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. 8,058,238
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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. 1005
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`TABLE OF CONTENTS
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`Page
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`I. Qualifications and Background ...................................................................... 4
`A. Education and Experience; Prior Testimony ................................................ 4
`B. Bases for Opinions and Materials Considered ............................................ 10
`C. Scope of Work ............................................................................................. 10
`II. Summary of Opinions .................................................................................... 11
`III. Legal Standards .............................................................................................. 13
`IV. Person of Ordinary Skill in the Art .............................................................. 15
`V. The ‘238 Patent ............................................................................................... 16
`VI. Background ..................................................................................................... 23
`A. Use of Surfactants, Biosurfactants and Lipopeptides ................................. 23
`B. Biosurfactant Purification and State of the Art in 2000 .............................. 27
`VII. Scope and Content of the Prior Art References .......................................... 34
`A. U.S. Patent No. 4,874,843 (‘843 Patent) (Ex. 1007) .................................. 34
`B. U.S. Patent No. 4,331,594 (‘594 Patent) (Ex.1009) ................................... 35
`C. U.S. Patent No. 5,912,226 (‘226 Patent) (Ex.1010) ................................... 36
`D. Mulligan and Gibbs, “Recovery of Biosurfactants by Ultrafiltration,”
`Journal of Chemical Technology & Biotechnology, 47:23-9 (1990)
`(“Mulligan”) (Ex.1013) ............................................................................... 38
`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) ................................................................ 39
`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) ..................................................................................................... 41
`G. U.S. Patent No. 5,227,294 (‘294 Patent) (Ex. 1016) .................................. 43
`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) ..................... 44
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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) .......................... 44
`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) .............................................. 45
`K. Osman et al., “Tuning micelles of a bioactive heptapeptide biosurfactant
`via extrinsically induced conformational transition of surfactin assembly”
`J. Peptide Sci., 4:449-458 (1998) (Ex. 1017) .............................................. 46
`VIII.INVALIDITY OF THE ‘238 PATENT ....................................................... 47
`A. Claims 21-25, 27-33, 35-44, 48, 49, 92-109, 113, 115-21, 123-51, 153-59,
`161, 162, 176-84, and 189 of the ‘342 Patent are Anticipated by the ‘843
`Patent ........................................................................................................... 47
`B. Claims 3-7, 49-52, 55-57, 61-63, 66, 85, 87-89, 164-167, 175, 183, and
`190 of the ‘238 Patent are Anticipated by the ‘226 Patent ......................... 69
`C. Claims 1-19, 21-44, 48-51, 92-107, 112-146, 151-167, 176, 177, 179, and
`183-189 of the ‘238 Patent are Obvious Over the ‘843 Patent In View of
`Mulligan, Lin II, and Lakey ........................................................................ 80
`D. Claim 53 of the ’238 Patent is Invalid as Obvious Over Over the ‘843
`Patent in View of Mulligan, Lin II, Lakey, and Tally ..............................118
`E. Claim 49-52, 54-65, 85-91, 175, 183, and 190 of the ‘342 Patent are
`Invalid as Obvious Over the ‘843 Patent, the ’226 Patent, Mulligan, Lin II,
`and/or Lakey ..............................................................................................122
`F. Claims 20, 45-47, 108-111, 147-150, 168-174, 178, 180, 181 of the ‘238
`Patent are Obvious Over the ‘843 Patent In View of Mulligan, Lin I, Lin II,
`Lakey, Sweadner, and Osman ...................................................................134
`G. Claims 66-84, 182, and 191-192 of the ‘238 Patent are Obvious Over the
`‘843 Patent In View of he ’594 Patent, Mulligan, Lin I, Lin II, Lakey,
`Baltz, and Sweadner ..................................................................................151
`X. CONCLUSION ............................................................................................. 164
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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”)
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`(Ex. 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,
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`Inc. I further understand that Fresenius will request that the United States Patent
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`and 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 ‘238
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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 ‘342 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 1005 in Case Nos. IPR2015-00141-44. Because I agreed with many of
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`the statements and opinions set forth therein, I have repeated those herein and
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`revised 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 ‘238 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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`‘238 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 many of the challenged claims are “product by
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`process” claims, which are composition claims that list manufacturing process
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`steps. I have been told that as a result of the claims being classified as “product by
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`process” claims, the claims should be analyzed for validity purposes with respect
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`to the claimed composition only, and not through the specific methods that are
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`recited in the claims. I have reviewed the daptomycin prior art, and find that each
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`of U.S. Patent No. 4,874,843 (the “‘843 patent”) (Ex. 1007) and U.S. Patent No.
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`5,912,226 (the “‘226 patent”) (Ex. 1010) to Eli Lilly and Company disclosed a
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`daptomycin composition identical to many of the compositions claimed in the ’238
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`patent. With respect to the remaining product by process claims of the ’238 patent,
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`I conclude that it would have been obvious to the person of ordinary skill in the art
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`to further purify the composition of either the ’843 or ’226 patent, resulting in a
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`composition identical to those claimed compositions.1
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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 ‘238 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 (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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`1
`The few process claims are likewise either anticipated and/or rendered obvious by the
`’843 and/or ’226 patents.
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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 ‘238 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, either expressly or inherently, in a single prior art
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`reference as understood in the context of the skill and knowledge of one of
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`ordinary skill in 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 ‘238 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 ’238
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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 ‘238 Patent
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`39.
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`I have read the ‘238 patent, which is entitled “High Purity
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`Lipopeptides.” The ‘238 patent issued from US Patent Application No.
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`11/739,180, filed April 24, 2007, which is a continuation of US Patent Application
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`No. 10/747,485, which was filed on December 29, 2003, now abandoned, which is
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`a division of US Patent Application No. 09/735,191, which was filed on November
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`28, 2000, now U.S. Patent No. 6,696,412. The ‘238 patent also claims priority to
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`U.S. Provisional Application No. 60/177,170, filed on January 20, 2000. The ‘238
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`patent issued November 15, 2011, and names Thomas Kelleher, Jan-Ji Lai, Joseph
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`P. DeCourcey, Paul Lynch, Maurizio Zenoni and Auro Tagliani as inventors.
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`40.
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`I understand that Fresenius is challenging all claims (1-192) of the
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`‘342 patent. Claims 1, 3, 8, 10, 21, 49, 50, 176, 180, 183, and 191 are independent
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`claims.
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`41.
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`Independent claim 1 recites “[a] composition comprising essentially
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`pure daptomycin purified by a process comprising the steps of: (a) subjecting
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`daptomycin to conditions forming a daptomycin aggregate; and (b) obtaining the
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`essentially pure daptomycin from the daptomycin aggregate.”
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`42.
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`I understand that the claim terms in the ‘238 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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`‘238 patent defines “essentially pure” daptomycin as “at least 98% of a sample is
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`daptomycin.” See Ex. 1001 at 7:41-46.
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`43.
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`Independent claim 3 of the ‘238 patent recites “[a] composition
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`comprising daptomycin that is substantially free of anhydro-daptomycin and
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`substantially free of β-isomer of daptomycin, the daptomycin being purified by a
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`process comprising the steps of: (a) subjecting daptomycin to conditions forming a
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`daptomycin aggregate; and (b) and obtaining the daptomycin that is substantially
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`free of anhydro-daptomycin and substantially free of β-isomer of daptomycin from
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`the daptomycin aggregate.
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`44.
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`The ‘238 patent defines daptomycin as “substantially free” of another
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`compound when the compound is present “in an amount that is no more than 1%
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`of the amount of the daptomycin.” See Ex. 1001 at 7:47-51.
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`45.
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`Independent claim 8 of the patent recites “[a] composition comprising
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`purified daptomycin that is substantially free of each of impurities 1 to 14 defined
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`by peaks 1-14 shown in FIG. 12, the purified daptomycin being obtained by a
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`process comprising the steps of: (a) subjecting daptomycin to conditions forming a
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`daptomycin aggregate; (b) subjecting the daptomycin aggregate to conditions
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`forming monomeric daptomycin; and (c) obtaining the daptomycin from the
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`monomeric daptomycin, the daptomycin aggregate or a combination thereof.”
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`46.
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`Figure 12 of the ‘238 patent (reproduced below) is a chromatogram of
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`“[a]n impurity profile of the bulk daptomycin prior to chromatography on the
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`Poros P150 anion exchange resin,” with demarcations aligned with different peaks
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`in the chromatogram, labeled 1 to 14. See Ex. 1001 at 33:63-67, Example 10.
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`18 of 175
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`47.
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`Independent claim 10 of the ‘238 patent recites: “[a] pharmaceutical
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`composition comprising essentially pure daptomycin purified by a process
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`comprising the steps of: (a) forming micelles comprising daptomycin; (b)
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`converting the micelles to a non-micellar daptomycin composition comprising
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`daptomycin in a non-micellar state; and (c) obtaining the purified daptomycin from
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`the micelles, the non-micellar daptomycin composition, or a combination thereof.”
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`48.
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`The ‘238 patent defines micelles as “aggregates of amphipathic
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`molecules.” See Ex. 1001 at 8:20-26. The ‘238 patent further disclosed that
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`19 of 175
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`“[m]icelles form spontaneously in a solution containing amphipathic molecules if
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`the concentration of the molecules is high enough.” Id. at 15:15-48.
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`49.
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`Independent claim 21 recites “[a] composition comprising daptomycin
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`of greater than or about 93% purity relative to daptomycin impurities that arise in
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`fermentation or purification of daptomycin, and wherein the daptomycin impurities
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`comprise impurities 1-14 defined by peaks 1-14 shown in FIG. 12, and the
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`daptomycin is obtained by a process comprising the step of forming a micelle
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`comprising daptomycin.”
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`50.
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`Independent claim 49 recites “[a] purified daptomycin composition
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`comprising daptomycin of greater than or about 93% purity relative to impurities
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`1-14 defined by peaks 1-14 shown in FIG. 12, the daptomycin being obtained by a
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`process comprising the step of forming an aggregate comprising daptomycin.”
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`51.
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`Independent claim 50 recites “[a] composition comprising purified
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`daptomycin obtained from a daptomycin aggregate, the purified daptomycin
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`selected from the group consisting of: (a) essentially pure daptomycin, (b)
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`daptomycin that is substantially free of anhydro-daptomycin and substantially free
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`of β-isomer of daptomycin, (c) daptomycin that is essentially free of anhydro-
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`daptomycin and substantially free of β-isomer of daptomycin, (d) daptomycin that
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`is free of anhydro-daptomycin and substantially free of β-isomer of daptomycin,
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`(e) daptomycin that is substantially free of each of impurities 1 to 14 defined by
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`peaks 1-14 shown in FIG. 12, and (f) daptomycin that is essentially free of each of
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`impurities 1 to 14 defined by peaks 1-14 shown in FIG. 12.”
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`52.
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`The ‘238 patent defines daptomycin as “essentially free” of another
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`compound when the compound is present “in an amount that is no more than 0.5%
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`of the amount of the daptomycin.” Ex. 1001 at 7:52-56.
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`53.
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`Independent claim 176 recites “[a] purified daptomycin composition
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`of greater than or 93% purity relative to impurities 1-14 defined by peaks 1-14
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`shown in FIG. 12, the purified daptomycin composition obtained by a process
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`comprising the steps of: (a) subjecting daptomycin to conditions forming
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`daptomycin micelles and (b) obtaining the purified daptomycin from the
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`daptomycin micelles.”
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`54.
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`Independent claim 180 recites “[a] purified daptomycin composition
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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, the purified daptomycin composition obtained by a process
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`comprising the steps of: (a) subjecting an aqueous solution comprising daptomycin
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`at or above the critical daptomycin micelle concentration to a pH of 3.0 to 4.8 at a
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`temperature of about 2-15°C to form a daptomycin preparation; and (b) obtaining
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`the purified daptomycin from the daptomycin preparation obtained in step (a).”
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`55.
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`Independent claim 183 recites “[a] purified daptomycin composition
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`of greater than or about 93% purity relative to impurities 1-14 defined by peaks 1-
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`21 of 175
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`14 shown in FIG. 12, wherein the percent purity is measured by HPLC analysis,
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`and the purified daptomycin composition is obtained from a lipopeptide aggregate
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`comprising daptomycin.”
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`56.
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`Independent claim 191 recites “[a] purified daptomycin composition
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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, wherein the percent purity is measured by HPLC analysis,
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`and the purified daptomycin composition is obtained by a process comprising the
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`steps of: (a) fermenting a culture of Streptomyces roseosporus to produce
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`daptomycin; (b) contacting the daptomycin from step (a) with an anion exchange
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`resin; (c) eluting the daptomycin from the anion exchange resin in step (b) with a
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`solvent having a pH of about 6.0-6.5 to obtain a daptomycin solution; (d) adjusting
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`the pH of the daptomycin solution from step (c) to about 3.0 to 4.8 and a
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`temperature to about 2-15°C to obtain a daptomycin aggregate solution comprising
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`daptomycin aggregates; and (e) filtering the daptomycin aggregate solution to
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`separate daptomycin aggregates from the daptomycin aggregate solution; and (f)
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`obtaining the purified daptomycin from the daptomycin aggregates.”
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`57.
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`The ‘238 patent defines daptomycin as “free” of another compound
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`when the compound is present “in an amount that is no more than 0.1% of the
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`amount of the daptomycin.” See Ex. 1001 at 7:57-60. The ‘238 patent defines
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`“substantially