amendments were codified at 21 C.F.R. § 201.323, which also
`
`requires manufacturers to include the following warning statement in connection
`
`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
`
`
`1 (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”) (“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).”).)
`
`6 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).)
`
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`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.7
`The Sandoz Label
`
`B.
`
`31. Years before the ’719 patent’s effective filing date, Sandoz Inc.
`
`(“Sandoz”) marketed L-Cysteine Hydrochloride Monohydrate Injection, 50 mg/mL
`
`(“Sandoz L-Cysteine Product”) in the United States.8 According to the Label and
`
`Prescribing 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
`
`
`7 Ex. 1068 at 1-2 (21 C.F.R. § 201.323(e).)
`
`8 Ex. 1022 at 3-4, ¶¶8-9 (Johnson Decl.); Ex. 1005 at 5, 11; Ex. 1004 at 8-9, 14; see
`
`also Ex. 1016 at 2 (Cysteine, DRUGBANK, https://www.drugbank.ca/drugs/DB00151
`
`(last visited May 7, 2020).)
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`receiving total parenteral nutrition.”9 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.”10 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.11
`
`32.
`
`The Sandoz Label advises that the Sandoz L-Cysteine Product
`
`“[c]ontains no more than 5,000 mcg/L [i.e., 5,000 ppb] of aluminum,”12 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
`
`9 Ex. 1005 at 2, 7; Ex. 1004 at 6, 11.
`
`10 Ex. 1005 at 1, 6; Ex. 1004 at 5, 11.
`
`11 See Ex. 1005 at 5, 11; Ex. 1004 at 8, 13-14.
`
`12 Ex. 1005 at 5, 10; Ex. 1004 at 8, 13.
`
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`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.13
`33.
`I understand that Allergy Laboratories, Inc. (“Allergy”) manufactured
`
`the Sandoz L-Cysteine Product.14 The aluminum levels measured in the Sandoz L-
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`Cysteine Product were at the very low end of the no more than (“NMT”) 5,000 ppb
`
`range stated on the Sandoz Label.15
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`I understand that the aluminum levels were
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`typically first measured less than a month after manufacture and were typically
`
`below about 100 ppb.16
`
`I understand that the aluminum levels were analyzed by
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`Metrics Inc.17
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`I have reviewed and understand the Metrics aluminum data and
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`supporting notebook pages, which confirm that at least sample lots #2100115,
`
`
`13 Ex. 1005 at 2, 8; Ex. 1004 at 6, 12.
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`14 Ex. 1022 at 3-4, ¶¶8-9 (Johnson Decl.)
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`15 Ex. 1022 at 6-7, ¶15 (Johnson Decl.); see Ex. 1005 at 5, 10; Ex. 1004 at 8, 13.
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`16 Ex. 1022 at 6-7, ¶15 (Johnson Decl.)
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`17 Ex. 1022 at 5, ¶12 (Johnson Decl.); Ex. 1078 at 1 (Metrics Decl.)
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`14
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`2081915, 2012114, and 2072115 contained less than 100 ppb aluminum.
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`I also
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`understand that the aluminum levels would gradually increase (typically to several
`
`hundred ppb) from 1-24 months after manufacture.18 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.19 Nevertheless, I understand that the amount
`
`of aluminum that leached into the Sandoz L-Cysteine drug product over the
`
`
`18 Ex. 1022 at 6-7, ¶15 (Johnson Decl.)
`
`19 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)
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`(“with respect to glass leachables,” minor extractables include aluminum); see also
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`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
`
`containers
`
`.
`
`.
`
`.
`
`”); Ex.
`
`1055
`
`at
`
`4
`
`(W. Mihatsch
`
`et
`
`al.,
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`ESPGHAN/ESPEN/ESPR/ESPEN Guidelines on Pediatric Parenteral Nutrition:
`
`Calcium, Phosphorus and Magnesium, 37 CLINICAL NUTRITION 2360 (2018)
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`(“Acidic solutions packaged in glass vials . . . are contaminated with aluminum and
`
`should not be used in PN.”).).)
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`15
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`product’s projected shelf life was well-below the NMT 5,000 ppb limit set forth in
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`the Sandoz Label.20
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`C.
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`Regulatory and Market Demand For Reducing Aluminum
`
`34. 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
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`[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
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`of Al contamination, Al exposure and the potential for Al toxicity can be reduced.”21
`
`By around 2017, FDA appeared to have picked-up on this call for action. For
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`example, I understand that the Patent Owner filed a New Drug Application (“NDA”)
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`for an L-Cysteine Product currently branded as ELCYS®. In a communication dated
`
`August 4, 2017, the FDA advised Patent Owner that, based upon the FDA’s
`
`experience with SVP drug products used in total parenteral nutrition, the amount of
`
`aluminum delivered by the Patent Owner’s L-Cysteine product should be limited to
`
`
`20 Ex. 1022 at 6-7, ¶15 (Johnson Decl.)
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`21 Ex. 1006 at 8 (Hernández-Sánchez.)
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`≤ 0.6 mcg/kg/day.22 To comply with this aluminum dose level, the FDA instructed
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`that the Patent Owner’s L-Cysteine product should be limited to ≤ 145 mcg/L (i.e.,
`
`145 ppb) aluminum.23 As the FDA explained, the 145 ppb limit was “derived based
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`on the maximum dose of total amino acid at 3.5 gram/kg/day with 40 mg/gram of
`
`amino acid of L-[C]ysteine added.”24
`
`35.
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`FDA apparently communicated the same ≤0.6 mcg/kg/day aluminum
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`limit for other SVP drug products intended for use in a total parenteral nutrition
`
`admixture. The following statement appears on the label for Selenious Acid
`
`Injection: “Exposure to aluminum from Selenious Acid Injection is not more than
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`0.6 mcg/kg/day. When prescribing Selenious Acid Injection for use in PN
`
`containing other small volume parenteral products, the total daily patient exposure
`
`to aluminum from the admixture should be considered and maintained at no more
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`than 5 mcg/kg/day.”25 Similarly, labeling was reissued for Zinc Sulfate Injection
`
`
`22 Ex. 1019 at 1 (August 4, 2017 Letter from Donna Griebel, M.D., Director of
`
`Division of Gastroenterology and Inborn Errors Products, CDER, to Patent Owner
`
`(“August 4, 2017 Letter to Patent Owner”).)
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`23 Ex. 1019 at 1 (August 4, 2017 Letter to Patent Owner.)
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`24 Ex. 1019 at 1 (August 4, 2017