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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. 10,478,453
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`DECLARATION OF BARRETT RABINOW
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`TABLE OF CONTENTS
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`I.
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`INTRODUCTION ................................................................................................ 1
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`II. SUMMARY OF OPINIONS ............................................................................... 1
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`III. BACKGROUND/QUALIFICATIONS ............................................................... 2
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`IV. DOCUMENTS AND MATERIALS CONSIDERED ......................................... 4
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`V. LEGAL PRINCIPLES ......................................................................................... 5
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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 ......................................... 9
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`A. L-Cysteine and Aluminum Toxicity.......................................................... 9
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`B. The Sandoz Label ....................................................................................12
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`C. Regulatory and Market Demand For Reducing Aluminum ....................16
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`D. L-Cysteine’s Known Oxygen Sensitivity ................................................22
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`E. Other Impurities Including Heavy Metals ...............................................33
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`F. Optimizing The Sandoz L-Cysteine Product ..........................................34
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`VIII. THE ’453 PATENT .........................................................................................50
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`A. Summary ..................................................................................................50
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`B. Prosecution History .................................................................................56
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`IX. CLAIM CONSTRUCTION ...............................................................................63
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`X. CLAIMS 1-22 ARE UNPATENTABLE UNDER § 103 ..................................64
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`A. Claim 1 ....................................................................................................65
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`B. Claim 2 ....................................................................................................73
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`C. Claim 3 ....................................................................................................74
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`D. Claim 4 ....................................................................................................75
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`E. Claim 5 ....................................................................................................75
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`F. Claim 6 ....................................................................................................76
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`G. Claim 7 ....................................................................................................77
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`H. Claim 8 ....................................................................................................78
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`I. Claim 9 ....................................................................................................82
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`J. Claim 10 ..................................................................................................83
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`K. Claim 11 ..................................................................................................83
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`L. Claim 12 ..................................................................................................85
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`M. Claim 13 ..................................................................................................85
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`N. Claim 14 ..................................................................................................86
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`O. Claim 15 ..................................................................................................87
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`P. Claim 16 ..................................................................................................91
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`Q. Claim 17 ..................................................................................................95
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`R. Claim 18 ..................................................................................................99
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`S. Claim 19 ................................................................................................100
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`T. Claim 20 ................................................................................................101
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`U. Claim 21 ................................................................................................102
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`V. Claim 22 ................................................................................................107
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`XI. SECONDARY CONSIDERATIONS ..............................................................111
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`XII. CONCLUSION ..............................................................................................112
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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 1-22 of U.S. Patent No. 10,478,453 (“’453 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 1-22 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 ’453 patent issued with twenty-two claims. Claims 1-14 and 21,
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`respectively, are directed to an L-Cysteine composition and a method for making
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`such a composition. Claims 15-20 and 22, respectively, are directed to a total
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`parenteral nutrition composition comprising an L-Cysteine composition admixed
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`with an amino acid composition and method for preparing the same. Claims 1-22
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`are obvious in view of the prior art Sandoz Label (which discloses the Sandoz L-
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`Cysteine Product), the method for making the product that is the subject of the
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`Sandoz Label, and its indicated use in an admixture with an amino acid composition.
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`In short, claims 1-22 are the reasonably expected result of optimizing the product
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`disclosed on the Sandoz Label (and method for making the same) using well-known
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`techniques to minimize aluminum (a known toxic impurity) in response to regulatory
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`and market demand, while also preventing oxidative degradation of L-Cysteine
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`(which was known to be oxygen sensitive) and the formation of its known oxidative
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`degradation impurities, L-Cystine and pyruvic acid, using art-recognized techniques.
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`III. BACKGROUND/QUALIFICATIONS
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`5.
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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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`6. 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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`7. 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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`8. 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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`9.
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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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`10.
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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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`11.
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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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`12.
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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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`13. 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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`14. To form the opinions included in this Declaration, I reviewed the ’453
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`patent, the prosecution history of the ’453 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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`15. 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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`16.
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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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`17.
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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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`18.
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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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`19.
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`I understand that the effective filing date for the claims of the ’453
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`patent is January 15, 2019. Thus, prior art to the ’453 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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`20.
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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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`21.
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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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`22.
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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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`23.
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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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`24.
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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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`25. The ’453 patent generally relates to stable L-Cysteine compositions for
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`parenteral administration, total parenteral nutrition compositions for parenteral
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`administration and methods of preparing same. In my experience, a POSITA at the
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`time of the alleged invention would have had at least a Ph.D. degree in chemistry or
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`biochemistry and at least 2 years of experience (or less education but more years of
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`experience, i.e., an M.S. with at least 3-5 years of experience, or a B.S. with a
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`minimum of 6 years of experience) with pharmaceutical drug product formulation,
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`analysis, and development, optimization, and manufacture, including experience
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`with processes and techniques for minimizing impurities in and improving the
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`stability of, pharmaceutical drug products during manufacture and storage.
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`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)
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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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`27. According to the “Background” of the ’453 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 ’453
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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 ’453 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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`28. 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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`1 Ex. 1001 at 13 (’453 patent, 1:20-22.)
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`2 Ex. 1001 at 13 (’453 patent, 1:22-24.)
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`3 Ex. 1001 at 13 (’453 patent, 1:25-31.)
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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
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`29. Aluminum was (and still is) a known toxic impurity in parenteral
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`nutritional compositions.5 As such, the FDA amended the labeling requirements for
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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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`pre-date the ’453 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 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.”6
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`30. 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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`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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`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).”).)
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`6 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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`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.7
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`B. The Sandoz Label
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`31. Years before the ’453 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.8 According to the Label and Prescribing
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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.”9 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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`7 Ex. 1068 at 1-2 (21 C.F.R. § 201.323(e).)
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`8 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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`visited May 7, 2020).)
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`9 Ex. 1005 at 2, 7; Ex. 1004 at 6, 11.
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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.”10 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.11
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`32. The Sandoz Label advises that the Sandoz L-Cysteine Product
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`“[c]ontains no more than 5,000 mcg/L [i.e., 5,000 ppb] of aluminum,”12 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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`10 Ex. 1005 at 1, 6; Ex. 1004 at 5, 11.
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`11 See Ex. 1005 at 5, 11; Ex. 1004 at 8, 14.
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`12 Ex. 1005 at 5, 10; Ex. 1004 at 8, 13.
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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.13
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`33.
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`I understand that Allergy Laboratories, Inc. (“Allergy”) manufactured
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`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
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`range stated on the Sandoz Label.15 I understand that the aluminum levels were
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`typically first measured less than a month after manufacture and were typically
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`below about 100 ppb.16 I understand that the aluminum levels were analyzed by
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`Metrics Inc.17 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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`13 Ex. 1005 at 2, 8; Ex. 1004 at 6, 12.
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`14 Ex. 1022 at 3, ¶¶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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`hundred ppb) from 1-24 months after manufacture.18 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.19 Nevertheless, I understand that the amount
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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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`18 Ex. 1022 at 6-7, ¶15 (Johnson Decl.)
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`19 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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`containers
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`.
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`.
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`.
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`”); Ex.
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`1055
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`at
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`4
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`(W. Mihatsch
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`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 2360 (2018)
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`(“Acidic solutions packaged in glass vials . . . are contaminated with aluminum and
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`should not be used in PN.”).).)
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`the Sandoz Label.20
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`C. Regulatory and Market Demand For Reducing Aluminum
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`34. 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.”21
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`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
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`August 4, 2017, the FDA advised Patent Owner that, based upon the FDA’s
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`experience with SVP drug products used in total parenteral nutrition, the amount of
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`aluminum delivered by the Patent Owner’s L-Cysteine product should be limited to
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`≤ 0.6 mcg/kg/day.22 To comply with this aluminum dose level, the FDA instructed
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`20 Ex. 1022 at 6-7, ¶15 (Johnson Decl.)
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`21 Ex. 1006 at 8 (Hernández-Sánchez.)
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`22 Ex. 1019 at 1 (August 4, 2017 Letter from Donna Griebel, M.D., Director of
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`that the Patent Owner’s L-Cysteine product should be limited to ≤ 145 mcg/L (i.e.,
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`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
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`amino acid of L-[C]ysteine added.”24
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`35. 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
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`admixture. The following statement appears on the label for Selenious Acid
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`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
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`containing other small volume parenteral products, the total daily patient exposure
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`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
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`with the same wording: “Exposure to aluminum from Zinc Sulfate Injection is not
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`Division of Gastroenterology and Inborn Errors Products, CDER, to Patent Owner
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`(“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 Letter to Patent Owner.)
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`25 Ex. 1042 at 4-5 (Prescribing Information for Selenious Acid Injection); see also
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`Ex. 1043 at 3 (July 10, 2019 Press Release regarding Selenious Acid Injection.)
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`more than 0.6 mcg/kg/day. When prescribing Zinc Sulfate Injection for use in
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`parenteral nutrition containing other small volume parenteral products, the total
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`daily patient exposure to aluminum from the admixture should be considered and
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`maintained at no more than 5 mcg/kg/day.”26
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`36.
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`I also understand that AL Pharma Inc. (“AL Pharma”) filed an NDA
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`via the 505(b)(2) pathway for a 5% L-Cysteine HCl Injection product.27 The
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`Proposed Finished Product Release Specifications (“Specifications”) for the 5% L-
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`Cysteine HCl Injection product recited, among other things, an Aluminum Content
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`of NMT 5,000 ppb and NMT 2.0% Cystine.28
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`37. With respect to AL Pharma’s proposed aluminum specification, by e-
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`mail dated March 9, 2018, FDA advised AL Pharma that:
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`The drug product L-Cy[s]teine Hydrochloride Injection is a small volume
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`parenteral drug product used in TPN. Based on our previous experience with
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`small volume parenteral drug products intended for addition to the TPN, we
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`have determined that the aluminum dose delivered by your drug product, 5%
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`L-Cysteine Hydrochloride Injection, USP, should be limited to ≤0.6
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`mcg/kg/day. To comply with this limit, the aluminum content in the final drug
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`product should be controlled to ≤350 mcg/L. This calculation is based on the
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`26 Ex. 1044 at 5 (Prescribing Information for Zinc Sulfate Injection.)
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`27 Ex. 1022 at 9-10, ¶19 (Johnson Decl.)
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`28 Ex. 1022 at 10, ¶20 (Johnson Decl.)
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`clinical dose of 15 mg cysteine free base per gram of amino acid per day.
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`Therefore, the proposed acceptance limit for the aluminum content in the
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`finished drug product specification (3.2.P.5.1) must be revised to ≤350 mcg/L.
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`The drug product registration batches manufactured at OKC Allergy Supplies,
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`Oklahoma City, OK have not been shown to meet the required acceptance
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`limit for aluminum content.29
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`38. Thus, by around the 2017-2018 timeframe, i.e., before the ’453 patent’s
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`effective filing date, FDA required manufacturers to achieve and maintain specified
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`maximum low aluminum levels below the NMT 5,000 ppb set forth on the Sandoz
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`Label to receive regulatory approval. FDA was tightening aluminum levels below
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`what they had been, as further indicated by the August 2017 Dear Health Care
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`Provider warning, issued by Exela.30 “The current carton and v