UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`Nexus Pharmaceuticals, Inc.,
`Petitioner
`v.
`Exela Pharma Sciences LLC,
`Patent Owner
`_____________________
`Case No.: Unassigned
`Patent No. 11,642,370
`
`DECLARATION OF PASQUALE N. CONFALONE, Ph.D.
`
`Nexus Ex. 1003
`Page 1 of 105
`
`

`

`
`
`
`TABLE OF CONTENTS
`
`
`Page
`
`PETITIONER’S EXHIBIT LIST ............................................................................ iii
`I.
`QUALIFICATIONS ........................................................................................ 1
`II.
`SCOPE OF ASSIGNMENT AND SUMMARY OF OPINION ..................... 4
`III. LEGAL STANDARDS ................................................................................... 5
`A.
`Enablement ............................................................................................ 6
`B.
`Obviousness ........................................................................................... 6
`IV. PERSON OF ORDINARY SKILL IN THE ART .......................................... 8
`V.
`INTRODUCTION ........................................................................................... 9
`A.
`Background on L-cysteine products ...................................................... 9
`B.
`The Sandoz Label ................................................................................ 11
`C.
`Regulatory and Market Demand For Reducing
`Aluminum ............................................................................................ 12
`L-Cysteine’s Known Oxygen Sensitivity ............................................ 13
`D.
`VI. BACKGROUND ........................................................................................... 16
`A.
`The ’370 Patent ................................................................................... 16
`B.
`The ’370 Patent Prosecution History .................................................. 20
`VII. The Claims of the ’370 Patent are not Enabled ............................................. 28
`A.
`Related District Court Litigation: Exela v. Eton ................................. 29
`B.
`Related Post Grant Review Petition .................................................... 36
`C.
`A POSA Would Not Have Been Able to Practice the Full
`Scope of the Claims Without Undue Experimentation ....................... 38
`VIII. The Claims of the ’370 Patent Would Have Been Obvious .......................... 62
`
`
`
`Nexus Ex. 1003
`Page 2 of 105
`
`

`

`A.
`
`B.
`C.
`D.
`E.
`F.
`G.
`H.
`I.
`J.
`
`4.
`
`5.
`
`6.
`
`2.
`
`3.
`
`Claim 1 ................................................................................................ 63
`1.
`“A solution of L-cysteine for use in total parenteral
`nutrition (TPN) comprising” ..................................................... 63
`“about 10 mg/L to about 100 mg/mL of L-cysteine
`or a pharmaceutically acceptable salt of hydrate
`thereof, in a pharmaceutically acceptable carrier;
`wherein:” ................................................................................... 63
`“after 12 months of storage in a sealed vial at room
`temperature:” ............................................................................. 64
`“the total amount of oxygen within the sealed vial
`is no more than about 5%; and” ................................................ 64
`“the solution: contains no more than 250 ppb
`aluminum” ................................................................................. 66
`“is substantially free of visually detectable
`particulate matter, and” ............................................................. 68
`“has a pH form 1.0 to 2.5” ........................................................ 69
`7.
`Claim 2 ................................................................................................ 69
`Claim 3 ................................................................................................ 70
`Claim 4 ................................................................................................ 71
`Claim 5 ................................................................................................ 71
`Claims 6-9 ........................................................................................... 73
`Claims 10-18 ....................................................................................... 74
`Claims 19-27 ....................................................................................... 75
`Claims 28-30 ....................................................................................... 75
`Secondary Considerations of Non-Obviousness ................................. 76
`
`
`
`ii
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`Nexus Ex. 1003
`Page 3 of 105
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`

`

`PETITIONER’S EXHIBIT LIST
`Description
`Exhibit No.
`Exhibit 1001 U.S. Patent No. 11,642,370 (“the ’370 patent”)
`Exhibit 1002
`’370 Patent File History
`Exhibit 1003 Declaration of Pasquale N. Confalone Ph.D.
`Exhibit 1004 Affidavit of Christopher Butler
`Exhibit 1005
`
`Sandoz Label
`Way Back Machine Screenshots of
`https://web.archive.org/web/20170403170533/http:/drugsdb.eu/drug.ph
`p?d=L-cysteine%20Hydrochloride&m=Sandoz%20Inc&id=083366d6-
`0437-4ee0-90d4-440a5b5d03b5.xml and
`https://web.archive.org/web/20160824090050/http:/drugsdb.eu/drug.ph
`p?d=L-cysteine%20Hydrochloride&m=Sandoz%20Inc&id=083366d6-
`0437-4ee0-90d4-440a5b5d03b5.xml
`Exhibit 1006 A. Hernandez-Sanchez et al., Aluminum in Parenteral Nutrition: A
`Systematic Review, 67 Eur. J. Clinical Nutrition 230 (2013)
`
`Exhibit 1007
`
`Exhibit 1009
`
`Exela Pharma Sciences, LLC v. Eton Pharmaceuticals, Inc., 620
`F.Supp.3d 108 (D. Del. 2022)
`Exhibit 1008 D. Bohrer et al., Influence of the Glass Packing on the Contamination
`of Pharmaceutical Products by Aluminum. Part II: Amino Acids for
`Parenteral Nutrition, 15 J. Trace Elements Med. & Biology 103 (2001)
`(“Bohrer II”)
`P. Nasa, A Review on Pharmaceutical Packaging Material, World J. of
`Pharm. Res., vol. 3, Issue 5, 344-368 (2015)
`Exhibit 1010
`Reserved
`Exhibit 1011 D. Bohrer et al., Ion-exchange and potentiometric characterization of
`Al-cystine and Al-cysteine complexes, J. Biol Inorg. Chem. 11, 991-991
`(2006)
`Exhibit 1012 D. Bohrer et al., Influence of the Glass Packing on the Contamination
`of Pharmaceutical Products by Aluminum. Part III: Interaction
`Container-Chemicals During the Heating for Sterilisation, 17 J. Trace
`Elements med. & Biology 107 (2003) (“Bohrer III”)
`iii
`
`
`
`Nexus Ex. 1003
`Page 4 of 105
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`

`

`Description
`
`Exhibit 1021
`
`Exhibit 1030
`Exhibit 1031
`
`Exhibit 1032
`
`Exhibit No.
`Exhibit 1013
`Reserved
`Exhibit 1014 Michael J Akers, Parenteral Preparations, in Remington the Science
`and Practice of Pharmacy 810 (David B. Troy et al. eds., 21st ed. 2006)
`Exhibit 1015 United States Patent No. 10,583,155 (“the ’155 patent”)
`Exhibit 1016 United States Patent No. 10,905,713 (“the ’713 patent”)
`Exhibit 1017
`Reserved
`Exhibit 1018 United States Patent No. 10,912,795 (“the ’795 patent”)
`Exhibit 1019 United States Patent No. 10,478,453 (“the ’453 patent”)
`Exhibit 1020
`Loyd V. Allen, L-Cysteine Hydrochloride 50 mg/mL Injection, 36 U.S.
`Pharmacist 41 (Sept. 20, 2011)
`Essential of Pharmaceutical Chemistry (Donald Cairns ed., 4th ed.
`2012).
`Exhibit 1022 United States Patent No. 10,933,089 (“the ’089 patent”)
`Exhibit 1023
`’089 patent file history
`Exhibit 1024
`’453 patent file history
`Exhibit 1025 Drug Facts and Comparison (2015)
`Exhibit 1026
`Copyright Registration Number for Drug Facts and Comparisons
`(2015)
`Exhibit 1027 Kenneth C. Waterman et al., Stabilization of Pharmaceuticals to
`Oxidative Degradation, 7 Pharmaceutical Dev. & Tech. 1 (2002)
`Exhibit 1028
`Reserved
`Exhibit 1029 Alpaslan Yaman, Engineering Considerations in Sterile Powder
`Processes, in Sterile Pharmaceutical Products: Process Engineering
`Applications 297 (Kenneth E. Avis ed. 1995)
`Reserved
`Jalpa Patel et al., Stability Considerations for Biopharmaceuticals, Part
`1: Overview of Protein and Peptide Degradation Pathways, 2011
`BioProcess Int’l 20
`R.C. Whiting et al., Effect of Headspace Oxygen Concentration on
`Growth and Toxin Production by Proteolytic Strains of Clostridium
`Botulinum, 55 J. Food Protection 23 (1992)
`Exhibit 1033 Gaozhong Zhu et al., Formulation of Protein- and Peptide-Based
`Parental Products, in Pharmaceutical Dosage Forms (Sandeep Nema et
`al. eds. 2010)
`Farideh Jalilehvand et al., Lead(II) Complex Formation with LCysteine
`in Aqueous Solution, 54 Inorg. Chem. 2160 (2015)
`
`Exhibit 1034
`
`
`
`iv
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`Page 5 of 105
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`

`

`Description
`
`Reserved
`
`Aluminum in Large and Small Volume Parenterals Used in Total
`Parenteral Nutrition, 63 Fed. Reg. 176 (Jan. 5, 1998) (codified at
`21C.F.R. 201)
`Exhibit 1055 Aluminum in Large and Small Volume Parenterals Used in Total
`Parenteral Nutrition , 65 Fed. Reg. 4103 (Jan. 26, 2000) (codified at 21
`C.F.R. 201)
`Reserved
`
`Exhibit No.
`Exhibits 1035-
`1053
`Exhibit 1054
`
`Exhibits 1056-
`1060
`Exhibit 1061
`
`Exhibits 1062-
`1075
`Exhibit 1076 USP 32/NF 18, The U.S. Pharmacopeial Convention (1995).
`Exhibits 1077-
`Reserved
`1081
`Exhibit 1082
`
`Len Okabe, Studies on the Solubility of Cystine Under Various
`Conditions, and On A New Method of Cystine Preparation, 8 Biochem
`J. 441 (1927)
`Reserved
`
`Ian B. Butler et al., Removal of Dissolved Oxygen From Water: A
`Comparison of Four Common Techniques, 41 TALANTA 211 (1994).
`
`
`
`
`
`
`v
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`Nexus Ex. 1003
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`
`
`I.
`
`I, Pasquale N. Confalone, declare as follows:
`
`QUALIFICATIONS
`1.
`I offer this declaration at the request of counsel for Nexus
`
`Pharmaceuticals Inc. (“Petitioner”). I understand that Petitioner is seeking Post-
`
`Grant Review (“PGR”) of the patentability of claims 1-30 of U.S. Patent No.
`
`11,642,370 (“the ’370 patent”).
`
`2.
`
`I received my Ph.D. in organic chemistry at Harvard in 1970 with
`
`Nobel laureate Prof. R.B. Woodward. After a post-doctoral stint, also with Prof.
`
`Woodward, directed toward the total synthesis of Vitamin B12, I joined the
`
`Chemical Research Department of Hoffman-La Roche in 1972 where I worked as
`
`a medicinal chemist, eventually reaching a supervisory position and collaborating
`
`in numerous interdisciplinary efforts aimed at the development of novel
`
`pharmaceuticals in various disease areas.
`
`3.
`
`In 1981, I joined DuPont and led groups of chemists engaged in
`
`various areas of research including natural products synthesis, medicinal
`
`chemistry, synthetic methodology, and bioorganic chemistry. My bioorganic
`
`chemistry group developed the fluorescent dye-labeled reagents that were used in
`
`automated DNA sequencing, eventually employed in the human genome project.
`
`4.
`
`In 1986, I became Director of Medicinal Chemistry at DuPont and
`
`directed the research efforts of more than 200 chemists and personally recruited
`
`1
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`and built one of the best medicinal chemistry departments in the industry that
`
`generated 32 new chemical entities over a four-year period, including Cozaar®, a
`
`major anti-hypertensive based on angiotensin II antagonism, and Sustiva®, a highly
`
`successful NNRTI used to treat AIDS. My work involved all aspects of drug
`
`development chemistry, including process chemistry, chemical engineering, solid
`
`state chemistry, spectroscopy, analytical chemistry, and pilot plants. In 1996, I was
`
`promoted to Senior Vice President, R & D Division where my responsibilities
`
`included serving on three key decision-making boards: Drug Candidate Selection,
`
`Product Development Board, and the Development Commercialization Board.
`
`5.
`
`From 2002-2003, I held executive level R & D positions at Bristol-
`
`Myers Squibb and Adaptive Therapeutics, Inc. In 2003, I returned to DuPont as
`
`Vice President, Global R&D, Health, Nutrition, and Ag Products Platform where I
`
`was responsible for global R&D of DuPont’s Life Sciences Platform, directing a
`
`staff of more than 850 scientists with an annual budget of more than $220,000,000.
`
`6.
`
`I am currently an independent consultant to the biotechnology and
`
`pharmaceutical industry. I have presented more than 110 invited or plenary
`
`lectures worldwide, published more than 140 papers, and obtained more than 50
`
`U.S. Patents. I have received honors and awards, including the Harvard Graduate
`
`Society Prize, the Alpha Chi Sigma Award, Samuel McEvan Award, Robert A.
`
`Welch Lectureship, the Esther Humphrey Award, Philadelphia Organic Chemistry
`
`
`
`2
`
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`Award, and was nominated to the Harvard Society of Fellows. I am a co-founder
`
`of the French-American Chemical Society and the International Society of
`
`Chemical Ecology. I was Chairman of the Natural Products Gordon Conference
`
`and am on the Editorial Advisory Boards of Medicinal Chemistry Letters, Current
`
`Drugs, Bioorganic and Medicinal Chemistry, The Journal of Organic Chemistry,
`
`Synlett, Progress in Heterocyclic Chemistry, Synthesis, Medicinal Chemistry
`
`Research, Drug Design and Discovery, and Medicinal Chemistry Letters.
`
`7.
`
`I have been an adjunct professor at Rutgers, Drew University, and the
`
`University of Colorado, Boulder. I was elected chair of the Organic Division of the
`
`ACS and chairman of the ACS Committee on Chemistry and Public Affairs. I am
`
`on the Board of Directors of the Council for Chemical Research, the United States
`
`National Committee for IUPAC, the Delaware Technology Park, Board of
`
`Overseers of the Chemical Heritage Foundation, and am an elected Fellow of the
`
`American Association for the Advancement of Science. I was also recently elected
`
`Chairman of the Board of the American Chemical Society.
`
`8.
`
`I am the recipient of the 2020 Paul G. Gassman Distinguished Service
`
`Award awarded by the ACS Division of Organic Chemistry. See ACS Chemical
`
`Society Division of Organic Chemistry, Pat Confalone Selected as the 2020
`
`Gassman Awardee (Aug. 22, 2020), available at
`
`
`
`3
`
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`

`

`https://www.organicdivision.org/blog/2020/08/22/pat-n-confalone-2020-gassman-
`
`awardee/.
`
`9.
`
`I was also recently awarded the Earle B. Barnes Award for Leadership
`
`in Chemical Research Management sponsored by The Dow Chemical Company
`
`Foundation. See ACS Chemistry for Life®, 2021 Recipients, available at
`
`https://www.acs.org/content/acs/en/funding/ awards/national/recipients/2021-
`
`recipients.html (last accessed Nov. 27, 2021). This award is given for building and
`
`nurturing world-class R&D organizations in medicinal, agricultural, and process
`
`chemistry—driven by a lifelong passion for organic chemistry.
`
`10. A copy of my current curriculum vitae is filed as Exh. A, and it
`
`provides a comprehensive description of my academic and employment history. In
`
`the past four years, I have not provided expert testimony in deposition or at trial.
`
`11.
`
`I am being compensated at my standard rate of $600.00 per hour. My
`
`compensation is not contingent on the nature of my findings or the outcome of any
`
`proceeding.
`
`II.
`
`SCOPE OF ASSIGNMENT AND SUMMARY OF OPINION
`12.
`I have been asked by counsel for Petitioner to provide my opinion as
`
`to whether the ’370 patent specification enables a person of ordinary skill
`
`(“POSA”) to make and use the claimed invention of claims 1-30 without undue
`
`experimentation.
`
`
`
`4
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`13.
`
`I have also been asked by counsel for Petitioner to provide my
`
`opinion, in the alternative, regarding whether claims 1-30 of the ’370 patent are
`
`taught or disclosed in the prior art.
`
`14.
`
`I have also been asked to provide my opinion as to the knowledge and
`
`qualification of the POSA.
`
`15. As discussed in detail below, it is my opinion that:
`
` the ’370 patent specification fails to enable a POSA to practice
`
`the full scope of the invention of claims 1-30;
`
` in the alternative, the L-cysteine solutions recited in claims 1-
`
`30 of the ’370 patent were disclosed in the prior art in view of
`
`the knowledge of a POSA.
`
`16.
`
`In forming the opinions expressed in this declaration, I have reviewed
`
`the documents and materials cited in this declaration. I have also relied on my
`
`experience and education.
`
`III. LEGAL STANDARDS
`17.
`I am not an attorney, and I will offer no opinion on the law. I am,
`
`however, informed on several principles concerning patent validity which I have
`
`used in arriving at my opinions.
`
`
`
`5
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`

`

`A. Enablement
`18.
`I have been informed by counsel, and I understand that a patent
`
`specification must teach a POSA how to make and use the claimed invention
`
`without undue experimentation. Whether undue experimentation would be required
`
`is evaluated by considering factors such as the quantity of experimentation
`
`necessary, the amount of direction or guidance present, the presence or absence of
`
`working examples, the nature of the invention, the state of the prior art, the relative
`
`skill of those in the art, the predictability or unpredictability of the art, and the
`
`breadth of the claims. I have been informed and understand that the fact that
`
`experimentation may be complex does not necessarily make it undue, if the art
`
`typically engages in such experimentation.
`
`B. Obviousness
`19.
`I have been informed by counsel and I understand that an invention
`
`that would have been obvious to a POSA at the time of the invention is not
`
`patentable. To determine whether a claimed invention is obvious, one determines
`
`the scope and content of the prior art, ascertains the differences between the
`
`claimed invention and the prior art, and resolves the level of ordinary skill in the
`
`pertinent art. If, for example, a technique has been used to improve one product or
`
`method, and a POSA would recognize that it would improve similar products or
`
`methods in the same way, using the technique is obvious unless its actual
`
`
`
`6
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`

`

`application is beyond his or her skill. Other rationales that may support a
`
`conclusion of obviousness include combining prior art elements according to
`
`known methods to yield predictable results. However, a patent claim composed of
`
`several elements is not proved obvious merely by demonstrating that each of its
`
`elements was independently known in the prior art. Although common sense
`
`directs one to look with care at a patent application that claims as innovation the
`
`combination of known requirements according to their established functions, it is
`
`important to identify a reason that would have prompted a POSA in the relevant
`
`field to combine the requirements in the way the claimed new invention does. This
`
`is because inventions in most, if not all, instances rely upon building blocks long
`
`since uncovered, and claimed discoveries almost of necessity will be combinations
`
`of what, in some sense, is already known.
`
`20.
`
`Thus, a determination of obviousness may take into account whether
`
`there was some teaching, suggestion, or motivation that would have led a POSA to
`
`modify the prior art reference or to combine prior art reference teachings to arrive
`
`at the claimed invention. Teachings, suggestions, and motivations may be found in
`
`written references, including the prior art itself. However, teachings, suggestions,
`
`and motivations may also be found within the knowledge of a POSA, including
`
`inferences and creative steps that a POSA would employ. Additionally, teachings,
`
`
`
`7
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`

`suggestions, and motivations may be found in the nature of the problem solved by
`
`the claimed invention.
`
`21. One must be careful not to determine obviousness using hindsight
`
`because many inventions might seem obvious after the fact. A determination of
`
`obviousness should be based on the position of a POSA in the field of the
`
`invention at the time the claimed invention was made, and should not consider
`
`what is known today or what is learned from the teaching of the patent.
`
`22.
`
`I understand that objective evidence relevant to the issue of
`
`obviousness must also be considered. Such evidence may include evidence of
`
`commercial success, long-felt but unsolved needs, failure of others, and
`
`unexpected results. I understand that such evidence may be included in the
`
`specification as filed, accompany the application on filing, or be provided in a
`
`timely manner at some other point during the prosecution of the asserted patents.
`
`In addition, I understand that such objective evidence may be raised for the first
`
`time during litigation. I reserve the right to address any issues related to objective
`
`evidence should patentee or its expert(s) assert them as evidence of non-
`
`obviousness.
`
`IV. PERSON OF ORDINARY SKILL IN THE ART
`23.
`I have been informed by counsel and I understand that the POSA is a
`
`hypothetical person who is presumed to be familiar with the relevant scientific
`
`
`
`8
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`

`field and its literature at the time of the invention. This hypothetical person is also
`
`a person of ordinary creativity capable of understanding the scientific principles
`
`applicable to the pertinent field.
`
`24.
`
`The ’370 patent generally relates to an L-cysteine solution for use in
`
`parenteral nutrition. Accordingly, a POSA at the time of the alleged invention
`
`would have had education and work experience in the fields of pharmaceutical
`
`drug product formulation and development. For example, a person who had
`
`obtained a Ph.D. or equivalent in chemistry, biochemistry or related
`
`pharmaceutical sciences and at least two years of experience—at least by January
`
`2019—with pharmaceutical drug product formulation, analysis, and development
`
`optimization, and manufacture, including experience with processes and
`
`techniques for minimizing impurities in, and improving the stability of,
`
`pharmaceutical drug products during manufacture and storage. A POSA may also
`
`have lesser levels of education but more years of experience. For example, a
`
`POSA may have had an M.S. with at least 3-5 years of experience or a B.S. with a
`
`minimum of 6 years of work experience as described above.
`
`V.
`
`INTRODUCTION
`A. Background on L-cysteine products
`25. According to the “Background” of the ’370 patent, L-Cysteine is
`
`generally classified as a “non-essential” or “semi-essential” amino acid because it
`
`
`
`9
`
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`

`can be synthesized in small amounts by the human body. Ex. 1001 at 1:36-38.
`
`Nevertheless, the ’370 patent notes that some adults can benefit from L-Cysteine
`
`supplementation. Ex. 1001 at 1:38-40. With respect to pre-term infants, the ’370
`
`patent reports that L-Cysteine supplementation can be beneficial due to their
`
`biochemical immaturity of the enzyme cystathionase, which is involved in L-
`
`Cysteine synthesis. Ex. 1001at 1:41-44.
`
`26. Aluminum was known as a toxic impurity in parenteral nutritional
`
`compositions long before 2019. See Ex. 1006 at 1 (“Aluminum (Al) toxicity in
`
`parenteral nutrition solutions (PNS) has been a problem for decades and is still
`
`unresolved.”). The FDA required labels for parenteral drug products to address the
`
`“evidence linking the use of parenteral drug product containing aluminum to
`
`morbidity and mortality among patients on TPN therapy, especially among
`
`premature neonates and patients with impaired kidney function.” Ex. 1054 at 1
`
`(Aluminum in Large and Small Volume Parenterals Used in Total Parenteral
`
`Nutrition, 63 Fed. Reg. 176 (Jan. 5, 1998 (codified at 21 C.F.R. pt. 201). The FDA
`
`requires manufacturers to include the following warning statement in connection
`
`with products used in total parenteral nutrition (“TPN”).:
`
`WARNING: This product contain aluminum that may be toxic.
`Aluminum may reach toxic levels with prolonged parenteral
`administration if kidney function is impaired. Premature neonoates
`are particularly at risk because their kidneys are immature, and they
`
`
`
`10
`
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`

`

`require large amount of calcium and phosphate solutions, which
`contain aluminum.
`
`Research indicates that patients with impaired kidney function,
`including premature neonates, who receive parenteral levels of
`aluminum at greater than 4 to 5 [micro]g/kg/day accumulate
`aluminum at levels associated with central nervous system and bone
`toxicity. Tissue lading may occur at even lower rates of
`administration.
`
`
`Ex. 1005 at 5, 11
`
`B.
`The Sandoz Label
`27. Years before the ’370 patent’s effective filing date, Sandoz Inc.
`
`(“Sandoz”) marketed L-Cysteine Hydrochloride Injection, 50 mg/mL (“Sandoz
`
`Product”) in the United States. Ex. 1005 at 5, 11. According to the Label and
`
`Prescribing Information (“the Sandoz Label”), the Sandoz Product was indicated
`
`“for use only after dilution as an additive to Crystalline Amino Acid Injections to
`
`meet the intravenous amino acid nutritional requirements of infants receiving total
`
`parenteral nutrition.” Ex. 1005 at 1, 6. The Sandoz Label further provides that
`
`“[e]ach mL [of the Sandoz Product] contains: 50 mg of L-Cysteine Hydrochloride
`
`Monohydrate USP; Water for Injection, USP q.s.; Air replaced with Nitrogen. pH
`
`1.0-2.5. Ex. 1005 at 1, 6. Because, as discussed below, L-Cysteine is oxygen
`
`sensitive and subject to oxidative degradation in the presence of oxygen, a POSA
`
`
`
`11
`
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`

`

`would have understood that air was replaced with nitrogen in the Sandoz Product
`
`to stabilize and prevent the oxidative degradation of L-Cysteine.
`
`28.
`
`The Sandoz Label advises that the Sandoz Product “[c]ontains no
`
`more than 5,000 mcg/L [i.e., 5,000 ppb] of aluminum,” (Ex. 1005 at 5, 10) which a
`
`POSA would have understood to mean aluminum in an amount falling somewhere
`
`within the range of 0 ppb to 5,000 ppb, and includes the following warning:
`
`WARNING: This product contains aluminum that may be toxic.
`Aluminum may reach toxic levels with prolonged parenteral
`administration if kidney function is impaired. Premature neonates are
`particularly at risk because their kidneys are immature, and they
`require large amounts of calcium and phosphate solutions, which
`contain aluminum. Research indicates that patients with impaired
`kidney function, including premature neonates, who receive parenteral
`levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate
`aluminum at levels associated with central nervous system and bone
`toxicity. Tissue loading may occur at even lower rates of
`administration.
`
`
`Ex. 1005, 2, 8.
`
`C. Regulatory and Market Demand For Reducing Aluminum
`29. A POSA would have been motivated to reduce the amount of
`
`aluminum in an L-cysteine solution long before 2019. In addition to the FDA
`
`requirements described above (¶ 26), a 2013 paper by A. Hernandez-Sanchez et al.
`
`noted that aluminum toxicity in parenteral nutrition solutions (“PNS”) has been a
`12
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`problem for decades and is still unresolved. Ex. 1006 at 1. The authors also
`
`recommended that manufacturers improve manufacturing techniques in order to
`
`provide a wide range of low aluminum content product, that “healthcare providers
`
`should ensure [PNS] ingredients with the lowest amount of Al are used in the
`
`preparation of PNS.” Ex. 1006 at 8.
`
`30.
`
`I also understand that my opinion that a POSA would have been
`
`motivated to reduce aluminum content in L-cysteine solutions is consistent with
`
`the district court’s conclusions in the Exela v. Eton case. Exela Pharma Sciences,
`
`LLC v. Eton Pharms., Inc., 620 F.Supp.3d 108 (D. Decl. 2022) (Ex. 1007)
`
`(summarized below in ¶¶ 60-73). Specifically, the district court stated that there
`
`was an “undisputed strong motivation to reduce aluminum in cysteine
`
`compositions.” Ex. 1007 at 144.
`
`D. L-Cysteine’s Known Oxygen Sensitivity
`31. A POSA would have known that L-cysteine is susceptible to oxidative
`
`degradation to cystine. See, e.g., 1031 at 1 (J. Patel et al., Stability Considerations
`
`for Biopharmaceuticals, Part 1: Overview of Protein and Peptide Degradation
`
`Pathways, 2011 Bioprocess Int’l 20-31) (Explaining that certain amino acids are
`
`susceptible to oxidation by oxygen and including cysteine in list of amino acids
`
`“most susceptible to oxidation”).
`
`
`
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`32. As a general matter, a POSA would have been concerned about even a
`
`small amount of degradation to cystine because pharmaceutical compositions are
`
`subject to strict regulatory requirement requiring characterization of even trace
`
`amounts of degradation products. A POSA would have been particularly concerned
`
`about a cystine impurity because cystine has a much lower solubility that L-
`
`cysteine and would precipitate out of the solution, forming particulates. Ex. 1061
`
`(Okabe) at 1-2. Particulates are always undesirable in a pharmaceutical product but
`
`are particularly so in a parenteral formulation, in addition to the undesirable
`
`degradation of L-cysteine. A POSA would have understood that a parenteral
`
`solution should be essentially free of such particles. See Ex. 1076 at 9 (USP23/NF
`
`18 (The U.S. Pharmacopeial Convention, 1995) (“Particulate matter consists of
`
`mobile, randomly-sourced, extraneous substances, other than gas bubbles, that
`
`cannot be quantitated by chemical analysis due to the small amount of material that
`
`it represents and to its heterogeneous composition. Injectable solutions, including
`
`solutions constituted from sterile solids intended for parenteral use, should be
`
`essentially free from particles that can be observed on visual inspection.”)
`
`33. Accordingly, a POSA would have taken steps to remove oxygen and
`
`prevent the formation of cystine. Indeed, the Sandoz Label notes that in that
`
`product, which had a pH of 1.0-2.5, air was replaced with nitrogen to reduce
`
`oxygen. Ex. 1005 at 1. The process would consist of sparging the solution and
`
`
`
`14
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`displacing the headspace gas with nitrogen or argon, which may offer some
`
`advantages. See ¶¶ 34-35.
`
`34. As suggested by the Sandoz Label, a POSA would have understood
`
`that oxidative degradation of L-cysteine requires the presence of molecular oxygen
`
`in this particular formulation. Ex. 1021 at 12 (“Essentials of Pharmaceutical
`
`Chemistry 217 (Donald Cairns ed. 4th ed. 2012). Of course, there are many other
`
`oxidants that react with L-cysteine but are not present here. Pharmaceutical
`
`manufacturing practices for excluding oxygen during manufacture and storage of
`
`oxygen sensitive drug products, including injectables, were well-known. For
`
`example, oxygen can be removed by sparging with an inert gas or by
`
`manufacturing the drug product under a blanket of inert gas. Similarly, dissolved
`
`oxygen in the drug product and headspace oxygen can be removed using an inert
`
`gas such as nitrogen or argon. For example, “blanketing” vials with nitrogen prior
`
`to filling and sealing with a stopper can results in residual oxygen between 5 and
`
`15 percent. Ex. 1029 at 41 (Yaman). With additional precautions, the oxygen
`
`content in the headspace can be reduced to less than 2%. Id.; see also Ex. 1027 at
`
`27 (K. Waterman et al., Stabilization of Pharmaceuticals to oxidative Degradation,
`
`7 Pharm. Dev. & Tech. 1 (2002) (“For oxygen -sensitive compounds in liquid
`
`formulations, including a nitrogen sparge during the manufacturing process and a
`
`nitrogen headspace in the final package can suppress oxidation of the drug. . . . An
`
`
`
`15
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`oxygen level between 3 and 8% in the headspace is generally attainable at most
`
`manufacturing sites. However, if these levels are not attainable, using argon (which
`
`is a heavier gas) instead of nitrogen is an option to explore, though this will entail a
`
`higher manufacturing cost.”).
`
`35.
`
`There were also well-known techniques to reduce the amount of
`
`oxygen dissolved in the parenteral solution. See, e.g., Ex. 1033 at 33 (Gaozhong
`
`Zhu et al., Formulation of Protein- and Peptide-Based Parental Products, in
`
`Pharmaceutical Dosage Forms (Sandeep Nema et al. ed. 2010) Zhu explaines that
`
`“[i]f the product is sensitive to dissolved oxygen in solution, several manufacturing
`
`process steps should be designed appropriately. Degassing the solution and
`
`overlaying inert gas (nitrogen or argon) in the head space of the vials may be
`
`required to minimize oxidation due to dissolved oxygen in the product.” Ex. 1033
`
`at 33.
`
`VI. BACKGROUND
`A. The ’370 Patent
`36.
`The ’370 patent is entitled “Stable, Highly Pure L-Cysteine
`
`Compositions for Injection and Methods