UNITED STATES PATENT AND TRADEMARK OFFICE
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`________________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`________________________
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`FRESENIUS KABI USA LLC,
`Petitioner,
`v.
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`CUBIST PHARMACEUTICALS, INC.
`Patent Owner.
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`__________________________________________________________________
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`
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`U.S. Patent No. 8,129,342
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`________________________
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`Cases IPR2015-01566, IPR2015-01570, IPR2015-01571, IPR2015-01572
`________________________
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`EXPERT DECLARATION OF RALPH TARANTINO, PH.D.
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`FRESENIUS-KABI, Exh. 1006
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`TABLE OF CONTENTS
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`Page
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`I. Qualifications and Background ...................................................................... 1
`A. Education and Experience; Prior Testimony ................................................ 1
`B. Bases for Opinions and Materials Considered .............................................. 7
`C. Scope of Work ............................................................................................... 7
`II. Summary of Opinions ...................................................................................... 8
`III. Legal Standards .............................................................................................. 10
`IV. Person of Ordinary Skill in the Art .............................................................. 12
`V. The ‘342 Patent ............................................................................................... 13
`VI. Background ..................................................................................................... 19
`A. Use of Surfactants, Biosurfactants and Lipopeptides ................................. 19
`B. Biosurfactant Purification and State of the Art in 2000 .............................. 22
`VII. Scope and Content of the Prior Art References .......................................... 29
`A. U.S. Patent No. 4,874,843 (‘843 Patent) (Ex. 1007) .................................. 29
`B. U.S. Patent No. 4,331,594 (‘594 Patent) (Ex.1009) ................................... 30
`C. U.S. Patent No. 5,912,226 (‘226 Patent) (Ex.1010) ................................... 31
`D. Mulligan and Gibbs, “Recovery of Biosurfactants by Ultrafiltration,”
`Journal of Chemical Technology & Biotechnology, 47:23-9 (1990)
`(“Mulligan”) (Ex.1013) ............................................................................... 33
`E. Lin and Jiang, “Recovery and Purification of the Lipopeptide Biosurfactant
`Bacillus subtilis by Ultrafiltration,” Biotechnology Techniques, 11:413-6
`(June 1997) (“Lin I”) (Ex. 1014) ................................................................ 34
`F. Lin et al., “General Approach for the Development of High-Performance
`Liquid Chromatography Methods for Biosurfactant Analysis and
`Purification,” Journal of Chromatography, 825:149-59 (1998) (“Lin II”)
`(Ex.1015) ..................................................................................................... 36
`G. U.S. Patent No. 5,227,294 (‘294 Patent) (Ex. 1016) .................................. 38
`H. Lakey and Ptak, “Fluorescence Indicates a Calcium-Dependent Interaction
`between the Lipopeptide Antibiotic LY146032 and Phospholipid
`Membranes,” Biochemistry, 27, 4639-45 (1988) (Ex. 1033) ..................... 39
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`I. Tally et al., “Daptomycin: A Novel Agent for Gram-positive Infections,”
`Expert Opin. Invest. Drugs 8:1223-38 (1999) (Ex. 1018) .......................... 40
`J. Sweadner et al., “Filtration Removal of Endotoxin (Pyrogens) in Solution
`in Different States of Aggregation, Applied and Environmental
`Microbiology, vol. 34, no. 4, 382-85 (1977) .............................................. 40
`VIII.INVALIDITY OF THE ‘342 PATENT ....................................................... 41
`A. Claims 1, 3, 9, and 51 of the ‘342 Patent are Anticipated by the ‘843 Patent
` ..................................................................................................................... 41
`B. Claims 1, 3, 4, 7-11, 17-24, 30, 33, 34, 40-43, 49, 51, and 52 of the ‘342
`Patent are Anticipated by the ‘226 Patent ................................................... 46
`C. Claims 1-4, 7-16, and 51-52 of the ‘342 Patent are Obvious Over the ‘843
`Patent In View of Mulligan, Lin II, and Lakey........................................... 58
`D. Claims 17-50 and 53-54 of the ‘342 Patent are Invalid as Obvious Over the
`‘843 Patent in View of Mulligan, Lin II, Lakey, and Tally ........................ 72
`E. Claims 5-6 and 50 of the ‘342 Patent are Obvious Over the ‘843 Patent In
`View of Mulligan, Lin I, Lin II, Lakey, and Sweadner .............................. 93
`IX. CONCLUSION ............................................................................................... 98
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`1. My name is Ralph Tarantino, Ph.D. I have been retained by counsel
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`for Fresenius Kabi USA LLC (Fresenius). I understand that Fresenius intends to
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`petition for inter partes review of U.S. Patent No. 8,129,342 (the ‘342 patent) [Ex.
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`1002], which is assigned to Cubist Pharmaceuticals, Inc. I also understand that
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`Fresenius intends to petition for inter partes review of U.S. Patent No. 8,058,238
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`(the ‘238 patent) [Ex. 1001], which is also assigned to Cubist Pharmaceuticals, Inc.
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`I further understand that Fresenius will request that the United States Patent and
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`Trademark Office cancel the claims of the ‘342 patent and the ‘238 patent as
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`unpatentable in the Inter Partes Review petitions. I submit this expert declaration,
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`which addresses and supports Fresenius’s Inter Partes Review petition for the ‘342
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`patent. I have prepared and submitted a separate declaration which addresses and
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`supports Fresenius’s Inter Partes Review petition for the ‘238 patent.
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`I.
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`Qualifications and Background
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`A.
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`2.
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`Education and Experience; Prior Testimony
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`I am currently a Pharmaceutical Consultant and Principal of Steritech
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`Solutions, LLC. I have an undergraduate degree in Pharmacy from Long Island
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`University and a Ph.D. in Pharmaceutical Sciences from St. John’s University. I
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`am a registered pharmacist in the State of New York.
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`3.
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`After receiving my doctorate in 1989, I joined Hoffmann-La Roche,
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`Inc. in Nutley, New Jersey. Since its founding in 1896, Hoffmann-La Roche has
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`grown into one of the world’s leading healthcare companies with a focus on
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`pharmaceutical and biotechnology therapies. Roche has identified and developed
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`leading cancer therapies and other significant treatments including, for example,
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`Roferon-A®, Valium®, Bactrim®, Hivid® and Accutane®. I worked at
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`Hoffmann La Roche until 2011, when I founded Steritech Solutions, LLC.
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`4.
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`Since its incorporation in 2011, I have been the Principal of Steritech
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`Solutions, LLC. Steritech provides consulting services directly to the
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`pharmaceutical industry and other businesses involved with pharmaceuticals such
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`as investment or legal firms. I have consulted on peptide/protein formulations and
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`processing, quality assurance, manufacturing, drug delivery devices and primary
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`packaging issues. My work at Steritech has focused on injectable drug products.
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`5.
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`At Hoffmann-La Roche, I primarily worked in the areas of
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`peptide/protein preformulation, formulation development, and the manufacture of
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`toxicology and clinical supplies for injectable products. I was the head of sterile
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`clinical manufacturing for 17 years. In this capacity, I managed two Good
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`Manufacturing Practice (“GMP”) sterile suites and one Good Laboratory Practice
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`(“GLP”) sterile suite.
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`6.
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`In my role at Hoffmann-La Roche, I was responsible for the
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`sterilization processes for equipment, facilities and drug products, as well as the
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`validation of these processes for both GLP and GMP sterile products. I developed
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`sterilization processes that included dry heat, steam sterilization and aseptic
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`filtration.
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`7.
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`I also worked on formulation development throughout my career. For
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`example, I developed formulations for Small Volume Parenterals (“SVPs”), Large
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`Volume Parenterals (“LVPs”), small organic molecules and polypeptides. I
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`manufactured LVPs at Roche using glass bottles and also directed antibiotic
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`product development with outside contractors. I frequently tested LVPs in
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`intravenous admixture stability studies. I also performed excipient compatibility
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`high performance liquid chromatography (“HPLC”) studies for development and
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`for marketed products, and I conducted particle size analysis tests and HPLC
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`methods to determine the potency and purity of Roche drug products.
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`8.
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`In 1995, I became Director of Clinical Manufacturing. In this
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`capacity, I led the clinical manufacturing and packaging group for all Roche U.S.
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`clinical supplies, sterile and oral dosage forms. In addition to leading the
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`Preformulation Group, I also evaluated drug delivery systems and devices for
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`investigational and marketed products. The Preformulation function performs
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`physical and chemical characterization of drug substances intended for use in drug
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`products.
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`9.
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`In 2000, I became head of Sterile Product Formulation and Clinical
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`Manufacturing. In this capacity, I was responsible for the development and
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`technology transfer of formulations and container closure systems for all
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`toxicology, clinical and marketed products for Hoffmann-La Roche USA and
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`preformulation for peptides/proteins I also researched container closure systems
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`for parenteral drug products and evaluated drug delivery systems and devices for
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`investigational and marketed products. At this time, I was appointed Co-Chair of
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`the Roche Parenteral Technology International Working Group, which set global
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`technical and scientific standards and policies for the development and
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`manufacture of all Roche pharmaceutical sterile products.
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`10.
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`The Peptide/Protein Preformulation Group conducted analyses such as
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`HPLC, reverse-phase HPLC, ion exchange chromatography, hydrophobic
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`interaction chromatography, circular dichroism, laser light scattering analysis and
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`gel electrophoresis to characterize new peptide/protein products. The use of these
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`chromatography techniques as well as ultrafiltration and diafiltration were
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`employed to concentrate and/or purify peptide/protein as needed for further
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`development and in support of API processing.
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`11. During this period I led the formulation development of three new
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`Peptide/Protein products, PEGAYSY®, MIRCERA® and FUZEON® and the
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`development of multiple line extensions and drug delivery systems for peptides
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`and proteins. I was also appointed FDA trainer for “Protein Formulation and
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`Stability,” an assignment involving the training of FDA inspectors on formulation
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`and stability issues encountered during the development of therapeutic peptides
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`and proteins.
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`12.
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`In 2009, I became Research Director and Global Head of the Sterile
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`Product Formulation Group. In that role, in addition to continuing the duties of my
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`previous position, I managed international technology transfer, harmonization
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`processes and clinical manufacturing outsourcing for sterile clinical products.
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`13. At Hoffmann-La Roche, I led the development of nine marketed
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`parenteral drug products, including ready-to-use injectable products for infusion
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`and lyophilizate products that required reconstitution prior to infusion. I worked
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`on over 100 parenteral drug products that entered clinical trials and numerous pre-
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`clinical parenteral drug formulations.
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`14.
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`Early in my career, for about ten years, I was directly involved in the
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`testing of active pharmaceutical ingredients and dosage forms that involved
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`analytical techniques. A significant portion of that time was spent in the lab
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`performing analytical tests on pharmaceutical formulations. Those analytical tests
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`include HPLC, including reversed phase HPLC, thin layer chromatography
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`(“TLC”), gel electrophoresis and ultraviolet-visible spectroscopy (“UV-VIS”). My
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`responsibilities included reviewing and approving analytical methods.
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`15. During this time, I also was a “CMC” leader at Hoffmann-La Roche.
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`“CMC” refers to the technical or Chemistry, Manufacturing and Control sections
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`of NDAs and INDs. A CMC Leader leads a multidisciplinary team generating the
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`data needed for an NDA or IND. The team includes formulation, analytical,
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`chemistry, manufacturing, packaging and quality control scientists. The CMC
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`Leader ensures the data’s scientific validity and interacts with regulatory agencies.
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`In that role, I reviewed the entire technical submission—including several
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`submissions related to parenteral formulations—for NDAs and INDs.
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`16.
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`For an additional ten years, I supervised the package research and
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`preformulation laboratories, which relied on the techniques described above as
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`well as additional analytical techniques including, for example, gas
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`chromatography mass spectrometry (“GC MS”).
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`17.
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`I am a member of the American Association of Pharmaceutical
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`Scientists, the Parenteral Drug Association and the American Pharmacists
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`Association. From 1990-1995, I served as an adjunct assistant professor in
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`Pharmaceutical Sciences at Long Island University. From 1995-1996, I served as
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`elected Chair of Basic Pharmaceutical Sciences at the American Pharmaceutical
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`Association. I have authored or co-authored 27 published, peer-reviewed articles,
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`abstracts, and presentations, most of which were related to parenteral dosage
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`forms. I am a named inventor on one U.S. patent related to parenteral dosage
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`forms.
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`18.
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`In 1995, I was Elected Chair, Basic Pharmaceutical Sciences,
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`Academy of Pharmaceutical Research and Science of the American Pharmacists
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`Association. At this time, I was also awarded the title of Adjunct Assistant
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`Professor in Pharmaceutical Sciences at Long Island University for my work
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`mentoring pharmacy interns from Long Island University in all aspects of
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`industrial pharmacy.
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`19. My curriculum vitae is attached as Exhibit A.
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`B.
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`20.
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`Bases for Opinions and Materials Considered
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`Exhibit B includes a list of the materials I considered, in addition to
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`my experience, education, and training, in providing the opinions contained herein.
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`21.
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`In addition to the materials set forth in Exhibit B, I have also reviewed
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`the Expert Declaration of Catherine Mulligan, Ph.D., which I understand was filed
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`as Exhibit 1006 in Case No. IPR2015-00140. Because I agreed with many of the
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`statements and opinions set forth therein, I have repeated those herein and revised
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`only as necessary.
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`C.
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`22.
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`Scope of Work
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`I have been retained by Fresenius as a technical expert in this matter
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`to provide various opinions regarding the ‘342 patent. I receive $325.00 per hour
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`for my services. No part of my compensation is dependent upon my opinions given
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`or the outcome of this case. I do not have any other current or past affiliation as an
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`expert witness or consultant with Fresenius. I do not have any current or past
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`affiliation with Cubist Pharmaceuticals, Inc., or any of the named inventors on the
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`‘342 patent.
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`II.
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`Summary of Opinions
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`23.
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`To summarize, for the reasons set forth below, it is my opinion that
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`each claim of the ‘342 patent is anticipated and/or obvious in view of the prior art.
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`24.
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`I understand that the challenged claims are “product by process”
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`claims, which are composition claims that list manufacturing process steps. I have
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`been told that as a result of the claims being classified as “product by process”
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`claims, the claims should be analyzed for validity purposes with respect to the
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`claimed composition only, and not through the specific methods that are recited in
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`the claims. I have reviewed the daptomycin prior art, and find that each of U.S.
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`Patent No. 4,874,843 (‘843 patent) [Ex. 1007] and U.S. Patent No. 5,912,226 (‘226
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`patent) [Ex. 1010] to Eli Lilly and Company disclosed a daptomycin composition
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`identical to many of the compositions claimed in the ’342 patent. With respect to
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`the remaining claims of the ’342 patent, I conclude that it would have been obvious
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`to the person of ordinary skill in the art to further purify the composition of either
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`the ’843 or ’226 patent, resulting in a composition identical to those claimed
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`compositions.
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`25. Moreover, the processes (if considered as part of the claim language)
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`were all well-known and used by those of ordinary skill in the art. In 1990, ten
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`years before the earliest filing of the ‘342 patent, Mulligan (Ex. 1013)
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`demonstrated that the propensity for biosurfactants such as lipopeptides (including
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`the cyclic lipopeptide surfactin) to form micelles could be exploited to purify
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`lipopeptide preparations when used in conjunction with high molecular weight
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`ultrafiltration cell membranes. The process outlined by Mulligan showed that this
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`one-step process significantly reduced processing times and required and retained
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`in excess of 96% of surfactin in the crude fermentation preparation while
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`simultaneously removing smaller molecular weight impurities in the process. It
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`would have thus been obvious by January 2000, as others were doing for cyclic
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`lipopeptides, to employ a micelle formation and ultrafiltration step in the
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`purification of daptomycin. Lin I (Ex.1014) and Lin II (Ex. 1015) disclosed similar
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`micelle ultrafiltration steps, and also disclosed de-aggregating the biosurfactants
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`and subsequent ultrafiltration of the monomer form, such that larger impurities are
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`removed. Lin II also suggested employing HPLC to obtain homogenous
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`biosurfactants. Furthermore, Lakey et al. (Ex. 1033) reported that aggregation of
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`LY146032 (daptomycin) occurs at concentrations in excess of 10-3 M, establishing
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`that daptomycin, as would be expected of a cyclic lipopeptide, does form micelles.
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`26.
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`In addition, the combination of a micelle formation and ultrafiltration
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`step with other purification processes, such as anion-exchange chromatography,
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`hydrophobic interaction chromatography, HPLC preparative and other column
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`chromatography techniques to reach certain purity levels and to further remove
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`impurities in the preparation would have also been obvious to employ for cyclic
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`lipopeptides, such as daptomycin, prior to January 2000. These techniques were
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`routinely employed to obtain API preparations approaching homogeneity.
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`Specifically, well before the filing of the ‘342 patent, biosurfactant preparations,
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`including for the cyclic lipopeptide surfactin, were routinely purified to greater
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`than 98%, and greater than 99% purity levels.
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`27. Moreover, the use of HPLC to identify and analyze impurities in
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`lipopeptide preparations was also well known to those of ordinary skill in the art
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`by January 2000. Chromatography and other mass-, size-, polarity, and charge-
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`based analysis techniques, including mass spectrometry and HPLC, were routinely
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`employed by those of ordinary skill in the art. It would have thus been obvious to
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`use HPLC to identify and analyze impurities in lipopeptide preparations, such as
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`daptomycin.
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`III. Legal Standards
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`28.
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`In forming the opinions set forth in this declaration, I have been
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`informed of certain legal principles. I have used my understanding of those
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`principles in forming my opinions. My understanding of those principles is
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`summarized below.
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`29.
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`I have been told that Fresenius bears the burden of proving invalidity
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`by a preponderance of the evidence. I am informed that this preponderance of the
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`evidence standard means that Fresenius must show invalidity is more probable than
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`not. I have taken this standard into account when forming my opinions in this case.
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`30.
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`I have also been told that claims should be construed given their
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`broadest reasonable interpretation in light of the specification from the perspective
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`of a person of ordinary skill in the art.
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`31.
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`I have also been told that the concept of anticipation requires that each
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`element of a claim be found, expressly or inherently, in a single prior art reference
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`as understood in the context of the skill and knowledge of one of ordinary skill in
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`the art.
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`32.
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`I also understand that a reference inherently discloses a particular
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`element of a claim when one of ordinary skill in the art could determine such a
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`feature is implicitly described based on factual and/or technical reasoning showing
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`that the feature necessarily flows from the disclosure’s express teachings.
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`33.
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`I have also been told that the claims in the ‘342 patent are “product by
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`process claims,” where a composition is claimed in terms of recited process steps.
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`34.
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`I have also been told that the concept of patent obviousness involves
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`four factual inquiries: (1) the scope and content of the prior art; (2) the differences
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`between the claimed invention and the prior art; (3) the level of ordinary skill in
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`the art; and (4) secondary considerations of non-obviousness.
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`35.
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`I have also been told that when there is some recognized reason to
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`solve a problem, and there are a finite number of identified, predictable and known
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`solutions, a person of ordinary skill in the art has good reason to pursue the known
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`options within his or her technical grasp. If such an approach leads to the expected
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`success, it is likely not the product of innovation but of ordinary skill and common
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`sense. In such a circumstance, when a patent simply arranges old elements with
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`each performing its known function and yields no more than one would expect
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`from such an arrangement, the combination is obvious.
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`IV. Person of Ordinary Skill in the Art
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`36.
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`I have been informed by counsel that the obviousness analysis is to be
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`conducted from the perspective of a person of ordinary skill in the art (a “person of
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`ordinary skill”) at the time of the invention.
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`37.
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`I have also been informed by counsel that in defining a person of
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`ordinary skill in the art the following factors may be considered: (1) the
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`educational level of the inventor; (2) the type of problems encountered in the art;
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`(3) prior art solutions to those problems; (4) rapidity with which innovations are
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`made; and (5) sophistication of the technology and educational level of active
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`workers in the field.
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`38. A person of ordinary skill in the art (“POSA”) related to the ’342
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`patent typically would have held a Master’s degree or Ph.D. in chemistry,
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`biochemistry, chemical engineering, or a related field, and several years of
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`experience in manufacturing, analyzing, characterizing, and/or purifying proteins,
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`peptides, or lipopeptides for medicinal use.
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`V.
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`The ‘342 Patent
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`39.
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`I have read the ‘342 patent, which is entitled “High Purity
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`Lipopeptides.” The ‘342 patent issued from US Patent Application No.
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`12/888,233, which was filed September 22, 2010, and is a continuation of US
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`Patent Application No. 11/739,180 (‘342 patent) filed April 24, 2007, now U.S.
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`Patent No. 8,058,238, which is a continuation of US Patent Application No.
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`10/747,485, which was filed on December 29, 2003, now abandoned, which is a
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`continuation of US Patent Application No. 09/735,191, which was filed on
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`November 28, 2000, now U.S. Patent No. 6,696,412. The ‘342 patent also claims
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`priority to U.S. Provisional Application No. 60/177,170, filed on January 20, 2000.
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`The ‘342 patent issued March 6, 2012, and names Thomas J. Kelleher, Jan-Ji Lai,
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`Joseph P. DeCourcey, Paul D. Lynch, Maurizio Zenoni and Auro R. Tagliani as
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`inventors. I understand that Fresenius is challenging all claims (1-54) of the ‘342
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`patent. Claims 1, 17, 30, 40, 50 and 51 are independent claims.
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`40. Claim 1 recites “[a] composition obtained by a process comprising the
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`step of forming a daptomycin aggregate, the composition comprising daptomycin
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`of greater than or about 93% purity relative to impurities 1-14 defined by peaks 1-
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`14 shown in FIG. 12 and having less than 4% of anhydro-daptomycin and having
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`less than 4% of β-isomer of daptomycin.” ’342 patent at 37:35-40.
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`41.
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`FIG. 12 is a chromatogram from an HPLC assay, which shows peak
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`numbers 1-14 in the margins:
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`Independent claim 17 of the ‘342 patent recites “[a] pharmaceutical
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`42.
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`composition compatible with a pharmaceutically acceptable carrier for the
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`treatment of an infection of the blood, skin or soft tissue, the composition
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`comprising daptomycin obtained by a process comprising the step of forming a
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`daptomycin aggregate, the composition having daptomycin with greater than or
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`about 93% purity relative to impurities 1-14 defined by peaks 1-14 shown in FIG.
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`12.” Id. at 38:23-29.
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`43.
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`Independent claim 30 recites “[a] pharmaceutical composition for the
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`treatment of an infection, the composition comprising daptomycin having greater
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`than 93% purity relative to impurities 1-14 defined by peaks 1-14 shown in FIG.
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`12, the daptomycin purified by a process comprising the formation of micelles
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`comprising daptomycin.” Id. at 39:29-34.
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`44.
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`Independent claim 40 recites “[a] pharmaceutical composition for the
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`treatment of an infection of the blood, skin or soft tissue, the pharmaceutical
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`composition comprising a solution of a pharmaceutically acceptable carrier for
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`intravenous administration and daptomycin, the daptomycin having greater than
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`93% purity relative to impurities 1-14 defined by peaks 1-14 shown in FIG. 12,
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`and the daptomycin obtained from a purification process comprising the formation
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`of a daptomycin micelle.” Id. at 39:62-40:2.
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`45.
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`Independent claim 50 recites “[a] vial containing a lyophilized powder
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`pharmaceutical composition compatible with a pharmaceutically acceptable carrier
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`for the treatment of an infection by a daily intravenous dose of the lyophilized
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`powder reconstituted in the pharmaceutically acceptable carrier, the composition a)
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`having daptomycin with greater than or about 93% purity relative to impurities 1-
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`14 defined by peaks 1-14 shown in FIG. 12; and b) the composition comprising
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`daptomycin purified by a process including the steps of forming a daptomycin
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`aggregate, converting the daptomycin aggregate to monomers and obtaining the
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`daptomycin in the composition from the monomers by a process including one or
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`more steps selected from the group consisting of anion exchange chromatography
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`and hydrophobic interaction chromatography.” Id. at 40:29-45.
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`46.
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`Independent claim 51 recites “[a] composition obtained by a process
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`comprising the steps of forming a daptomycin aggregate, converting the
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`daptomycin aggregate to monomers and obtaining the daptomycin in the
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`composition from the monomers by a process including one or more steps selected
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`from the group consisting of anion exchange chromatography and hydrophobic
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`interaction chromatography, the composition comprising daptomycin of greater
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`than or about 93% purity relative to impurities 1-14 defined by peaks 1-14 shown
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`in FIG. 12.” Id. at 45-54.
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`47. Dependent claims 2-16, 18-29, 31-39, 41-49 and 52-54 relate to
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`various purity and impurity levels of the claimed daptomycin compositions (claims
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`2-4, 7-16, 18, 32-34, 41-43 and 52), pharmaceutical compositions and doses
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`comprising excipients for intravenous administration, including physiological
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`saline (claims 19-21, 49 and 53-54), use of the pharmaceutical compositions in the
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`treatment of infections (claims 25-29, 35-39, 44-48), and additional processing
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`steps, including the lyophilization of the claimed daptomycin compositions,
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`filtration, and the use of anion exchange chromatography and hydrophobic
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`interaction chromatography (claims 5-6, 22-24, 31).
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`48.
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`I understand that the claim terms in the ‘342 patent are presumed to
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`take on their ordinary and customary meaning based on the “broadest reasonable
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`construction in light of the specification of the patent in which it appears.” The
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`‘342 patent defines “essentially pure” daptomycin as “at least 98% of a sample is
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`daptomycin.” See ‘342 patent at 7:34-39. The ‘342 patent defines “substantially
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`free” daptomycin as daptomycin purity relative to another compound “in an
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`amount that is no more than 1% of the amount of the daptomycin.” See ‘342
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`patent at 7:40-44. The ‘342 patent defines micelles as “aggregates of amphipathic
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`molecules.” See ‘342 patent at 8:14-20. The ‘342 patent defines “essentially free”
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`daptomycin as the daptomycin purity relative to another compound “is present in
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`an amount that is no more than 0.5% of the amount of the daptomycin.” ‘342
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`patent at 7:45-49. The ‘342 patent defines “free” daptomycin as daptomycin purity
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`relative to another compound “in an amount that is no more than 0.1% of the
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`amount of the daptomycin.” See ‘342 patent at 7:50-53. The ‘342 patent defines
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`“substantially pure” daptomycin as “at least 95% of a sample is daptomycin.” See
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`‘342 patent at 7:28-30. The ’342 patent defines “purified” daptomycin as
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`daptomycin that is substantially pure, essentially pure, or substantially free,
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`essentially free, or free of another compound. See ’342 patent at 7:61-67.
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`VI. Background
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`A.
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`49.
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`Use of Surfactants, Biosurfactants and Lipopeptides
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`Lipopeptides are substances produced by microorganisms, and are
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`typically cyclic peptides with a fatty acyl chain. These cyclic lipopeptides vary in
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`terms of the amino acid content, as well as in the chain length and structure of the
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`fatty acid component. The presence of lipophilic and hydrophilic regions within a
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`molecule classifies a molecule as a surfactant.
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`50.
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`Surfactants are amphiphilic compounds that can reduce the free
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`energy of a system by replacing bulk molecules of higher energy at an interface.
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`Surfactant molecules contain two physically separate regions: a hydrophobic
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`portion with little affinity for a hydrophilic bulk medium (e.g., water), and a
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`hydrophilic portion that is attracted to a hydrophilic bulk medium. As amphiphiles,
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`surfactants are able to reduce interfacial/surface tension at liquid-liquid and liquid-
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`gas interfaces, making these compounds invaluable for a variety of industrial and
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`therapeutic applications, including solubility enhancement and surface tension
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`reduction in food, as well as in the pharmaceutical and cosmetic industries. Sung-
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`Chyr Lin et al., General Approach for the Development of High-Performance
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`Liquid Chromatography Methods for Biosurfactant Analysis and Purification,
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`JOURNAL OF CHROMATOGRAPHY, 825:145-49 (1998) (“Lin II”) (Ex. 1015),
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`at 149-151.
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`51.
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`Surfactants form micelles (structured but dynamic aggregates that
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`form with the hydrophilic “head” region in contact with a hydrophilic bulk
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`medium, and the hydrophobic “tail” sequestered in the micelle center). The Critical
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`Micelle Concentration (CMC) value represents the concentration at which micelle
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`structures will form. Sung-Chyr Lin and Horng-Jyh Jiang, Recovery and
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`Purification of the Lipopeptide Biosurfactant Bacillus subtilis by Ultrafiltration,
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`BIOTECHNOLOGY TECHNIQUES, 11:413-16 (1997) (“Lin I”) (Ex. 1014), at
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`413; Ex. 1015 at 151.
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`52. Biologically-produced surfactants are sometimes called
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`biosurfactants. Surfactin, which was first discovered in 1968 by Arima, is an
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`example of a biosurfactant lipopeptide. See Arima et al., “Surfactin, a crystalline
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`peptide lipid surfactant produced by Bacillus subtilis: Isolation, characterization
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`and its inhibition of fibrin clot formation,” Biochem. Biophys. Res. Comm. 31:488-
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`94 (1968) (Ex. 1021), at 488. Surfactin, also known as subtilysin, consists of a
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`seven-amino acid sequence in a cyclical structure with a 13-16 carbon fatty acid
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`tail. Kakinuma et al., “Confirmation of the structure of surfactin by mass
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`spectrometry,” Ag. Biol. Chem. 33:1669-72 (1969) (Ex. 1022).
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`53.
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`Surfactin was shown to be a potent antimicrobial, disrupting bacterial
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`spheroplasts and protoplasts. See, e.g., Bernheimer et al. “Nature and properties of
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`a cytolytic agent produced by Bacillus subtilis,” J. Gen. Microbiol. 61:361-69
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`(1970) (Ex. 1023