Case 1:14-cv-00781-SLR Document 53 Filed 04/30/15 Page 1 of 24 PageID #: 762
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
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`Civil Action No. 14-781 (SLR)
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`))))))))))))))
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`DECLARATION OF LEE E. KIRSCH, PH.D
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`I, Lee E. Kirsch, Ph.D., declare and state as follows.
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`1. I am currently a Professor at the University of Iowa College of Pharmacy, Division of
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`Pharmaceutics. I make this declaration in support of CFT Pharmaceuticals LLC’s Answering
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`Claim Construction brief in the above-referenced case.
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`I.
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`Qualifications and Background Information
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`2. A complete list of my publications, presentations, professional activities, and honors that
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`I have received are fully set forth in my curriculum vitae, a true and correct copy of which is
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`attached hereto at Exhibit A.
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`3. I received a B.S. degree in Pharmacy in 1975 from Purdue University and received a
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`Ph.D. in Pharmaceutical Chemistry in 1982 from the Ohio State University. From 1982 to 1994,
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`I was a research scientist at Lilly Research Laboratories in the Pharmaceutical Product
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`Development Division. During my time at Lilly, my responsibility was to develop drug
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`formulations for new drug substances and to address formulation issues associated with marketed
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`1
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`PFIZER INC., WYETH LLC, PFIZER
`PHARMACEUTICALS LLC, PF PRISM C.V.,
`and PFIZER MANUFACTURING
`HOLDINGS LLC,
`
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`Plaintiffs,
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`
`
`v.
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`CFT PHARMACEUTICALS LLC,
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`Defendant.
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`

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`Case 1:14-cv-00781-SLR Document 53 Filed 04/30/15 Page 2 of 24 PageID #: 763
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`drug products. My particular area of focus was injectable drug product design and development
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`including drugs intended for intravenous and extravascular administration. During my industrial
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`tenure my research focus was on drug stability issues as evidenced by my publication and
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`presentation history during this time period.
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`4. In 1994, I took a position at the University of Iowa College of Pharmacy first as an
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`Associate Professor, and then in 2010 as a full Professor. During my time at Iowa, my research
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`has continued to focus on issues of drug product design and development and especially drug
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`product stability. In addition to conducting fundamental research on drug stability phenomena, I
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`have also had the opportunity to work on numerous industrially-supported projects addressing
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`various drug product performance and design issues for injectable, solid oral, topical and various
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`other types of drug formulations.
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`5. I have also taught courses at Iowa including drug degradation kinetics and mechanisms,
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`drug stability, pharmaceutical proteins, advanced compounding, solid dosage forms,
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`lyophilization, pharmaceutical product development, pharmacokinetics and biopharmaceutics,
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`pharmaceutical package design and integrity, and pharmaceutical technology.
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`6. I have received numerous awards and honors, including the Distinguished Service Award
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`from the Parenteral Drug Association, Jack L. Beal Post Baccalaureate Award from The Ohio
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`State University, Fred Simon Award for the best paper in the PDA Journal of Pharmaceutical
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`Science and Technology, Editor-in-chief for the AAPS PharmSciTech Journal, and Editor of the
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`PDA Journal of Pharmaceutical Science and Technology.
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`7. I have authored or co-authored over 50 published scientific articles in the areas of
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`pharmaceutical chemistry, drug stability, drug delivery, pharmacokinetics, pharmaceutical
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`package integrity, and analytical chemistry. I have served as a peer-reviewer on various well-
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`Case 1:14-cv-00781-SLR Document 53 Filed 04/30/15 Page 3 of 24 PageID #: 764
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`respected pharmaceutical science and technology journals, including Journal of Pharmaceutical
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`Science, Drug Development and Industrial Pharmacy, Pharmaceutical Research, International
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`Journal of Pharmaceutics, PDA Journal of Pharmaceutical Science and Technology, Journal of
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`Pharmaceutical Innovation, Pharmaceutical Development and Technology, AAPS
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`PharmSciTech, and International Journal of Chemical Kinetics.
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`8. In the last four years, I have testified at trial or by deposition in the following cases:
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`AstraZeneca v. Mylan, (10-cv-05519) (D.N.J. 2012); Helsinn Healthcare S.A. et al. v. DRL et al.,
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`(11-cv-3962/11-cv-5579) (D.N.J. 2011); and UCB, Inc. et al. v. Teva Pharmaceuticals USA, Inc.
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`et al., (12-cv-4420) (N.D. Ga. 2012).
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`9. My compensation for consulting with attorneys for CFT Pharmaceuticals is not
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`contingent or dependent in any way upon the outcome of this case or any portion of this case.
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`10. I have been asked to provide background scientific information relevant to the subject
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`matter of United States Patent No. 7,879,828, referred to here as the “’828 patent,” as well as
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`provide opinions about how a person of ordinary skill in the art would interpret certain aspects of
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`the ’828 patent. To assist with this task I have reviewed the ’828 patent, its prosecution history,
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`and relevant materials I relied upon which I cite herein. In explaining the science and rendering
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`my opinions I also rely upon the knowledge and skill of one of ordinary skill in the art.
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`II.
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`Scientific Background
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`11. A person of ordinary skill in the art with respect to the ’828 patent includes an individual
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`with an advanced degree in a field such as chemistry, organic chemistry, medicinal chemistry,
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`Pharmaceutics, or Pharmacy Sciences and experience developing or conducting research on
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`pharmaceutical formulations and compositions.
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`Case 1:14-cv-00781-SLR Document 53 Filed 04/30/15 Page 4 of 24 PageID #: 765
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`12. The ’828 patent asserts that tigecycline compositions containing a lactose excipient and
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`having a specified pH range have improved stability. (I explain the concept of pH in greater
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`detail below.) The patent asserts that tigecycline undergoes a known degradative process called
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`oxidation when exposed to a pH value of approximately 7.8 and that if the pH were lowered, the
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`oxidative process decreases. (See JA-1463 at 2:23–50.) The patent further asserts that at lower
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`pH values, a different known degradative process called epimerization becomes the prominent
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`degradation pathway. (See id. at 2:48–50.) According to the ’828 patent, the inventors discovered
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`that adding lactose to tigecycline exposed to lower pH values avoids oxidation and minimizes
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`epimerization and thus creates a product more stable than the prior art. (See generally JA-1464–
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`65 at 4:49 – 6:5.)
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`A. Manufacture and Use of Lyophilized Infusion Products Including Tigecycline
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`13. Tigecycline is sold as a lyophilized (freeze-dried) powder in single use vials which are
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`reconstituted by the end user and administered intravenously. In the manufacture of a lyophilized
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`finished dosage product such as tigecycline, the active pharmaceutical ingredient tigecycline,
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`other excipients, and sterile water for injection are added to a vessel such as a stainless steel tank
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`under carefully controlled conditions. These conditions include a prescribed order in which the
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`ingredients are added and careful monitoring and adjustment of factors such as the temperature,
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`pH, oxygen levels in the solution, as well as the method and timing of how the solution is mixed.
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`This process is called “compounding” and the solution in the tank is referred to as the “bulk
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`solution.” Once this step is completed, the solution is passed through lines which filter the
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`solution in order to ensure sterility, and eventually small specified volumes are filled into
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`individual sterile vials. The filled vials are then placed into a lyophilizer in preparation for
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`freeze-drying.
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`Case 1:14-cv-00781-SLR Document 53 Filed 04/30/15 Page 5 of 24 PageID #: 766
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`14. In the lyophilization process, the product is first frozen, typically by lowering the shelf
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`temperature to -40 to -50 °C of the shelves in the chamber housing the vials. Then the chamber is
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`subjected to vacuum condition and the shelf temperature is raised to supply heat flow needed for
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`the removal of solid ice by a process called sublimation whereby the frozen water in the product
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`evaporates immediately without melting. At the completion of sublimation, the temperature of
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`the lyophilizer shelves is raised again and drying is continued by evaporation. After one or more
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`such steps or similar steps a dried powder or cake is produced. The individual vials are then
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`stoppered under sterile conditions. The advantage of lyophilization (as opposed to producing
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`ready-to-use liquid products) is typically enhanced stability. The pH of the product is ordinarily
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`adjusted during the preparation of the bulk solution but is not measured or adjusted during the
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`lyophilization process. The lyophilized product in single use vials can be stored at controlled
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`storage temperatures, typically room temperature or refrigeration.
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`15. The lyophilization process can transform crystalline drug formulation components
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`(including the active drug substance) from a crystalline form to an amorphous form wherein
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`crystalline structures are lost.
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`16. With lyophilized products in single-use vials designed for intravenous infusion, the health
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`care provider will commonly reconstitute the lyophilized powder in a small volume of liquid and
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`either inject or infuse that volume into the patient, or further dilute that volume into a larger
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`volume before administering into the patient. In the United States the storage, handling, and
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`administration of such products is outlined in the product label that is approved by the FDA. For
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`example, in order to administer tigecycline, according to the approved Tygacil product label the
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`health care provider must first reconstitute the lyophilized powder in approximately 5 mL of
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`either a 0.9% sodium chloride solution, a 5% dextrose solution, or a lactated Ringers solution.
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`Case 1:14-cv-00781-SLR Document 53 Filed 04/30/15 Page 6 of 24 PageID #: 767
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`(See Section 2.4 of Tygacil product label, attached as Exhibit B, which was provided to me by
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`counsel). All of these solutions are commonly used in hospital and clinic settings. The
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`reconstituted solution is then added to a 100 mL intravenous (IV) bag which is used for infusion
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`into the patient. No specific type of infusion solution is required for the IV bag except that it be
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`“compatible with tigecycline and with any other drug(s) administered” through the IV line. The
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`reconstituted or further diluted solution must be used within 24 – 48 hours after reconstitution,
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`depending upon the temperature at which it is stored.
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`17. With respect to the approved Tygacil product label, at no time after the lyophilized
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`powder is initially reconstituted does the label instruct the health care provider to measure or
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`adjust pH, or to add any other excipient such as lactose to the tigecycline formulation. Further, it
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`is well-understand that in the United States health care providers do not typically adjust the pH
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`of single-use intravenous pharmaceutical formulations after preparing them for patient
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`administration. Any such measurement and/or adjustment of pH after reconstitution would have
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`to be conducted aseptically which is beyond the training of most health care practitioners and
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`beyond the capabilities of the typical facilities used to prepare reconstituted drug products for
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`injectable administration.
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`B. pH
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`18. In lay terms, pH is a measure of the acidity of a solution. It is determined by the
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`concentration of hydrogen ions (H+) in a solution – the greater the concentration of hydrogen
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`ions, the lower the pH of a solution and the more “acidic” it will be. Values for pH are defined
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`on a scale of 1 – 14, with a pH of 7 considered “neutral,” pH values less than 7 considered
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`acidic, and pH values greater than 7 considered “basic.” Each change of pH value represents a
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`ten-fold change in hydrogen ion concentration. For example, a solution with a pH of 6.0 has a
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`Case 1:14-cv-00781-SLR Document 53 Filed 04/30/15 Page 7 of 24 PageID #: 768
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`ten-fold higher concentration of hydrogen ions than a solution with a pH of 7.0, a solution with a
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`pH of 5.0 has a hundred-fold higher concentration of hydrogen ions that a solution with a pH of
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`7.0, and so on. Pure water has a pH of 7.0. These concepts are well-known and are described in
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`multiple sources. For example, attached as Exhibit C is a true and correct copy of a printout
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`obtained from http://academic.brooklyn.cuny.edu/biology/bio4fv/page/ph_def.htm describing
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`these basic concepts.
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`19. The pH of a solution is dependent upon many factors, including its temperature, the
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`nature of the solution itself, and the solutes dissolved within it. Electrochemical forces affecting
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`a chemical compound in solution may cause some hydrogen atoms on the compound to
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`“dissociate” from the compound into the solution, thereby raising the hydrogen ion concentration
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`of the solution. Similarly, a compound may accept hydrogen ions from solution, thereby
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`lowering the hydrogen ion concentration of the solution. A strong acid is a compound that
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`readily dissociates and contributes hydrogen ions to a solution, and a strong base is a compound
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`that readily accepts hydrogen ions from a solution; the addition of either obviously affects the pH
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`of a solution.
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`20. For some organic molecules called pH indicator compounds the phenomenon of
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`dissociation or association of hydrogen atoms in response to solution pH can be observed
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`visually:
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`Case 1:14-cv-00781-SLR Document 53 Filed 04/30/15 Page 8 of 24 PageID #: 769
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`21. For many organic compounds dissolved in aqueous solutions even small changes in the
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`pH of a solution can dramatically affect the chemical reactions that occur within that solution.
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`For example, for many drug substances (such as esters) their rate of degradation can be
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`proportional to the concentration of hydrogen ions in solution in specific pH regions. Thus an
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`increase in solution pH value of 0.1 in such a pH region could cause a 20% decrease in the shelf-
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`life of the drug solution.
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`22. The measurement of pH in laboratory solutions and industrial applications such as
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`pharmaceutical manufacturing is fairly straightforward. Digital instruments commonly measure
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`pH values to the nearest hundredth and pH values are commonly reported to the nearest tenth of
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`a pH unit. In some applications where further precision is needed digital instruments commonly
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`measure pH values to the nearest thousandth of a pH unit. Examples of common typical
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`commercial digital measuring devices are pictured in Exhibit D. These are true and correct
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`copies of printouts obtained from http://cdn2.us.yokogawa.com/2015-02-
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`1278_Biotech_Pharma_BU-WEB.pdf, http://shop.hannainst.com/hi5222-research-grade-ph-ise-
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`8
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`Case 1:14-cv-00781-SLR Document 53 Filed 04/30/15 Page 9 of 24 PageID #: 770
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`orp-meter-with-cal-check.html?id=040002&ProdCode=HI%25205222, and
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`http://hannainst.com/usa/prods2.cfm?id=040002&ProdCode=HI 2212.
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`III.
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`Interpretation of the Phrase “pH of the composition in a solution is”
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`23. I am informed that the primary source for claim construction analysis is the patent’s
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`specification and claim language, and that the prosecution history can also be considered. I
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`understand that other evidence extrinsic to the patent can also be considered but is less important
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`than the first three sources.
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`24. Claim 1 of the ’828 patent recites:
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`A composition comprising tigecycline, lactose, and an acid selected from
`hydrochloric acid and gentisic acid, wherein the molar ratio of tigecycline to
`lactose is between about 1:0.2 and about 1:5 and the pH of the composition in a
`solution is between about 3.0 and about 7.0.
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`Another independent claim, claim 12, similarly recites “the pH of the composition in a solution
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`is,” and other dependent claims also incorporate that language. This language implicates several
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`different solutions. First, it implicates the pH of the bulk solution. (See JA-1465 at 5:27–32.)
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`Second, it implicates the pH of the “reconstituted” solution created when the lyophilized product
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`is reconstituted. (See id. at 5:41–43.) Third, it implicates solutions made by further diluting
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`reconstituted solutions such as for use in IV bags for patient administration. The patent refers to
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`this process as “admixing” and to these solutions as “admixtures.” (See JA1463–65 at 2:4–8,
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`5:44–46, and 6:50–62.) Fourth, the language standing on its own implicates any solution
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`whatsoever.
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`25. A person of ordinary skill in the art would interpret the language “the pH of the
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`composition in a solution” in this claim and in the other claims of the ’828 patent to refer to the
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`pH of bulk solution, for a number of reasons. First, the entire specification of the patent
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`Case 1:14-cv-00781-SLR Document 53 Filed 04/30/15 Page 10 of 24 PageID #: 771
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`repeatedly and exclusively refers to creating a tigecycline product in which the pH of the
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`composition in a solution is measured by the pH of the bulk solution. Thus, a person of ordinary
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`skill would understand from the patent that the claimed tigecycline product possesses its
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`advantageous properties of improved solid state and reconstituted stability only when the bulk
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`solution possesses the specified pH limitations. Second, the claims would not make sense to a
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`person of ordinary skill if the above pH limitation could be applied to reconstituted solutions in
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`the absence of applying it to the bulk solution. That is because there is no instruction in the
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`patent on how to reconstitute a solution to measure its pH, and there is no data in the patent to
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`support the existence of any product with the recited pH limitations where the pH is obtained by
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`adjustment of the solution after lyophilization and reconstitution. Moreover there is no practical
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`way to put such a claim into clinical practice without the disclosure of specific sterile diluent
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`formulations that could be used to make pH adjustments and a practical means of making aseptic
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`pH measurements in a typical clinical setting.
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`A. The Patent Focuses on the pH of the Bulk Solution
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`26. The first example of the fact that the patent focuses exclusively on the pH of the bulk
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`solution can be found in the first descriptive paragraph of the specification itself. The language
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`of the specification begins with the statement that the present invention relates to “improved
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`tigecycline compositions and methods for making such compositions.” (JA-1463 at 1:7–8.) The
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`specification then notes that the compositions of the invention are comprised of tigecycline, a
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`suitable carbohydrate, and an acid or buffer that achieve improved stability “when dissolved,
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`lyophilized, reconstituted, and/or diluted than compositions of tigecycline not made according to
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`the invention.” (Id. at 1:11–21.) However, a compound cannot be reconstituted and further
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`diluted without first having been dissolved in the bulk solution and lyophilized. Thus, according
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`10
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`Case 1:14-cv-00781-SLR Document 53 Filed 04/30/15 Page 11 of 24 PageID #: 772
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`to the specification the claimed compositions are a result of the manufacturing process. As
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`discussed below, the only method of making the claimed tigecycline compositions described in
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`the patent involves one in which the pH of the bulk solution meets the recited limitations.
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`27. The patent then goes on to describe that tigecycline is manufactured as a lyophilized
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`powder and that the typical process for preparing these powder compositions involves
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`compounding followed by lyophilization. (Id. at 1:54–62.) The patent further explains that to
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`administer the product, it is first reconstituted and then admixed, and that prior art tigecycline
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`compositions degrade quickly during these processes. (Id. at 1:66 – 2:27.) The patent explains
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`that the same degradative processes occur during lyophilization. (JA-1464 at 3:23–31.) The
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`specification then describes prior art manufacturing processes in order to contrast them with the
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`current invention. (Id. at 3:46 – 4:48.)
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`28. In further discussing the comparison between the prior art and claimed inventions, the
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`specification refers to the pH at which lyophilization occurs. (See id. at 4:34–41.) A person of
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`ordinary skill in the art would understand that a solid composition such as a lyophilized cake
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`does not have a “pH” because the concept refers to hydrogen ion activity in solutions. Thus, a
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`person of ordinary skill would understand the pH at which lyophilization occurs to refer to the
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`pH of the solution immediately before lyophilization, which is derived from the bulk solution.
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`29. After the above discussion of the prior art, the patent then turns to “the present
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`invention.” The patent explains that “[b]y lyophilizing an aqueous solution containing
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`tigecycline and a suitable carbohydrate at an acidic pH, we have prepared tigecycline
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`compositions that are more stable against both oxidative degradation and epimerization than
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`existing compositions. Because the pH is acidic, oxidative degradation has been minimized.” (Id.
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`at 4:52–57.) The present invention thus requires that the pH limitation be met before
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`11
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`Case 1:14-cv-00781-SLR Document 53 Filed 04/30/15 Page 12 of 24 PageID #: 773
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`lyophilization , i.e., in the bulk solution, and attributes the desired result – minimizing oxidative
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`degradation – to the pH of the bulk solution. 
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`30. The same portion of the specification also refers to compositions of the invention being
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`“more stable in the lyophilized state” than prior art compositions. (Id. at 4:60–61.) Again, one
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`cannot have compositions of the invention in the lyophilized state without first having such
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`compositions possess a pH within the recited range during the compounding stage – because no
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`other solution exists. Referring to the above lyophilized state, the patent then says that “[s]uch
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`compositions are also expected to possess reconstitution and admixture stability times greater
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`than that of existing compositions.” (Id. at 4:63–67.) By linking the lyophilized compositions
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`(“such compositions”) to the later compositions resulting after reconstitution and admixture, the
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`patent is saying that it is the lyophilized product, made at the required pH and containing a
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`suitable carbohydrate that is causing the reconstituted and admixed solutions to possess better
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`stability. 
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`31. Similarly, the patent states that the compositions of the invention “include solutions, such
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`as those prepared prior to lyophilization, containing tigecycline, a suitable carbohydrate, and an
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`acid or buffer.” (JA-1465 at 5:27–29.) This obviously refers to bulk solutions. The patent goes on
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`to state that compositions of the invention “further include lyophilized powders or cakes
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`containing tigecycline, a suitable carbohydrate, and an acid or buffer.” (Id. at 5:32–34.) Again,
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`one cannot have compositions of the invention in the lyophilized state without first having such
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`compositions possess a pH within the recited range during the compounding stage. Finally, the
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`patent then states that “[c]ompositions of the invention also include solutions made from the
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`lyophilized powder or cake by, for example, reconstitution with saline or other pharmaceutically
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`acceptable diluents. Compositions of the invention further include solutions resulting from
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`12
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`Case 1:14-cv-00781-SLR Document 53 Filed 04/30/15 Page 13 of 24 PageID #: 774
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`diluting those reconstituted solutions with pharmaceutically acceptable diluents for use in
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`intravenous bags.” (Id. at 5:41–46.) The patent thus makes clear that in order for these
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`reconstituted solutions to be compositions of the invention, they must first have been lyophilized
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`powder – which itself was derived from having the bulk solution meet the required pH
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`limitations. The patent further makes clear that the admixed solutions are also derived from the
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`reconstituted solutions of the lyophilized cake. Thus, reconstituted solutions and admixtures can
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`be compositions of the invention – as long as they are derived from a lyophilized cake derived
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`from a bulk solution meeting the claim limitations.
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`32. Consistent with the above, the only procedure described in the patent for making the
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`claimed compositions involves one in which the pH of the bulk solution meets the recited
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`limitation. It states that once tigecycline is dissolved in water to form a bulk solution, “[t]he pH
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`of the solution is subsequently lowered by addition of an acid or buffer.” (Id. at 6:10–11.) The
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`bulk solution also includes a suitable carbohydrate. (Id. at 6:15–16.) “After the pH of the solution
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`is adjusted so that it is acidic, the solution may then be lyophilized to dryness.” (Id. at 6:16–18.)
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`In discussing the pH to be used for lyophilization, the specification instructs:
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`[W]hen preparing tigecycline solutions of the invention for lyophilization, one adds sufficient
`acid or buffer to the aqueous solution containing tigecycline to obtain a pH of from about 3.0
`to about 7.0 including from about 4.0 to about 5.0 and from about 4.2 to about 4.8.
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`(Id. at 6:31–35.) The product is then lyophilized and the resultant “[r]econstituted solutions of
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`the invention” can then be used. (Id. at 6:36–50.) These discussions uniformly contemplate that
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`the pH of the bulk solution is adjusted to be acidic prior to lyophilization. Nowhere does the
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`patent describe a process for making the claimed composition that does not involve using the
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`recited pH range in the bulk solution, and nowhere does the patent describe a reconstituted or
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`13
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`Case 1:14-cv-00781-SLR Document 53 Filed 04/30/15 Page 14 of 24 PageID #: 775
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`admixed composition of the invention that also did not meet the recited pH range when in bulk
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`solution form.
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`33. The specification concludes with six examples detailing several experiments “where
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`tigecycline was dissolved with a carbohydrate in aqueous acidic solution, lyophilized, and
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`analyzed for degradation.” (Id. at 6:65–67.) In each example, the pH is adjusted in the bulk
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`solution prior to lyophilization. (JA-1465–69 at 6:63–14:32.) The examples measure stability in
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`lyophilizates, reconstituted solutions, and admixtures made from further dilution of the
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`reconstituted solutions under various conditions. None of the examples show a pH adjustment to
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`the reconstituted or admixed solutions. None of the examples measure pH of the reconstituted or
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`admixed solutions. More importantly, the patent distinguishes samples in which the pH was
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`measured in the bulk solution, which it refers to as compositions of the invention, with those in
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`which pH was not measured in the bulk solution, which are not compositions of the invention.  
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`34. This can be seen, for example, in Example 1, where the pH of each composition of the
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`invention was adjusted prior to lyophilization. (JA-1466 at 8:8–26.) In contrast, no pH
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`adjustment was made to two control samples prior to lyophilization. (Id. at 7:66 – 8:8.) In
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`presenting the data, the patent explains that “[o]f the 7 cakes tested in example 1, 5 were
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`compositions of the invention and the first two (tigecycline alone without pH adjustment and
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`tigecycline plus lactose without pH adjustment) were controls.” (Id. at 8:34–38.) Thus, the
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`patent itself states that the 2 tigecycline cakes in which the pH adjustment did not take place in
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`the bulk solution are “controls,” i.e., not compositions of the invention.  
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`35. The patent explains that a similar process was followed for Example 2. It states for
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`Example 2a that tigecycline compositions were prepared at various pHs “in the same manner”
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`that the tigecycline compositions were prepared in Example 1 and then lyophilized. (JA-1467 at
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`Case 1:14-cv-00781-SLR Document 53 Filed 04/30/15 Page 15 of 24 PageID #: 776
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`(9:2–13.) These lyophilized cakes were used for Examples 2b and 2c. (Id. at 9:18–19 and 9:36–
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`38.) The data from these experiments are shown in Tables 2a, 2b, and 2c and discussed in
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`column 9 of the patent.  
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`36. I was asked to comment specifically on certain statements in column 9 discussing pH
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`values and on whether the values discussed referred to the pH of the bulk solution or the pH of
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`reconstituted solutions or admixtures. The patent is clear that the discussion relates to the pH of
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`bulk solutions. These statements are discussed below.  
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`37. Column 9, lines 21 – 24 states the following: 
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`Separate aliquots of the solutions at pH of about 5.0 and about 4.5 were
`reconstituted with 5% Dextrose, instead of saline, to a concentration of about 10
`mg/ml and kept at room temperature for 6 hours. Each of the solutions was then
`analyzed by HPLC, and the results are shown in Table 2b.
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`(Id. at 9:21–24.)This statement is immediately preceded by text explaining that lyophilized cakes
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`had been prepared from bulk solutions at various pHs – including about 5.0 and about 4.5 – and
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`that those lyophilized cakes had been reconstituted. (Id. at 9:3–25.) This statement means that
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`lyophilized cakes derived from bulk solution having a pH of about 5.0 and about 4.5 were
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`reconstituted. This statement does not mean that the pH of the reconstituted solutions were about
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`5.0 and about 4.5, because there is nothing in the patent indicating that the pH of the
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`reconstituted solution was measured. This fact is also evident from the way the data is presented
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`in Table 2b, which refers to the dextrose samples in column 1 of the table in the same manner as
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`it refers to the other bulk solution samples.
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`38. Column 9, lines 29 -31 states: 
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`In one embodiment, where the pH was about 4.5 and the diluent was saline, at the
`end of the 6 hour reconstitution period, only 1.60% of epimer was present.
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`15
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`Case 1:14-cv-00781-SLR Document 53 Filed 04/30/15 Page 16 of 24 PageID #: 777
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`(Id. at 9:29–31.)This statement follows the statement in the preceding paragraph and is also
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`referring to the results of the experiment discussed in the preceding paragraph. In that context
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`and from the data in Table 2b, it is clear that this statement does not mean that the pH of the
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`reconstituted solution was about 4.5. Rather, it refers to the fact that a lyophilized cake derived
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`from a bulk solution having a pH of about 4.5 was reconstituted and contained 1.60% epimer
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`degradation product after 6 hours.
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`39. Column 9 lines 45-49 states:
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`The sample at about pH 4.5 with lactose and without dextrose had its epimer
`concentration increase from 1.60% to only 1.80% on going from reconstitution to
`admixture whereas the overall tigecycline content decreased only slightly for that
`sample from 98.15% to 97.97%. These results on the about pH 4.5 sample
`illustrate that that sample is sufficiently stable after the lyophilized cake is stored
`under accelerated stability conditions for 39 days followed by 6 hours of
`reconstitution and 18 hours of admixture.
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`(Id. at 9:45–49.)This statement is referring to results of testing an admixture ultimately derived
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`from a bulk solution with a pH of about 4.5. The text immediately preceding this statement
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`makes clear that the admixture in question was generated from a reconstituted solution described
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`in the preceding paragraph, which itself was generated from a lyophilized cake made from a bulk
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`solution in which the pH was about 4.5. Again, this can also be clearly seen from the data in
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`Table 2c, which refers to the dextrose samples in column 1 of the table in the same manner as it
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`refers to the other bulk solution samples. This passage is not describing the pH of the admixture
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`itself. The latter is never measured or reported in the patent.
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`40. The remaining examples all refer to the pH of the bulk solution and do not measure or
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`refer to the pH of any other solution. For example, Example 3 at column 10, lines 44-51 states:
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`Solution samples of tigecycline, lactose, and an acid were prepared at pHs of
`about 5.8, 5.1, and 4.5 according to the methods of example 1 except that gentisic
`acid was used to lower the pH of the bulk solution rather than 1.0 N HCl. An
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`16
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`Case 1:14-cv-00781-SLR Document 53 Filed 04/30/15 Page 17 of 24 PageID #: 778
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`additional two samples of tigecycline solutions without lactose were prepared,
`one at a pH of about 5.1 and another at a pH of about 4