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` Filed on behalf of: American Regent, Inc.
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`PHARMACOSMOS A/S,
`Petitioner,
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`v.
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`AMERICAN REGENT, INC.,
`Patent Owner.
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`
`Case PGR2020-00009
`Patent No. 10,478,450
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`DECLARATION OF DANIEL COYNE, M.D.
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`PGR2020-00009
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`Table of Contents
`I.
`Introduction ............................................................................................. 1
`II. Qualifications........................................................................................... 2
`III. Background and State of the Art ............................................................... 4
`A.
`Prior Art Parenteral Iron Treatments ................................................ 4
`1.
`Immunogenicity of Iron Dextran ............................................ 7
`2.
`Safer Non-Dextran IV Iron Products .................................... 11
`The ’450 Patent ............................................................................ 14
`B.
`IV. Level of Ordinary Skill in the Art............................................................ 17
`V. Claim Construction ................................................................................ 19
`A.
`“Iron Polyisomaltose Complex” .................................................... 20
`B.
`“The Iron Carbohydrate Complex is Substantially Non-
`Immunogenic” .............................................................................. 20
`“The Iron Carbohydrate Complex . . . Has Substantially No
`Cross Reactivity With Anti-Dextran Antibodies” ........................... 21
`1.
`The ’450 Patent Focuses on Immune Response .................... 21
`2.
`The Inventor Defined “Substantially No Cross-Reactivity
`With Anti-Dextran Antibodies” During Prosecution ............. 23
`Dr. Adkinson’s Construction is Unsupported........................ 25
`3.
`VI. The ’450 Patent and the ’119 Provisional Application Describe the
`Claimed Subject Matter .......................................................................... 26
`A.
`The ’450 Patent and the ’119 Provisional Application Explicitly
`Disclose the Claimed “Iron Polyisomaltose Complex” ................... 27
`B. Dr. Adkinson’s Arguments Ignore the ’450 Patent’s Teachings,
`the Prosecution History, and the State of the Art at the Time .......... 30
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`C.
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`VII. A Skilled Artisan Could Make and Use the Claimed Subject Matter ......... 34
`VIII. The Claims Are Not Indefinite ................................................................ 39
`IX. Conclusion ............................................................................................. 41
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`I.
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`PGR2020-00009
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`Introduction
`I, Daniel Coyne, M.D., have been retained by Finnegan, Henderson,
`1.
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`Farabow, Garrett & Dunner LLP (“Finnegan”) on behalf of American Regent, Inc.
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`(“Patent Owner”) as an independent expert in nephrology and the treatment of iron
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`deficiency, particularly the treatment of iron deficiency anemia in patients with
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`chronic kidney disease (“CKD”) using intravenous iron carbohydrate complexes.
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`2.
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`I understand that this proceeding involves U.S. Patent No. 10,478,450
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`(“the ’450 patent”). Ex. 1001. I understand that the application for the ’450 patent
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`was filed on April 10, 2015, as U.S. Patent Application No. 14/683,415, and that the
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`patent issued on November 19, 2019. Ex. 1001. I understand that the ’450 patent
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`claims priority to Provisional Application No. 60/757,119, filed on January 6, 2006
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`(“the ’119 provisional application”). Ex. 1001; Ex. 1003.
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`3.
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`I understand that Pharmacosmos A/S (“Petitioner”) has alleged that the
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`’450 patent is not entitled to its priority date because the ’119 provisional application
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`does not describe, or teach how to make and use, the inventions claimed in the ’450
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`patent, particularly an “iron polyisomaltose complex” that is “substantially non-
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`immunogenic” and has “substantially no cross reactivity with anti-dextran
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`antibodies.” I also understand that Petitioner has asserted that the scope of certain
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`claims of the ’450 patent is not clear and that certain claims are anticipated and/or
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`obvious. I have considered the ’450 patent and its prosecution history, the Petition,
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`the Declaration of N. Franklin Adkinson, M.D. (Ex. 1103) and the references cited
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`therein, the Declaration of Lee Josephson, Ph.D. (Ex. 1102), and the additional
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`materials listed in Appendix A. I have also reviewed the Declaration of Todd
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`Lowary, Ph.D. (Ex. 2001) submitted in support of Patent Owner’s Preliminary
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`Response. This Declaration sets forth my opinions based on my review of these
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`materials.
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`II. Qualifications
`I received a Bachelor of Arts degree in Chemistry from St. Louis
`4.
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`University in 1979. I obtained my Medical Degree from Case Western Reserve
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`School of Medicine in 1983. From 1983 to 1986, I completed my internship and
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`residency in internal medicine at Emory University, during which time I received
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`training in the causes and treatments of anemia, including iron deficiency anemia.
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`5.
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`From 1986 to 1989, I completed a fellowship in the Renal Division at
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`Washington University School of Medicine. I received further training in the causes
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`and management of anemia during this period. From 1989 to 1990, I was an
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`Instructor in Medicine at the Washington University School of Medicine in St.
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`Louis. From 1990-1993, I was an Assistant Professor at Case Western Reserve
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`School of Medicine. In 1993, I joined the Washington University School of
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`Medicine where I was Assistant Professor, then Associate Professor in the Renal
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`Division. Since 2005, I have been a Professor of Medicine at the Washington
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`University School of Medicine in the Division of Nephrology. Since 1993, I have
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`been the Hemodialysis Director or Medical Director of our academic teaching
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`hemodialysis unit. Because anemia and iron deficiency are almost universal among
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`hemodialysis patients, I have studied, taught, and managed the treatment of these
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`disorders throughout my career.
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`6.
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`I am also a full-time clinician and clinical researcher. I am the medical
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`director of the primary academic dialysis facility, and medical director of the
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`Nephrology and Multispecialty Medicine Clinics and the associated Infusion Center
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`at Washington University’s Center for Advanced Medicine.
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`7.
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`As part of my clinical practice, I treat patients with intravenous iron
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`products, and I am aware of the immunological considerations associated with these
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`products. I care for approximately 200 patients on chronic dialysis at our dialysis
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`facility and other facilities in the region, a much larger number of non-dialysis
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`patients with chronic kidney disease in our outpatient clinic, and many patients with
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`acute and chronic kidney disorders in our hospital. I treat patients with iron
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`deficiency anemia in all these clinical settings and supervise the administration of
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`intravenous iron products to patients in the above-mentioned Infusion Center.
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`8. My clinical research has been focused on the development of
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`intravenous iron therapies for the treatment of iron deficiency anemia. I have been
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`a principal investigator or co-investigator for several clinical trials related to
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`treatments for iron deficiency anemia, including a pharmacokinetics study of iron
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`isomaltoside, and randomized trials of iron isomaltoside compared to iron sucrose
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`and oral iron. I was also a lead investigator of the phase 3 clinical trials of sodium
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`ferric gluconate in the United States (Ex. 2030; Ex. 2015), and a prospective
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`evaluation of the long-term safety of sodium ferric gluconate (Ex. 2031). I have also
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`been involved in clinical trials related to the efficacy of intravenous iron in dialysis
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`patients with elevated ferritin being treated with epoetin. I have published over a
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`hundred scholarly articles. Several of my publications are related to intravenous
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`treatments for iron deficiency anemia, including INFeD®, Ferrlecit®, Venofer®,
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`Dexferrum®, Monofer®, Feraheme®, and Injectafer®. I have also been involved in
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`studies assessing immunologic reactions to parenteral irons. I am therefore familiar
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`with iron carbohydrate complexes and their related immunological issues.
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`9. My professional qualifications are described in further detail in my
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`curriculum vitae, which is attached as Exhibit 2004. I am being compensated for the
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`time I spend on this matter, but no part of my compensation depends on the outcome
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`of this proceeding.
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`III. Background and State of the Art
`Prior Art Parenteral Iron Treatments
`A.
`10.
`Iron deficiency anemia (“IDA”) is characterized by a deficiency or a
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`functional abnormality in red blood cells causing impaired transport of oxygen in
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`the blood due to a negative iron balance. Ex. 2014 at 17. Iron deficiency is the most
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`common nutritional deficiency and is the leading cause of anemia throughout the
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`world. Id.; 2032 at 1. Iron deficiency may be due to blood loss, inadequate dietary
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`intake, iron malabsorption, or increased iron demands. Ex. 2014 at 17; Ex. 2032 at
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`2. IDA is a common complication of chronic kidney disease (“CKD”) and is
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`associated with many other diseases or conditions as well, such as gastrointestinal
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`conditions, heart failure, and cancer.
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`11. Historically, the preferred treatment for iron deficiency has been oral
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`iron because it was simple to administer and did not have the life-threatening side-
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`effects commonly associated with intravenous (“IV”) iron therapies. Ex. 2028 at 1,
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`3; Ex. 2032 at 5. However, oral irons have a high incidence of gastrointestinal
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`adverse events often resulting in low adherence to therapy. Ex. 2028 at 1, 3.
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`Additionally, heightened inflammatory state and other factors can also cause poor
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`absorption of oral irons. Id. Therefore, it was recognized that IV iron treatments
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`were necessary to treat iron deficiency in patients who did not absorb oral iron well,
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`patients with severe iron deficiency or chronic blood loss, or patients who could not
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`tolerate oral iron. Id. IV iron therapy was also considered necessary for chronic
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`dialysis patients receiving erythropoietin to provide adequate iron for erythropoiesis.
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`Id. at 3.
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`12. The first intravenous iron preparations were colloidal ferric hydroxide
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`preparations, but these compositions had high toxicity and administration commonly
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`resulted in severe hypotensive reactions that prevented them from routine use.
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`Ex. 1036 at 1. Chelating colloidal ferric hydroxide to a carbohydrate drastically
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`improved the safety of parenteral iron products. Id. However, available IV iron
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`carbohydrate complexes were still limited by serious safety risks and/or dosage
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`limitations. Ex. 1079 at 2-4; Ex. 1039 at 2-3.
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`13.
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`In particular, for many years, the only form of parenteral iron available
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`in the United States were “iron dextran” products. Ex. 1036 at 1. Iron dextran is a
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`carbohydrate complex comprised of an iron core surrounded by a carbohydrate shell
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`made of dextran. Ex. 1036 at 1. However, iron dextran formulations were associated
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`with a significant risk of potentially life-threatening anaphylactoid/hypersensitivity
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`reactions. Ex. 2030 at 10-11; Ex. 2020 at 2-3.
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`14. Sodium ferric gluconate and iron sucrose were later introduced in the
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`United States as safer alternatives to iron dextran. Ex. 1039 at 2-3; Ex. 1079 at 2-4.
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`These IV iron preparations were also iron carbohydrate complexes comprised of an
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`iron core surrounded by a carbohydrate shell. Ex. 1036 at 1-3. They shared identical
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`iron core chemistry as iron dextran but had different iron core sizes and different
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`carbohydrate shells. Id. It was understood that differences in core size and
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`carbohydrate chemistry influenced pharmacologic and biologic properties such as
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`iron release rate and maximum tolerated dose and rate of infusion. Id. These
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`alternatives were also believed to be safer and less immunogenic because their
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`carbohydrate components did not contain dextran. Ex. 2031 at 4; Ex. 1039 at 2-3.
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`However, these alternatives required multiple administrations to provide repletion
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`doses. Ex. 2019 at 4, 6-7.
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`Immunogenicity of Iron Dextran
`1.
`15. Several different iron dextran products have been available over
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`various periods of time in the United States, including Imferon®, INFeD®, and
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`Dexferrum®. Ex. 1079 at 1-2. The first iron dextran to be approved was Imferon®
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`for intramuscular injection in the 1950s. Ex. 1036 at 1; Ex. 1079 at 1-2; Ex. 2023.
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`It became available for intravenous administration in 1971 and was withdrawn from
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`the market in 1996. Ex. 1036 at 1. The second formulation, INFeD®, which is also
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`referred to as low molecular weight (“LMW”) iron dextran, became available in
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`1992 and is still available today. Ex. 2018 at 466; Ex. 2024. The third formulation,
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`Dexferrum®, which is also referred to as high molecular weight (“HMW”) iron
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`dextran, was approved in 1996 and was withdrawn from the market in 2014. Ex.
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`2017.
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`16. All three iron dextran products were widely associated with highly
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`dangerous adverse reactions, including anaphylaxis and death. Ex. 2015 at 1; Ex.
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`2022; Ex. 1088; Ex. 2021; Ex. 2034. All three products required a test dose to test
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`potential immunogenicity prior to administration of the full treatment dose. Ex.
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`2023 at 2; Ex. 2017 at 1; Ex. 2024 at 4. Researchers believed that the high levels of
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`hypersensitivity and anaphylactoid reactions were due in large part to the dextran
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`carbohydrate component, as dextrans were known to elicit IgG and IgE mediated
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`antibody-mediated reactions. Ex. 2015 at 7, 11, 12; Ex. 2020 at 2-3. Researchers
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`also recognized that anaphylactoid adverse events could be triggered by labile iron
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`reactions, for instance if iron dextran were administered too quickly. Ex. 2020 at 2.
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`Many clinicians were reluctant to prescribe iron dextran because it was associated
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`with a significant risk of anaphylactic reactions. Ex. 2020 at 2-3.
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`17. Reaction rates may be affected by the underlying diseases in patients,
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`whether they had prior exposure to a dextran product, or have other drug allergies,
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`among other factors. Many researchers sought to quantify the risk of serious or life-
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`threatening anaphylactoid or hypersensitivity reactions to iron dextran through
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`various prospective clinical studies or retrospective studies based on chart or
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`database review or post-marketing surveillance and found similar rates of adverse
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`reactions. Ex. 2022; Ex. 1088; Ex. 2021; Ex. 2034. For example, in 1980, Hamstra
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`published a review examining the safety of Imferon® in 481 hemodialysis patients
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`administered in doses of 250 or 500 mg. Ex. 2022 at 4-5. In this patient group, life-
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`threatening reactions occurred in 3 patients (0.6%) “characterized by hypotension,
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`syncope, purpura, wheezing, dyspnea, respiratory arrest, and cyanosis. . .” Id. at 5.
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`Additionally, 12 patients (2.49%) were reported to experience non-life-threatening
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`systemic reactions “characterized by mild, transient hypotension, malaise, itching,
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`and urticaria, lasting less than five minutes and not otherwise interfering with normal
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`activity.” Id.
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`18. Fishbane in 1996 conducted a chart review in a large hospital network
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`on 573 hemodialysis patients receiving INFeD®. Ex. 2021 at 3, 5. This patient
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`population typically received a test dose of 10 to 50 mg followed by ten doses of
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`100 mg. Id. at 6. Four patients (0.7%) experienced serious potentially life-
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`threatening anaphylactoid reactions, including one patient that experienced cardiac
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`arrest and three other patients that “experienced dyspnea, hypotension, or chest
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`pain.” Id. at 4-5, 7. Additionally, approximately six other patients (10 patients total,
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`1.7%) experienced symptoms “consistent with anaphylactoid-type reactions (any
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`dyspnea, wheezing, hypotension, urticaria, or angioedema).” Id. at 7. The results in
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`Fishbane et al., and Hamstra et al., are consistent with other studies. Ex. 1088; Ex.
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`2034; Ex. 2018 at 465.
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`19.
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`In 2006, based on the extensive studies that had been published since
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`the 1980s, researchers understood severe adverse events for iron dextran to be at
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`least 0.6%. Ex. 1040 at 2 (“The risk for immediate severe anaphylactoid reactions
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`appears to be, at a minimum, approximately 0.6% with IV iron dextran, and this
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`agent has been associated with a number of deaths during the past several decades”).
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`20. While the reported definition of anaphylactoid and hypersensitivity
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`adverse events varied slightly between studies, researchers generally focused on
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`immediate severe reactions and symptoms typically associated with drug allergy,
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`including dyspnea, wheezing, chest pain, hypotension, urticaria, and angioedema.
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`Ex. 2021 at 4, 7. Further, limitations of retrospective determinations based on
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`patient chart and database review were believed to underestimate levels of adverse
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`events. Ex. 2030 at 10-11; Ex. 1039 at 1 (“The methodology employed, chart
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`abstraction, would tend to underestimate minor reactions, while offering a
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`reasonably accurate estimation of severe reactions.”). Additionally, to the extent
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`researchers understood there to be a difference in immunogenicity between different
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`dextran products, INFeD® was hypothesized to be less immunogenic than HMW
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`dextrans such as Dexferrum®. Ex. 2015 at 8, 12. However, a large-scale study
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`involving INFeD® reported a rate of 0.7% for anaphylactoid reactions when
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`delivered to hemodialysis patients at relatively low single-administration doses of
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`just 100 mg. Ex. 2021 at 3. Therefore, while specific studies might have reported
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`slightly different rates for the various iron dextran products and dosing regimens,
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`researchers understood the minimum overall rate to be at least 0.6% as discussed
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`above.
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`Safer Non-Dextran IV Iron Products
`2.
`21. Ferric sodium gluconate (Ferrlecit®) and iron sucrose (Venofer®) were
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`later introduced in the United States as safer alternatives to iron dextran. Ex. 1039
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`at 2-3; Ex. 1079 at 2-4; Ex. 2019. These non-dextran iron products still elicited
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`anaphylactoid and hypersensitivity reactions, but they were generally milder in
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`intensity and less frequent than with iron dextran. Ex. 1039 at 3. Also, unlike iron
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`dextrans, these new alternatives do not require a test dose to assess immunogenicity
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`prior to administration of full treatment doses. Ex. 2019 at 4, 7. However, these
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`alternatives often necessitated multiple administrations, typically 8 to 10 doses, to
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`administer a typical treatment course of 1000 mg of iron. Ex. 2019 at 4, 7.
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`22.
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`It was not until 2013, many years after the priority date, that ferric
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`carboxymaltose (Injectafer®) was approved by the FDA to be administered to
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`patients at near repletion doses in a single rapid administration. Ex. 2025 at 1. For
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`the first time, Injectafer® provided a dextran-free treatment that could be
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`administered in a 750 mg dose in a single administration over 15 minutes or less. Id.
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`at 1-2.
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`23. As many researchers sought to find safer alternatives to iron dextran,
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`assessing and comparing anaphylactoid and hypersensitivity reaction rates of non-
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`dextran products to iron dextran became routine within the art. Ex. 2030; Ex. 2013.
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`To demonstrate these non-dextran products were generally safer and resulted in less
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`anaphylactoid/hypersensitivity reactions than dextran, researchers designed large-
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`scale prospective clinical studies. Ex. 2030; Ex. 2031; Ex. 2013.
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`24. For example, in 2002, I was a lead investigator in clinical trials for
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`sodium ferric gluconate (Ferrlecit®) that included 2534 hemodialysis patients with
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`direct, blinded, observation, comparing reaction rates between sodium ferric
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`gluconate, placebo, and a historical control of iron dextran. Ex. 2030 at 8. The
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`historical control was based on a meta-analysis of publications describing rates of
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`events in patients treated with iron dextran. Id. at 9-11. Iron dextran was not
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`included as a concurrent control group because of its known high adverse-event
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`profile. Id. at 9. Patients previously intolerant to iron dextran were included in the
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`study. Id. The study design was approved by the FDA, and Petitioner’s expert,
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`Dr. N. Franklin Adkinson, was listed as a contributor on the study publication. Id.
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`at 8, 9. There were significantly fewer life-threatening events (0.04%), including
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`anaphylactoid and hypersensitivity reactions associated with the administration of
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`sodium ferric gluconate compared to the historical rate for iron dextran (0.61%). Id.
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`at 8, 13. We also published a continuation study in 2004 demonstrating repeated
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`doses of sodium ferric gluconate were well tolerated, as no life-threatening events
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`were observed in over 13,000 doses. Ex. 2031 at 1.
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`25. Similarly, Aronoff published an open-label clinical trial involving 665
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`hemodialysis patients to evaluate the safety of repeated doses of iron sucrose.
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`Ex. 2013 at 8. Patients previously intolerant to other parenteral iron products were
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`included in the study. Id. at 9. No serious adverse events or drug-related
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`hypersensitivity reactions (anaphylactic or allergic reactions) were reported in the
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`study. Id. at 10.
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`26. These trials indicated that ferric sodium gluconate and iron sucrose
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`were associated with significantly less anaphylactoid/hypersensitivity events than
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`the reported rates for iron dextran. They also demonstrated that researchers were
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`aware of techniques to assess relative immunogenicity and cross reactivity of iron
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`products compared to iron dextran. For example, because anaphylactoid and
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`hypersensitivity reactions were rare, researchers typically included enough patients
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`to ensure a high probability of determining adverse reaction rates below 0.6%.
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`Ex. 2030 at 11 (“The study was powered to ascertain an 80% likelihood of
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`identifying a 0.5% difference in life-threatening and drug intolerance event rates
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`between SFGC and iron dextran”); Ex. 2013 at 12 (explaining that post hoc
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`calculations confirmed study had a probability of 98% or greater of finding a drug
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`intolerance adverse event rate of 0.6%). Additionally, in order to determine potential
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`cross-reactivity in patients, researchers recognized that it was important to include
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`patients that were previously intolerant to other parenteral iron products such as iron
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`dextran. Ex. 2013 at 9; Ex. 2031 at 2; Ex. 2020 at 3. Also, because immunogenic
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`reactions can occur after multiple exposures, researchers would examine adverse
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`reactions over a course of multiple administrations. Ex. 2013 at 8; Ex. 2031 at 1, 2.
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`The ’450 Patent
`B.
`27. The ’450 patent is directed to methods of treating iron deficiency
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`conditions by rapidly administering a non-immunogenic, high-dose iron
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`carbohydrate complex. Ex. 1001 at Abstract.
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`28. The patent explains that iron dextran, the first parenteral iron product
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`in the United States, was “associated with an incidence of anaphylactoid-type
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`reactions (i.e., dyspnea, wheezing, chest pain, hypotension, urticaria, angioedema).”
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`Ex. 1001 at 1:52-59. The patent also explains “the incidence of anaphylaxis” is
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`“markedly lower” in other products that did not contain the dextran moiety. Id. at
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`1:59-62. However, the physical characteristics of the non-dextran products “lead to
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`dosage and administration rate limitations.” Id. at 1:64-66. The patent explains that
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`“doses of iron complexes higher than 200 mg of iron [were] generally unsuitable and
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`that the conventional therapy model prescribe[d] repeated applications of lower
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`doses over several days.” Id. at 2:14-18.
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`29. The patent describes various iron carbohydrate complexes, and their
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`characteristics, that can be used to achieve high-dose rapid iron administration. For
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`example, it explains that iron carbohydrate complexes were commercially available
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`or had well known syntheses, examples of which included “iron carboxymaltose,
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`iron sucrose, iron polyisomaltose, iron polymaltose, iron gluconate, iron sorbitol,
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`iron hydrogenated dextran.” Ex. 1001 at 10:61-11:1 (emphasis added). It further
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`describes the characteristics of iron carbohydrate complexes that make them
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`amenable to high-dose administration and use in the claimed methods. For example,
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`the patent teaches:
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`Preferably, iron carbohydrate complexes for use in the
`methods described herein are those which have one or
`more of the following characteristics: a nearly neutral pH
`(e.g., about 5 to about 7); physiological osmolarity; stable
`carbohydrate component; an iron core size no greater than
`about 9 nm; mean diameter particle size no greater than
`about 35 nm, preferably about 25 nm to about 30 nm; slow
`and competitive delivery of the complexed iron to
`endogenous iron binding site; serum half-life of over about
`7 hours; low toxicity; non-immunogenic carbohydrate
`component; no cross reactivity with anti-dextran
`antibodies; and/or low risk of anaphylactoid/hypersensit
`ivity reactions.
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`Ex. 1001 at 11:8-21 (emphases added).
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`30. The patent specification also explains that “[i]t is within the skill of the
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`art to test various characteristics of iron carbohydrate complexes as [t]o determine
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`amenability to use in the methods.” Ex. 1001 at 11:22-45. For example, the patent
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`specification states that “[h]ypersensitivity reactions can be monitored and assessed
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`as described in, for example, Bailie et al. (2005) Nephrol Dial Transplant, 20(7),
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`1443-1449.” Id. at 11:40-42. The specification also teaches that “[s]afety, efficacy,
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`and toxicity in human subjects can be assessed, for example, as described in
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`Spinowitz et al. (2005) Kidney Intl 68, 1801-1807.” Id. at 11:42-44.
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`31. Consistent with the understanding in the art described above, Bailie
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`provides techniques to retrospectively track anaphylactoid and hypersensitivity
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`adverse event rates and provides guidelines for identifying anaphylactoid reactions
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`based on standardized descriptors utilized by FDA, provided by the Medical
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`Dictionary for Regulatory Activities (MedDRA®). Ex. 1024 at 2-3. Spinowitz also
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`provides techniques to assess toxicity and immunogenicity on a small scale to
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`provide proof of principle data to design larger scale studies. Ex. 1080 at 2-3.
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`32. As one example of an iron complex having many of the characteristics
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`useful for safe and effective high-dose administration, the patent describes VIT-45,
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`an iron carboxymaltose complex. Ex. 1001 at 12:4-18. The patent includes several
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`examples pertaining to VIT-45, including efficacy and safety testing. Ex. 1001 at
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`18:10-27:4. These examples also provide techniques for assessing relative
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`immunogenicity of iron complexes.
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`33. The claims of the ’450 patent are directed to methods of treatment
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`comprising the high-dose administration of an iron polyisomaltose complex that has
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`diminished incidences of immunologic side effects as compared to the prior iron
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`dextran complexes. Ex. 1001 at 27:6-29:5. Independent claim 1 of the ’450 patent
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`recites:
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`1. A method of treating a disease, disorder, or condition
`characterized by iron deficiency or dysfunctional iron
`metabolism resulting in reduced bioavailability of dietary
`iron, comprising administering to a subject in need thereof
`an iron carbohydrate complex in a single dosage unit of at
`least 0.7 grams of elemental iron, wherein
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`the iron carbohydrate complex is substantially non-
`immunogenic, and has substantially no cross reactivity
`with anti-dextran antibodies; and
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`the iron carbohydrate complex is an iron polyisomaltose
`complex.
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`34. Dependent claims recite additional limitations, including the particular
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`disease, dosage, administration times, iron core, size, particle size, pH, osmolarity,
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`and half-life. Ex. 1001 at 27:18-29:5.
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`IV. Level of Ordinary Skill in the Art
`I understand that claim construction and patentability are assessed from
`35.
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`the perspective of a person of ordinary skill in the art. I understand that such a person
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`is presumed to have a defined level of knowledge and expertise in the relevant field
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`of art, including knowledge of all relevant prior art at the time of the invention.
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`36.
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`I understand the parties provide slightly different definitions of a person
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`of ordinary skill in the art. I understand that Petitioner defines a person of ordinary
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`skill in the art as “[a] person of skill in the art of the ’450 patent would have held at
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`least a bachelor’s degree in chemistry or biochemistry, with some related post-
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`graduate experience (academic or industrial) in the area of carbohydrates and their
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`metal complexes. The person of ordinary skill would be familiar with the chemistry
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`of iron carbohydrate complexes and the related immunological issues.” Pet. at 9;
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`Ex. 1103 at ¶ 62.
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`37.
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`I understand that Patent Owner states that “a person of skill in the art of
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`the ’450 patent would have at least a bachelor’s degree in chemistry, biochemistry,
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`medicine, or a related degree, with some related post-graduate experience
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`(academic, medical, or industrial) in the area of medical uses of carbohydrates and/or
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`their metal complexes. The person of ordinary skill would be familiar with, or know
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`to consult someone familiar with, the chemistry of iron carbohydrate complexes and
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`the immunological issues related to the administration of iron carbohydrate
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`complexes.”
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`38.
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`In my opinion, Patent Owner provides a more accurate definition in the
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`context of the ’450 patent. The claims are directed to methods of treatment, and
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`Patent Owner’s definition at least includes clinicians who practice the claimed
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`methods. I qualify as a person of ordinary skill in the art under either definition and
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`am therefore qualified to opine as to what a person of ordinary skill in the art would
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`have known and concluded as of the January 6, 2006 priority date of the claimed
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`invention. However, my opinions do not change based on whether Petitioner’s or
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`Patent Owner’s definition is applied.
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`V. Claim Construction
`I understand that Petitioner and Patent Owner disagree on the meaning
`39.
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`of certain terms in the claims of the ’450 patent. I am not an attorney, but counsel
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`has explained to me the legal standards for construing claim terms.
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`40.
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`I understand that claims are typically given their “ordinary and
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`customary” meaning, which I understand is the meaning that the claim terms would
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`have had to a person of ordinary skill in the art at the time of the invention. I also
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`understand that claims should be read in light of the patent specification and the
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`prosecution history. I also understand that if an inventor clearly defines a claim term
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`in the patent specification or the prosecution history, the inventor’s definition
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`controls, even if the inventor’s definition differs from the term’s ordinary and
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`customary meaning.
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`41.
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`I understand that the intrinsic evidence—i.e., the claims, the patent
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`specification, and the prosecution history—are always highly relevant to
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`understanding the claim terms. I also understand that extrinsic