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`———————
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`———————
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`ETON PHARMACEUTICALS, INC.,
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`Petitioner
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`v.
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`EXELA PHARMA SCIENCES, LLC,
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`Patent Owner
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`———————
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`U.S. PATENT NO. 10,583,155
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`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
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`III. BACKGROUND/QUALIFICATIONS ............................................................... 3
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`IV. DOCUMENTS AND MATERIALS CONSIDERED ......................................... 5
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`V. LEGAL PRINCIPLES ......................................................................................... 6
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`VI. PERSON OF ORDINARY SKILL IN THE ART ............................................... 8
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`VII. THE SCOPE & CONTENT OF THE PRIOR ART .......................................10
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`A. L-Cysteine and Aluminum Toxicity........................................................10
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`B. The Sandoz Label ....................................................................................14
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`C. Regulatory and Market Demand For Reducing Aluminum ....................18
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`D. L-Cysteine’s Known Oxygen Sensitivity ................................................25
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`E. Other Impurities Including Heavy Metals ...............................................36
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`F. Optimizing the Sandoz L-Cysteine Product ............................................37
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`G. The Sandoz Label Provides The Motivation for Combining the
`Sandoz and Hospira Labels .....................................................................55
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`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
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`VIII. THE ’155 PATENT .........................................................................................58
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`A. Summary ..................................................................................................58
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`B. Prosecution History .................................................................................62
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`IX. CLAIM CONSTRUCTION ...............................................................................73
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`X. CLAIMS 1-30 ARE UNPATENTABLE UNDER § 103 ..................................73
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`A. Claim 1 ....................................................................................................74
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`B. Claim 2 ....................................................................................................83
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`C. Claim 3 ....................................................................................................84
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`D. Claim 4 ....................................................................................................86
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`E. Claim 5 ....................................................................................................86
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`F. Claim 6 ....................................................................................................87
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`G. Claim 7 ....................................................................................................88
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`H. Claim 8 ....................................................................................................89
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`I. Claim 9 ....................................................................................................90
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`J. Claim 10 ..................................................................................................91
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`K. Claim 11 ..................................................................................................94
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`L. Claim 12 ..................................................................................................96
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`M. Claim 13 ..................................................................................................98
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`N. Claim 14 ................................................................................................100
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`O. Claim 15 ................................................................................................101
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`P. Claim 16 ................................................................................................105
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`Q. Claim 17 ................................................................................................108
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`R. Claim 18 ................................................................................................110
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`S. Claim 19 ................................................................................................111
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`T. Claim 20 ................................................................................................112
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`U. Claim 21 ................................................................................................114
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`V. Claim 22 ................................................................................................115
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`W. Claim 23 ................................................................................................119
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`X. Claim 24 ................................................................................................120
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`Y. Claim 25 ................................................................................................121
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`Z. Claim 26 ................................................................................................123
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`AA. Claim 27 ................................................................................................124
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`BB. Claim 28 ................................................................................................129
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`CC. Claim 29 ................................................................................................135
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`DD. Claim 30 ................................................................................................136
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`XI. SECONDARY CONSIDERATIONS ..............................................................137
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`XII. CONCLUSION ..............................................................................................137
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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
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`based on my education and background in the fields discussed below.
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`2.
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`I have been retained by, and submit this Declaration on behalf of, Eton
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`Pharmaceuticals, Inc. (“Eton” or “Petitioner”), which I understand is challenging the
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`validity of claims 1-30 of U.S. Patent No. 10,583,155 (“’155 patent”) in a petition
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`for post grant review (“PGR”). I have been asked to offer opinions generally
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`regarding the prior art, the understandings of the person of ordinary skill in the art,
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`and whether claims 1-30 would have been obvious to the person of ordinary skill in
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`the art. I reserve the right to supplement this Declaration in response to additional
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`evidence that may come to light or that I am asked to consider.
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`3.
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`I am being compensated for my time in connection with this PGR at my
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`standard consulting rate of $350 per hour. My compensation is not affected by the
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`substance of my opinions or the outcome of this matter.
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`II. SUMMARY OF OPINIONS
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`4.
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`The ’155 patent issued with thirty claims. Claims 1-27 are generally
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`directed to a method of treating a subject having an adverse health condition that is
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`responsive to L-Cysteine administration, comprising parenterally administering a
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`parenteral composition comprising a mixture of one or more amino acids,
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`intravenous fluid, and a stable L-Cysteine composition wherein the L-Cysteine
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`1
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`composition has a therapeutically effective amount of L-Cysteine (or its
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`pharmaceutically acceptable salt or hydrate thereof) and specified amounts of known
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`impurities Aluminum, L-Cystine and pyruvic acid. Claims 28-30 are directed to a
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`total parenteral nutritional composition comprising a mixture of a stable L-Cysteine
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`composition and one or amino acids selected from a recited group and wherein the
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`L-Cysteine composition has a therapeutically effective amount of L-Cysteine (or its
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`pharmaceutically acceptable salt or hydrate thereof) and specified amounts of known
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`impurities Aluminum, L-Cystine and pyruvic acid. the composition.
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`5.
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`Claims 1-30 are obvious in view of the combination of the prior art
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`Sandoz and Hospira Labels, in view of the knowledge of the person of ordinary skill
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`in the art. The Sandoz Label discloses a L-Cysteine composition for parenteral
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`administration and teaches mixing that composition with a dextrose solution and a
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`crystalline amino acid injection to meet the intravenous amino acid nutritional
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`requirements of infants receiving total parenteral nutrition (“TPN”). The Hospira
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`Label discloses a crystalline amino acid composition for injection comprising the
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`claimed amino acids. The claimed aluminum, L-cystine, and pyruvic acid levels are
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`the reasonably expected result of optimizing the Sandoz product by eliminating
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`aluminum in response to regulatory and market demand and preventing oxidation of
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`L-Cysteine (a known oxygen sensitive drug) and the formation of its known
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`oxidative degradation impurities, L-cystine and pyruvic acid, using art-recognized
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`techniques. Moreover, the claimed adverse health conditions that are responsive to
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`L-Cysteine were known in the art and thus do not patentably distinguish the claims
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`from the combination of the Sandoz and Hospira Labels.
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`III. BACKGROUND/QUALIFICATIONS
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`6.
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`I have over 39 years of industrial experience in pharmaceutical research
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`and development (“R&D”) and sterile drug development and consider myself an
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`expert.
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`7. My current work is consulting for the pharmaceutical industry,
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`involving R&D, manufacturing, regulatory, quality, and patent issues, with an
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`emphasis on sterile injectable dosage forms, and issues concerning chemical
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`reactions, formulations, stability, reaction rates, leaching, gas transmission through
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`plastic, closure/container technology, impurities, and generally characterization and
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`analysis of pharmaceutical products.
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`8. My relevant past professional activities have included: committee
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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”)
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`on issues of aluminum methodology, toxicology, and formulations for large volume
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`parenteral solutions, osmolarity and stability storage issues, consultant for the
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`Association for the Advancement of Medical Instrumentation on aluminum
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`methodology and the appropriate levels in dialysis solutions, and reviewer for the
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`Journal of Pharmaceutical Sciences.
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`9. My academic career concentrated on chemistry and clinical chemistry.
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`I received a Bachelor of Arts / atrium baccalaureus (AB), cum laude, in Chemistry
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`from Cornell University in 1968.
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`10.
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`In 1969, I earned a Master of Science (MS) in Organic Chemistry from
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`the University of Chicago, where my concentration was on synthesis, kinetics and
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`mechanism.
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`11.
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`In 1968, I started my doctoral work at the University of Chicago, where
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`I focused on fast reaction kinetics and mechanisms. In 1974, I completed my Ph.D.
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`in Physical Organic Chemistry. I then did post-doctoral work in electrochemistry at
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`the University of Chicago.
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`12.
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`I also received a Postdoctoral Fellowship in Clinical Chemistry funded
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`by the National Institutes of Health (“NIH”), at the former Michael Reese Medical
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`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
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`for the most serious chemical problems of high commercial impact, developing
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`novel methods and leading-edge techniques to solve critical research and
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`manufacturing problems. I also negotiated favorable outcomes for the company and
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`industry with the FDA.
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`13.
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`I also was responsible for global technical vision for new product /
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`process design, incorporating multiple disciplines. In this context, I led a research
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`team to develop a nanoparticle drug delivery platform currently in use for long-term
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`(e.g., 1-month) injections for treatment of HIV.
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`14. Other details concerning my background, academic work, and
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`professional history are set forth in my curriculum vitae, which is attached as
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`Exhibit A to this declaration.
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`IV. DOCUMENTS AND MATERIALS CONSIDERED
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`15. To form the opinions included in this Declaration, I reviewed the ’155
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`patent, the prosecution history of the ’155 patent, the materials cited in this
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`Declaration, and various prior art references. In forming my opinions, I have also
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`relied on my experience and education.
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`16. Certain references cited in my Declaration are drug product package
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`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,
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`the manufacturers’ website, or DrugsDB.eu) and in print (e.g., Physicians’ Desk
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`Reference (“PDR”) or accompanying the drug product). Those skilled in the art
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`would have understood that each of these sources were publicly available and could
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`be accessed to obtain reliable information about drug products, including the Sandoz
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`L-Cysteine Product and other drug products specifically addressed in this
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`Declaration.
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`V. LEGAL PRINCIPLES
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`17.
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`I am not an attorney, and I will offer no opinions on the law. I am,
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`however, informed on several principles concerning patent validity which I have
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`used in arriving at my opinions.
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`18.
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`I am advised that if each and every element or step of a claim is found
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`in a prior art publication or was in public use, on sale or otherwise available to the
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`public before the effective filing date of the claimed invention then the claim is
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`“anticipated” by the prior art publication or public use because the claimed invention
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`is not considered new or novel. I also understand that a claim may also be invalid
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`as “obvious” if the claimed subject matter would have been obvious to the
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`hypothetical person having ordinary skill in the art (“POSITA”) in view of the prior
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`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
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`all relevant prior art in the field of endeavor covered by the patent and all analogous
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`prior art.
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`19.
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`I am advised that a claim may be rendered obvious by a single prior-art
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`reference or from a combination of two or more prior art references.
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`20.
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`I understand that the effective filing date for the claims of the ’155
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`patent is January 15, 2019. Thus, prior art to the ’155 patent includes patents, printed
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`publications, public uses and disclosures (with certain limited exception I am
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`advised are not applicable here), and the knowledge possessed by the POSITA as of
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`January 15, 2019.
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`21.
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`I also understand
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`that an obviousness analysis requires an
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`understanding of the scope and content of the prior art, any differences between the
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`claimed invention and the prior art, and the level of ordinary skill in evaluating the
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`pertinent art.
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`22.
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`I further understand that certain factors may support or rebut the
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`obviousness of a claim, which are referred to as secondary considerations. I
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`understand that such secondary considerations include, among other things,
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`commercial success of the patented invention, skepticism of those having ordinary
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`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
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`invention by those having ordinary skill in the art, and copying of the alleged
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`invention by others in the field. I understand that there must be a nexus—a
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`connection—between any such secondary considerations and the claimed invention.
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`I also understand that contemporaneous and independent invention by others is a
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`secondary consideration tending to show obviousness.
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`23.
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`I further understand that a claim is obvious if it unites old elements with
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`no change to their respective functions or alters prior art by mere substitution of one
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`element for another known in the field, and that combination yields predictable
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`results. While it may be helpful to identify a reason for this combination, common
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`sense should guide, and no rigid requirement of finding a teaching, suggestion, or
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`motivation to combine is required. When a product is available, design incentives
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`and other market forces can prompt variations of it, either in the same field or
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`different one. If a POSITA can implement a predictable variation, obviousness
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`likely bars its patentability. For the same reason, if a technique has been used to
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`improve one device or product, and a POSITA would recognize that it would
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`improve similar devices or products in the same way, then using the technique is
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`obvious. I understand that a claim may be obvious if common sense directs one to
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`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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`24.
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`I am also informed that one should be cautious of using hindsight in
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`evaluating whether a claimed invention would have been obvious.
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`VI. PERSON OF ORDINARY SKILL IN THE ART
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`25.
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`I have been advised that there are multiple factors relevant to
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`determining the level of ordinary skill in the pertinent art, including the educational
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`level of active workers in the field at the time of the alleged invention, the
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`sophistication of the technology, the type of problems encountered in the art, and the
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`prior-art solutions to those problems.
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`26. The ’155 patent generally relates to an L-Cysteine parenteral
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`composition and methods of treatment comprising administering the same. In my
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`experience, a POSITA at the time of the alleged invention would have had at least a
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`Ph.D. degree in chemistry or biochemistry and at least 2 years of experience (or less
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`education but more years of experience, i.e., an M.S. with at least 3-5 years of
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`experience, or a B.S. with a minimum of 6 years of experience) with pharmaceutical
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`drug product
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`formulation, analysis, and development, optimization, and
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`manufacture, including experience with processes and techniques for minimizing
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`impurities in and improving the stability of, pharmaceutical drug products during
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`manufacture and storage.
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`27. 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)
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`reflect the knowledge that existed as of and prior to January 2019, at the very latest.
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`As of and prior to January 2019, I would have qualified as a POSITA according to
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`the above definition.
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`VII. THE SCOPE & CONTENT OF THE PRIOR ART
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`A. L-Cysteine and Aluminum Toxicity
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`28. According to the “Background” of the ’155 patent, L-Cysteine is
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`generally classified as a “non-essential” or “semi-essential” amino acid because it
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`can be synthesized in small amounts by the human body.1 Nevertheless, the ’155
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`patent notes that some adults can benefit from L-Cysteine supplementation.2 With
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`respect to pre-term infants, the ’155 patent reports that L-Cysteine supplementation
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`can be beneficial due to their biochemical immaturity of the enzyme cystathionase,
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`which is involved in L-Cysteine synthesis.3
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`29. Long before January 2019, L-Cysteine was (and still is) typically
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`provided as an L-Cysteine Hydrochloride Injection solution which, after
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`combination with an Amino Acid Injection solution, is administered parenterally to
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`meet the amino acid requirements of patients receiving total parenteral nutrition.4 In
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`1 Ex. 1001 at 13 (’155 patent, 1:27-29.)
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`2 Ex. 1001 at 13 (’155 patent, 1:29-31.)
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`3 Ex. 1001 at 13 (’155 patent, 1:31-35.)
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`4 Ex. 1005 at 1, 6; see also Ex. 1004 at 5, 11. Exhibits 1005 and 1004 include two
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`captures from the Internet Archive with the Sandoz Label, one dated April 3, 2017,
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`and the other dated August 24, 2016. Both versions contain the same language and
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`fact, in 1986, the FDA approved Hospira’s NDA for a 7.25% Cysteine
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`Hydrochloride Injection (NDA 19-523) that, according to the Hospira 7.25%
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`Cysteine HCl Label, was “indicated for use as an additive to amino acid solutions to
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`meet nutritional requirements of newborn infants requiring total parenteral nutrition
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`(TPN) and of adult and pediatric patients with severe liver disease who may have
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`impaired enzymatic processes and require TPN. It can also be added to amino acids
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`solutions to provide a more complete profile of amino acids for protein synthesis.”5
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`pre-date the ’155 patent’s January 2019 effective filing date by at least 2 years. For
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`the sake of completeness, parallel cites to the 2017 and 2016 captures are provided
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`herein.
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`5 Ex. 1092 at 1, 10 (Attachment 3 to May 8, 2018 Citizen Petition regarding Cysteine
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`Hydrochloride Injection 5%). In 2005, Hospira voluntarily asked FDA that the NDA
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`19-523 be withdrawn, and in 2010, FDA announced that Hospira’s 7.25% Product
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`“not withdrawn for reasons of safety or effectiveness.” Ex. 1091 at 2 (Determination
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`that Cysteine Hydrochloride Injection, USP, 7.25%, Was Not Withdrawn From Sale
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`for Reasons of Safety or Effectiveness, 75 Fed. Reg. 31,790 (June 4, 2010).) Years
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`later, on May 8, 2018, Lachman Consultant Services, Inc. submitted a Citizen
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`Petition, “requesting the Commissioner of the [FDA] to declare that Cysteine
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`Hydrochloride Injection 5% containing 34.6 mg/mL of Cysteine base are suitable
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`30.
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`I understand that Petitioner requested a copy of the file for Hospira’s
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`NDA 19-523 for 7.25% Cysteine HCl on July 11, 2017, and that Petitioner received
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`the requested materials on or about July 28, 2017.6
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`31. Aluminum was (and still is) a known toxic impurity in parenteral
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`nutritional compositions.7 As such, the FDA amended the labeling requirements for
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`for consideration in an abbreviated new drug application (ANDA).” Ex. 1092 at 1.
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`Attachment 3 to Lachman’s Citizen Petition is the “Approved labeling for reference-
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`listed drug, Cysteine Hydrochloride Injection 7.25%” (“Hospira Package Insert”).
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`Ex. 1092 at 3, 7-11.
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`6 Ex. 1093 at 2-3, ¶¶4-7 (Chilakuri Decl.)
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`7 E.g., Ex. 1006 at 1 (A Hernández-Sánchez et al., Aluminum in Parenteral Nutrition:
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`A Systematic Review, 67 EUR. J. CLINICAL NUTRITION 230 (2013) (“Aluminum
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`([“]Al[”]) toxicity in parenteral nutrition solutions ([“]PNS[”]) has been a problem
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`for decades and is still unresolved.”); Ex. 1007 at 1-2 (Robert L. Poole et al.,
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`Aluminum in Pediatric Parenteral Nutrition Products: Measured Versus Labeled
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`Content, 16 J. PEDIATRIC PHARMACOLOGY & THERAPEUTICS 92 (2011) (“Parenteral
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`nutrition ([“]PN[”]) has long been implicated as a major source of aluminum
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`exposure as a result of contamination of the component ingredients.”); Ex. 1008 at
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`1 (Denise Bohrer et al., Influence of the Glass Packing on the Contamination of
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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
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`therapy, especially among premature neonates and patients with impaired kidney
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`function.”8
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`32. Those amendments were codified at 21 C.F.R. § 201.323, which also
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`requires manufacturers to include the following warning statement in connection
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`Pharmaceutical Products by Aluminum. Part II: Amino Acids for Parenteral
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`Nutrition, 15 J. TRACE ELEMENTS MED. & BIOLOGY 103 (2001) (“Bohrer II”) (“The
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`presence of [Al] as contaminant in parenteral nutrition ([“]PN[”]) solutions is well-
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`known and has been very [sic] discussed in the literature in least years (1-5).”); Ex.
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`1064 at 1 (Mary S. Fewtrell et al., Symposium 2: Micronutrients Under the
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`Microscopt Aluminum Exposure From Parenteral Nutrition in Preterm Infants and
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`Later Health Outcomes During Childhood and Adolescensce, 70 PROCEEDINGS
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`NUTRITION SOC. 299 (2011) (“Parenteral nutrition (PN) solutions are liable to
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`contamination with aluminum, particularly from acidic solutions in glass vials,
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`notably calcium gluconate.”).)
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`8 Ex. 1054 at 1 (Aluminum in Large and Small Volume Parenterals Used in Total
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`Parenteral Nutrition, 63 Fed. Reg. 176 (Jan. 5, 1998) (codified at 21 C.F.R. pt. 201);
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`Ex. 1035 at 2 (same).)
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`with large volume parenteral (“LVP’s”), small volume parenteral (“SVP’s”), and
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`pharmacy bulk packaging (“PBP’s”) products used in total parenteral nutrition
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`(“TPN”):
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`WARNING: This product contains aluminum that may be toxic.
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`Aluminum may reach
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`toxic
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`levels with prolonged parenteral
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`administration if kidney function is impaired. Premature neonates are
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`particularly at risk because their kidneys are immature, and they require
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`large amounts of calcium and phosphate solutions, which contain
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`aluminum.
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`Research indicates that patients with impaired kidney function,
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`including premature neonates, who receive parenteral levels of
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`aluminum at greater than 4 to 5 [micro]g/kg/day accumulate aluminum
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`at levels associated with central nervous system and bone toxicity.
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`Tissue loading may occur at even lower rates of administration.9
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`B. The Sandoz Label
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`33. Years before the ’155 patent’s effective filing date, Sandoz Inc.
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`(“Sandoz”) marketed L-Cysteine Hydrochloride Injection, 50 mg/mL (“Sandoz L-
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`Cysteine Product”) in the United States.10 According to the Label and Prescribing
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`9 Ex. 1068 at 1-2 (21 C.F.R. § 201.323(e).)
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`10 Ex. 1022 at 3, ¶¶8-9 (Johnson Decl.); Ex. 1005 at 5, 11; Ex. 1004 at 9, 14; see also
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`Ex. 1016 at 2 (Cysteine, DRUGBANK, https://www.drugbank.ca/drugs/DB00151 (last
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`Information (“the Sandoz Label”), the Sandoz L-Cysteine Product was indicated
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`“for use only after dilution as an additive to Crystalline Amino Acid Injections to
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`meet the intravenous amino acid nutritional requirements of infants receiving total
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`parenteral nutrition.”11 The Sandoz Label further provides that “[e]ach mL [of the
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`Sandoz L-Cysteine Product] contains: 50 mg of L-Cysteine Hydrochloride
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`Monohydrate USP; Water for Injection, USP q.s.; Air replaced with Nitrogen. pH
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`1.0-2.5.”12 Because, as discussed below, L-Cysteine is oxygen sensitive and subject
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`to oxidative degradation in the presence of oxygen, a POSITA would have
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`understood that air was replaced with nitrogen in the Sandoz L-Cysteine Product to
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`stabilize and prevent the oxidative degradation of L-Cysteine. In addition, based
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`upon their absence from the list of ingredients on the Sandoz Label, the POSITA
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`would have interpreted the Sandoz Label as teaching that the product packaged
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`therein is free of antioxidants.13
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`34. The Sandoz Label advises that the Sandoz L-Cysteine Product
`
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`visited May 7, 2020).)
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`11 Ex. 1005 at 2, 7; Ex. 1004 at 6, 11.
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`12 Ex. 1005 at 1, 6; Ex. 1004 at 5, 11.
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`13 See Ex. 1005 at 5, 11; Ex. 1004 at 8, 14.
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`15
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`Eton Ex. 1003
`19 of 154
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`“[c]ontains no more than 5,000 mcg/L [i.e., 5,000 ppb] of aluminum,”14 which the
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`POSITA would have understood to mean aluminum in an amount falling somewhere
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`within the range of 0 ppb to 5,000 ppb, and includes the following warning:
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`WARNING: This product contains aluminum that may be toxic. Aluminum
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`may reach toxic levels with prolonged parenteral administration if kidney
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`function is impaired. Premature neonates are particularly at risk because their
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`kidneys are immature, and they require large amounts of calcium and
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`phosphate solutions, which contain aluminum.
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`Research indicates that patients with impaired kidney function, including
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`premature neonates, who receive parenteral levels of aluminum at greater than
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`4 to 5 mcg/kg/day accumulate aluminum at levels associated with central
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`nervous system and bone toxicity. Tissue loading may occur at even lower
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`rates of administration.15
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`35.
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`I understand that Allergy Laboratories, Inc. (“Allergy”) manufactured
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`the Sandoz L-Cysteine Product.16 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
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`range stated on the Sandoz Label.17 I understand that the aluminum levels were
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`14 Ex. 1005 at 5, 10; Ex. 1004 at 8, 13.
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`15 Ex. 1005 at 2, 8; Ex. 1004 at 6, 12.
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`16 Ex. 1022 at 3, ¶¶8-9 (Johnson Decl.)
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`17 Ex. 1022 at 6-7, ¶15 (Johnson Decl.); see Ex. 1005 at 5, 10; Ex. 1004 at 8, 13.
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`16
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`Eton Ex. 1003
`20 of 154
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`typically first measured less than a month after manufacture and were typically
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`below about 100 ppb.18 I understand that the aluminum levels were analyzed by
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`Metrics Inc.19 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,
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`2081915, 2012114, and 2072115 contained less than 100 ppb aluminum. I also
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`understand that the aluminum levels would gradually increase (typically to several
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`hundred ppb) from 1-24 months after manufacture.20 The POSITA would have
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`understood that a likely source of the aluminum (as initially observed and over time)
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`was the glass vial in which the Sandoz L-Cysteine drug product was packaged. Glass
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`vials were known to leach aluminum.21 Nevertheless, I understand that the amount
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`18 Ex. 1022 at 6-7, ¶15 (Johnson Decl.)
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`19 Ex. 1022 at 5, ¶12 (Johnson Decl.); Ex. 1078 at 1 (Metrics Decl.)
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`20 Ex. 1022 at 6-7, ¶15 (Johnson Decl.)
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`21 Ex. 1014 at 8 (Michael J Akers, Parenteral Preparations, in REMINGTON: THE
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`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
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`related to an interaction of these solutions with the aluminum present in the glass
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`container.”); Ex. 1054 at 1 (63 Fed. Reg. 176) (“Aluminum also leaches from glass
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`17
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`Eton Ex. 1003
`21 of 154
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`of aluminum that leached into the Sandoz L-Cysteine drug product over the
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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.22
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`C. Regulatory and Market Demand For Reducing Aluminum
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`36. As noted by A Hernández-Sánchez et al. in 2013, the market had been
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`slow to “universally embrace[]” and address the “Al problem” and recommended
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`that manufacturers improve manufacturing techniques in order to provide a wide
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`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
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`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.”23
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`By around 2017, FDA appeared to have picked-up on this call for action. For
`
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`containers
`.
`.
`.
`”); Ex.
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`1055
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`at
`
`4
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`(W. Mihatsch
`
`et
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`al.,
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`ESPGHAN/ESPEN/ESPR/ESPEN Guidelines on Pediatric Parenteral Nutrition:
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`Calcium, Phosphorus and Magnesium, 37 CLINICAL NUTRITION 236