`
`
`BEFORE THE PATENT TRIAL AND APPEALS BOARD
`
`
`AMNEAL PHARMACEUTICALS LLC
`Petitioner
`
`v.
`
`HOSPIRA, INC
`Patent Owner
`
`
`Inter Partes Review No. IPR2016-01580
`Patent 8,648,106
`
`
`DECLARATION OF ALPASLAN YAMAN, PH.D.
`
`
`
`
`
`
`
`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1003
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`
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`TABLE OF CONTENTS
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`INTRODUCTION ........................................................................................... 1
`
`
`I.
`
`II. QUALIFICATIONS & BACKGROUND ...................................................... 3
`
`III.
`
`INFORMATION CONSIDERED ................................................................... 4
`
`IV. THE ‘106 PATENT ......................................................................................... 4
`A.
`Background of the Technology ............................................................. 4
`i.
`History of Dexmedetomidine....................................................... 4
`ii.
`Formulation of Parenteral Drugs ............................................... 6
`iii.
`“Ready to Use” Formulations .................................................... 9
`Scope of the ‘106 Patent ......................................................................10
`
`B.
`
`V. CLAIM CONSTRUCTION .............................................................................11
`A.
`A Person of Ordinary Skill in the Art (POSA) .........................11
`B.
`Broadest Reasonable Interpretation ..........................................11
`C.
`Claim Terms of the ‘106 Patent ................................................12
`“Ready-To-Use” .......................................................................12
`“Dexmedetomidine” .................................................................14
`
`i.
`ii.
`
`VI. PRIOR-ART REFERENCES DISCLOSE ALL OF THE ELEMENTS
`OF THE CLAIMS OF THE ‘106 PATENT.................................................. 14
`A. A Person of Ordinary Skill in the Art Would Have Been
`Motivated to Make the Invention of Claims 1-9 of the ‘106
`Patent by the 2010 Precedex Label in View of Palmgren................... 16
`
`Claim 1 ......................................................................................16
`i.
`Claims 2-6 .................................................................................28
`ii.
`iii. Claims 7-8 .................................................................................29
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` i
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`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page i
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`Claim 9 ......................................................................................31
`iv.
`B. Ground 2: A Person of Ordinary Skill in the Art Would Have
`Been Motivated to Make the Invention of Claims 1-9 of the
`‘106 Patent by U.S. 6,716,867 in view of the 2010 Precedex
`Label and Palmgren ............................................................................. 35
`
`C. Ground 3: A Person of Ordinary Skill in the Art Would Have
`Been Motivated to Make the Invention of Claims 1-9 of the
`‘106 Patent by the 2010 Precedex Label in View of Giorgi,
`Eichhorn, Palmgren, and the Lavoisier Documents ............................ 42
`
`VII. CONCLUDING STATEMENTS ..................................................................47
`
`ii
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`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page ii
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`I.
`
`INTRODUCTION
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`I, Alpaslan Yaman, Ph.D., declare as follows:
`
`1.
`
`I am over 18 years of age. I have personal knowledge of the facts
`
`stated in this declaration and could testify competently to them if asked to do so.
`
`2.
`
`In this proceeding before the U.S. Patent and Trademark Office
`
`(“USPTO”), I have been retained by Amneal Pharmaceuticals LLC (“Amneal” or
`
`“Petitioner”) as an independent expert consultant. Although I am receiving
`
`compensation at my standard consulting rate for the time that I spend on this
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`proceeding, I have no other interest in its result. I also expect to be reimbursed for
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`reasonable expenses incurred in relation to my consulting. My compensation is
`
`independent of the opinions rendered or the outcome of this proceeding.
`
`3.
`
`I understand that this proceeding involves U.S. Patent No. 8,648,106
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`(“the ‘106 patent”), Ex. 1001, issued on February 11, 2014, and that the ‘106
`
`patent issued from U.S. Application No. 13/867,861 (“the ’861 application”), Ex.
`
`1050, filed on November April 22, 2013. The ’861 application was a continuation
`
`of U.S. Application No. 13/678,260 (“the ’260 application”), Ex. 1051, which was
`
`filed on November 15, 2012, and issued as U.S. Patent No. 8,436,033 (“the ’033
`
`patent”), Ex. 1052. The ’260 application was, in turn, a continuation of U.S.
`
`Application No. 13/541,524 (“the ’524 application”), Ex. 1048, which was filed on
`
`July 3, 2012, and issued as U.S. Patent No. 8,338,470 (“the ’470 patent”), Ex.
`
` 1
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`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 1
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`1053. The ’524 application, in turn, was a continuation of U.S. Application No.
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`13/343,672, Ex. 1008, which was filed on January 4, 2012, and issued as U.S.
`
`Patent No. 8,242,158 (“the ’158 patent”), Ex. 1047. Accordingly, the earliest
`
`possible effective filing date of the ‘106 patent is January 4, 2012.
`
`4.
`
`I have been asked by counsel for Amneal to explain the technical
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`subject matter of the ‘106 patent and its background. I have also been asked to
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`explain whether prior art discloses the compositions claimed in the ‘106 patent.
`
`My opinions are set forth below.
`
`5.
`
`Generally, the ‘106 patent disclosure and claims are directed to a
`
`premixed, or ready-to-use pharmaceutical compositions of dexmedetomidine for
`
`parenteral administration. Ex. 1001, col. 2, ll. 5 – 10. The specification identifies,
`
`as suitable containers for these formulations of the drug, glass vials, ampoules,
`
`syringes, and plastic flexible containers, such as polyvinyl chloride (PVC),
`
`VisIV™, polypropylene, and CR3 containers. Id. at col. 9, ll. 26–33. The
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`specification also exemplifies long term storage results of several premixed
`
`pharmaceutical compositions of dexmedetomidine. Id. at col. 13, l. 22 – col. 14, l.
`
`58.
`
`6.
`
`It is my opinion that a person of ordinary skill in the art (“POSA”)
`
`would have had a reason and the know-how to arrive at the subject matter recited
`
`in claims 1-9 by combining the disclosure of the 2010 Precedex Label, Ex. 1007, in
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`
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`2
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`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 2
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`view of the Palmgren reference, Ex. 1017, with a reasonable expectation of
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`success.
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`7.
`
`Also, it is my opinion that a person of ordinary skill in the art would
`
`have had a reason and the know-how to arrive at the subject matter recited in
`
`claims 1-9 by considering U.S. Patent No. 6,716,867 (“the ‘867 patent”), Ex. 1006,
`
`in view of the 2010 Precedex Label, Ex. 1007, and Palmgren, Ex. 1017.
`
`8.
`
`Finally, it is my opinion that a person of ordinary skill in the art would
`
`have had a reason and the know-how to arrive at the subject matter recited in
`
`claims 1-9 by considering the disclosure of the 2010 Precedex label, Ex. 1007, in
`
`view of Giorgi, Ex. 1015; Eichhorn, Ex. 1016; Palmgren, Ex. 1017; and the
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`Lavoisier Documents, Ex. 1018, with a reasonable expectation of success.
`
`II. QUALIFICATIONS & BACKGROUND
`9. My qualifications and credentials are fully set forth in my curriculum
`
`vitae, attached hereto as Exhibit A. I am an expert in the fields of drug
`
`development and formulation, and in particular with expertise in the development
`
`of Parenteral drug products. For the past 30 years, I have accumulated significant
`
`training and experience in these and related fields.
`
`10.
`
`In my 30 years in this industry I have contributed to the development
`
`of over 40 pharmaceutical products. Many of these have been sterile injectables of
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`which included pre-mix bags of 50 and 100 mL in addition to their accompanying
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`
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`3
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`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 3
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`20 mL glass vial concentrate solution, which was used either to make a diluted
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`solution or could be used directly as a ready to use solution.
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`11.
`
`I am not an attorney or patent agent and I offer no legal opinions
`
`herein. My opinions here are based on my professional experience, scientific
`
`expertise, and the materials I have reviewed.
`
`III.
`
`INFORMATION CONSIDERED
`
`12.
`
`In forming my opinions, I have reviewed the ‘106 patent, its
`
`prosecution history, and other prior art references cited in this declaration. In
`
`particular, I have reviewed the exhibits to Amneal’s petition listed in Exhibit B
`
`attached hereto.
`
`IV. THE ‘106 PATENT
`A. Background of the Technology
`i. History of Dexmedetomidine
`13. The medical field has recognized dexmedetomidine as a general
`
`sedation/analgesic agent since 1988. Ex. 1005, U.S. Pat. No. 4,910,214 (“the ‘214
`
`patent”), col. 3, ll. 55-59. Dexmedetomidine ((S)-4-[1-(2,3-dimethylphenyl)ethyl]-
`
`1H-imidazole), which
`
`is
`
`the S-enantiomer of medetomidine
`
`(4-[1-(2,3-
`
`dimethylphenyl)ethyl]-1H-imidazole), has the following structure:
`
`
`
`
`
`4
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`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 4
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`Hm”
`
`Dexmedetomidine
`
`medetomidine
`
`14. Medetomidine, a racemic mixture, was first disclosed in the prior art
`
`in 1985, Ex. 1004, U.S. Pat. No. 4,544,664 (“the ‘664 patent”), col- 19, 1. 47 — col.
`
`20,
`
`1. 38, and was
`
`separated into two enantiomers, one of which was
`
`dexmedetomidine, in 1988, Ex. 1005, col. 1, 11. 8-43.
`
`15. Administration of dexmedetomidine
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`to a patient parenterally,
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`including by intravenous bolus or infusion, intramuscular injection, intranasal and
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`buccal, as well as oral routes was also disclosed in the prior art. Ex. 1002, 1118. See
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`Ex. 1004; Ex- 1005; Ex. 1021, Dyck et al., Anesthesiology 78:813-820 (1993); Ex.
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`1022, Scheinin et al., Anesthesiology 78:1065—l075 (1993); Ex. 1023, Yuen et al.,
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`Anesth. Analg. 105:374-380 (2007).
`
`16- Additionally, as early as in 1999, the prior art disclosed methods of
`
`sedating a patient by administering dexmedetomidine, or a phannaceutically
`
`acceptable salt thereof, to the patient. Ex. 1024, Venn et al., Anaesthesia 5421136-
`
`1142 (1999); Ex. 1006.
`
`17.
`
`In the prior art, dexmedetomidine was provided as a concentrate to be
`
`diluted prior to administration to a patient. See, e.g., Ex. 1007, Sec. 2.4.
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`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC — Exhibit 1003 — Page 5
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`Dexmedetomidine formulations for sedation were commercially available in the
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`U.S. as early as December 23, 1999, as PrecedexTM injection for intravenous
`
`infusion following dilution (or alternatively “PrecedexTM Concentrate”). See, e.g.,
`
`Ex. 1007.
`
`ii. Formulation of Parenteral Drugs
`18. Parenteral pharmaceutical formulations include a variety of active
`
`ingredients, which may be incorporated into liquids. Ex. 1028, “The Keys to RTU
`
`Parenterals,” Pharmaceutical Formulation & Quality, Vol. 11, No. 5, p. 40,
`
`September 2009, pp. 2-4. A given formulation may require certain formulation or
`
`physiochemical parameters such as tonicity, a particular storage material, and/or
`
`active ingredient stability, of which one with ordinary skill in the field of
`
`parenteral drug formulation would routinely select, test for and analyze. Id.
`
`1. Storage material studies
`19. A pharmaceutical producer has a responsibility to make certain that a
`
`selected storage container does not interact physically or chemically with the
`
`pharmaceutical solution placed
`
`in
`
`it. Ex. 1025, “Packaging Drugs and
`
`Pharmaceuticals,” Wilmer A. Jenkins and Kenton R. Osborn, p. 259 (1993). For
`
`this reason, pharmaceutical producers routinely perform studies to evaluate
`
`interactions with materials involved in parenteral administration to determine, for
`
`example, the appropriate storage materials for any particular formulation. Ex.
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`
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`6
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`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 6
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`1026, “Pharmaceutical dosage forms, parenteral medications” edited by Kenneth
`
`E. Avis, et al. 2nd Edition, p. 161 (1992). Typical formulation studies include
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`storing, in various glass and plastic containers, prepared admixtures at a desired
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`concentration of the active pharmaceutical ingredient. Id. at 162. Samples are
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`periodically withdrawn from the containers as a function of time and evaluated for
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`potency, pH, color and particulate matter. Id. The container in which essentially
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`no potency change is observed, from the initial potency that is measured, is then
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`recommended for clinical use. Id.
`
`20.
`
`In some studies, plastic containers have been shown to absorb or
`
`adsorb active drug ingredients into or onto the plastic material, causing reduced
`
`potency and efficacy of the formulation. Ex. 1027, “Sterile Pharmaceutical
`
`Packaging: Capatibility and Stability,” Y. John Wang and Yie W. Chien, p. 16
`
`(1984). For example, medetomidine, from which dexemedetomidine is the
`
`optically active dextrorotary stereoisomer, is known to display deleterious
`
`interactions with polyvinylchloride. Ex. 1017. For at least this reason, glass has
`
`been traditionally considered “the container material of choice for most sterile
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`pharmaceutical products.” Id. at 3. Glass containers are generally classified
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`according
`
`to
`
`their degree of chemical resistance by
`
`the United States
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`Pharmacopeia. Id. at 7.
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`
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`7
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`2. Tonicity
`21. For solutions intended for parenteral administration or application to
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`mucous membranes, it is well known in the art that patient discomfort (and even
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`injury) is often minimized by adjusting the pharmaceutical solution to include a
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`buffer system that has approximate isotonicity with body fluid. See Ex. 1029
`
`“Parenteral Preparations,” Ch. 84, p. 1469, Remington’s Pharmaceutical Sciences
`
`16th Edition (1980). When introduced into a patient, an isotonic solution has an
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`osmotic pressure equal to that of the patient’s cells. Id. Consequently, the
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`intracellular volume stays constant because the osmotic pressure on the cell
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`membrane due to the parenteral solution is equalized. Id. It is well known that a
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`buffer system of 0.9% sodium chloride at 37°C mimics the approximate isotonicity
`
`of body fluid. Id. Introduction of isotonic fluids can reduce the risk of hemolysis
`
`in patient cells as compared to solutions with different tonicity. Ex. 1030, Ponder,
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`“The Tonicity-Volume Relations for Systems Containing Human Red Cells and
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`the Chlorides of Monovalent Cations,” The Journal of General Physiology, 398
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`(1949). Furthermore, it is known in the art that human red cells are least fragile in
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`isotonic NaCl solutions. Id. For at least these reasons, 0.9% sodium chloride
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`buffer are typically chosen for parenteral administration. Ex. 1029, at 1469.
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`3. The U.S. Food and Drug Administration requires
`stability studies
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`22. Pharmaceutical formulation studies typically include investigations
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`
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`about how the quality of a drug substance or drug product varies with time under
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`the influence of a variety of environmental factors, such as temperature, humidity,
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`and light. As part of a new drug application, the United States Food and Drug
`
`Administration (“FDA”) requires a written testing program designed to assess,
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`among other characteristics, the stability of all new pharmaceutical drug products.
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`21 C.F.R. § 211.166. The testing program must be based on the same container-
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`closure system in which the drug product is to be marketed and the results are used
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`to determine the appropriate storage conditions and expiration dates of the drug
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`product. Id.
`
`iii. “Ready to Use” Formulations
`It is well known in the art that some drug products intended for
`
`23.
`
`parenteral administration or application to mucous membranes may be premixed in
`
`an intravenous diluent and stored in a container until time of administration to a
`
`patient. Ex. 1028. Commercially available in 50 mL to 1000 mL glass or plastic
`
`containers, such products are referred to as ready to use (RTU) intravenous
`
`products or “premix” drug solutions. Id. There are many other examples of active
`
`pharmaceutical ingredients available in RTU form, such as nitroglycerine, id.,
`
`propofol microemulsions, Ex. 1032, U.S. Pat. App. Pub. No. 2010/0041769 A1
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`(“Pacheco”), and esmolol hydrochloride, Ex. 1033, U.S. Pat. No. 6,310,094
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`(“Liu”).
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`9
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`24. Historically, RTU medications were proposed as a way to standardize
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`drug preparation and improve medication safety. Ex. 1020, A. Gerlach et al., “A
`
`new dosing protocol reduces dexmedetomidine-associated hypotension in critically
`
`ill surgical patients,” Journal of Critical Care, Vol. 24, No. 4, 568-574 (2009); see
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`also Ex. 1015, I. Giorgi et al., “Risk and pharmacoeconomic analyses of the
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`injectable medication process in the paediatric and neonatal intensive care units,”
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`International Journal for Quality in Health Care, Vol. 22, No. 3, 170-178 (2010)
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`(advocating that the most effective way to reduce microbial contamination and
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`dilution error is use of ready to use solution) and Ex. 1034, P. Linden et al.,
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`“Ready-to-use injection preparations versus conventional reconstituted admixtures:
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`economic evaluation in a real-life setting,” PharmacoEconomics, Vol. 20, No. 8,
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`529-536 (2002) (citing substantial cost savings in using RTU pharmaceutical
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`products compared to conventional admixtures).
`
`Scope of the ‘106 Patent
`
`B.
`25. The ‘106 patent generally discloses premixed, or ready to use,
`
`pharmaceutical compositions of dexmedetomidine for parenteral administration to
`
`patients. Ex. 1001, col. 1, ll. 61-67. In particular, the specification discloses that
`
`suitable containers include glass vials, ampoules, syringes, and plastic flexible
`
`containers, such as polyvinyl chloride (PVC), VisIV™, polypropylene, and CR3
`
`containers. Id. at col. 9, ll. 17-23. The specification also discloses numerous
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`10
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`suitable concentrations for the premixed concentrations, including 4 μg/mL. Id. at
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`col. 7, l. 64 – col. 8, l. 16.
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`V. CLAIM CONSTRUCTION
`A. A Person of Ordinary Skill in the Art (POSA)
`I have been informed that the construction of the terms of a patent
`26.
`
`claim is to be done from the point of view of a POSA at the time of the invention.
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`For purposes of defining a POSA, I have assumed that the time of the invention is
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`the date of filing of the ‘672 application, namely January 4, 2012.
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`27.
`
`In formulating my opinions, I have relied upon my review of the
`
`references cited below, my experience in the relevant art and also considered the
`
`viewpoint of a POSA as of January 4, 2012. In my opinion, the POSA at the time
`
`of invention would have held an advanced degree, such as a M.S, or Ph.D. in
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`Pharmaceutics, Chemistry or Engineering with relevant experience in the field of
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`drug development and formulation. With respect to clinical drug use, the POSA
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`would have an M.D. with significant clinical experience in anesthesia or sedation
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`who has familiarity with the use of parenteral injection and/or familiarity with
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`ready to use medications.
`
`B.
`28.
`
`Broadest Reasonable Interpretation
`I have been advised that in an inter partes review proceeding before
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`the USPTO, like this one, a patent claim term is to receive the “broadest reasonable
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`interpretation” in light of the specification of the patent in which it appears. I have
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`also been advised that, at the same time, patent claim terms are generally given
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`their ordinary and customary meanings as would be understood by a POSA.
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`29.
`
`I have also been advised by counsel that patent claims are to be
`
`construed first in the context of the patent specification, including the plain
`
`meaning of the claims, of the patent. The prosecution history of the patent should
`
`also be considered to the extent that it provides clarification.
`
`30.
`
`I have kept in mind these claim construction principles in the analysis
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`set forth below. In some cases, and where I have stated as such, my opinions have
`
`also been informed by specific portions of the prosecution history of the ‘106
`
`patent.
`
`C. Claim Terms of the ‘106 Patent
`i. “Ready-To-Use”
`‘106 patent discloses an embodiment of
`31. The
`
`the claimed
`
`pharmaceutical composition as being a “ready to use” liquid pharmaceutical
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`composition. I have set forth my understanding, as a person of ordinary skill in the
`
`art, of what the term “ready to use” means below.1
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`32. First, the claims of the ‘106 patent describe the claimed liquid
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`pharmaceutical composition as being “ready to use” for parenteral administration.
`
`
`1 The dependent claims, in my opinion, do not introduce any terms that require
`
`construction.
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`For example, independent claim 1 of the ‘106 patent reads:
`
`A ready to use liquid pharmaceutical composition for parenteral
`administration to a subject, comprising dexmedetomidine or a
`pharmaceutically acceptable salt thereof disposed within a sealed
`glass container, wherein the liquid pharmaceutical composition when
`stored in the glass container for at least five months exhibits no more
`than about 2% decrease in the concentration of dexmedetomidine.
`
`Ex. 1001, col. 26, ll. 18-24.
`
`33. Also, the specification of the ‘106 patent discloses that the
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`formulation of dexmedetomidine can be “ready to use.” In particular, the
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`specification of the ’106 patent states:
`
`[i]n certain embodiments, the compositions of the present invention
`can be formulated as ‘ready to use’ compositions which refer to
`premixed compositions that are suitable for administration to a
`patient without dilution. For example, in certain embodiments, the
`compositions of the present invention are ‘ready to use’ upon
`removing the compositions from a sealed container or vessel.
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`Ex. 1001, at col. 3, l. 66-col. 4, l. 5 (emphasis added).
`
`34. Additionally, the term “ready to use” is a well-known term of art in
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`the medical and pharmaceutical industry. See, e.g., Ex. 1044. It is my opinion that
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`one of skill in the art would understand the term “ready to use” to mean “requiring
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`no further dilution or reconstitution before transfer to an administration device.”
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`35. Based on these descriptions, and the use of the term by persons of
`
`ordinary skill in the art, it is my opinion that the broadest reasonable interpretation
`
`of “ready to use” must include a liquid pharmaceutical composition that requires
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`
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`no further dilution or reconstitution before administration to a patient.
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`ii. “Dexmedetomidine”
`‘106 patent discloses an embodiment of
`36. The
`
`the claimed
`
`pharmaceutical composition as comprising dexmedetomidine. The specification
`
`further defines “dexmedetomidine” as “(S)-4-[1-(2,3-dimethylphenyl) ethyl]-1H-
`
`imidazole,” and provides the following chemical formula:
`
`Ex. 1001, col. 3, ll. 24-55.
`
`
`
`37. The specification of the ‘106 patent defines dexmedetomidine as a
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`“substantially pure, optically active dextrorotary stereoisomer of medetomidine, as
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`the free base or pharmaceutically acceptable salt.” Ex. 1001, col. 3, ll. 31-34.
`
`Therefore, it is my opinion that the broadest reasonable interpretation of
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`“dexmedetomidine” means “substantially pure, optically active dextrorotary
`
`stereoisomer of medetomidine, as the free base or pharmaceutically acceptable
`
`salt.” Id.
`
`VI. PRIOR-ART REFERENCES DISCLOSE ALL OF THE ELEMENTS
`OF THE CLAIMS OF THE ‘106 PATENT
`
`38.
`
`In my opinion, and as set forth in the chart below, a POSA would
`
`have had reason, with a reasonable expectation of success to, to arrive at an
`14
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`embodiment within the scope of claims 1-9 of the ‘106 patent by combining the
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`disclosure of the 2010 Precedex label, Ex. 1007, with the disclosure of the
`
`Palmgren reference, Ex. 1017 (“Ground 1”).
`
`39.
`
`It is also my opinion that a POSA would have had reason, with a
`
`reasonable expectation of success to, to arrive at an embodiment within the scope
`
`of claims 1-9 of the ‘106 patent by combining the disclosure of the ‘867 patent, Ex.
`
`1006, with the disclosure of the 2010 Precedex Label, Ex. 1007, and the Palmgren
`
`reference, Ex. 1017 (“Ground 2”).
`
`40. Finally, in my opinion, a POSA would have had reason, with a
`
`reasonable expectation of success to, to arrive at an embodiment within the scope
`
`of claims 1-9 of the ‘106 patent by combining the disclosure of the 2010 Precedex
`
`label, Ex. 1007, with the disclosure of the Giorgi reference, Ex. 1015; Eichhorn
`
`reference, Ex. 1016; Palmgren reference, Ex. 1017; and the Lavoisier Documents,
`
`Ex. 1018 (“Ground 3”).
`
`Ground 35 U.S.C. Claims
`1
`§ 103(a)
`1-9
`
`2
`
`3
`
`§ 103(a)
`
`1-9
`
`§ 103(a)
`
`1-9
`
`
`
`
`
`Prior Art References
`2010 Precedex Label (Ex. 1007) in view of
`Palmgren (Ex. 1017)
`US 6,716,867 (Ex. 1006) in view of the 2010
`Precedex Label (Ex. 1007) and Palmgren
`(Ex. 1017)
`2010 Precedex Label (Ex. 1007) in view of
`Giorgi (Ex. 1015), Eichhorn (Ex. 1016),
`Palmgren (Ex. 1017) and the Lavoisier
`Documents (Ex. 1018)
`
`15
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`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 15
`
`
`
`41.
`
`I have been advised by counsel that a patent claim may be invalid if,
`
`at the time of its alleged invention, a POSA would have found its subject matter as
`
`a whole to be obvious. I have been informed that obviousness is a legal
`
`determination that rests on factual inquiries including the scope and content of the
`
`prior art, the level of ordinary skill in the art to which the subject matter of the
`
`alleged invention pertains, the differences between the claimed invention and the
`
`prior art, and any objective indicia of nonobviousness that may exist.
`
`42. As noted above, I have been asked to consider January 4, 2012, the
`
`filing date of the ‘672 application, as the time of the alleged invention. I
`
`understand that each of the cited references precedes the filing date of the ‘672
`
`application and thus constitutes prior art under the relevant section of the patent
`
`code as I have been advised by counsel.
`
`A. A Person of Ordinary Skill in the Art Would Have Been
`Motivated to Make the Invention of Claims 1-9 of the ‘106 Patent
`by the 2010 Precedex Label in View of Palmgren
`
`43.
`
`I have been asked to opine whether the 2010 Precedex Label, Ex.
`
`1007, would have led a POSA to make the pharmaceutical composition of claims
`
`1-9 of the ‘106 patent if its teaching were considered in view of Palmgren, Ex.
`
`1017.
`
`i. Claim 1
`It is my opinion that the 2010 Precedex Label, in view of Palmgren,
`
`44.
`
`
`
`16
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`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 16
`
`
`
`would have led a POSA to make a ready to use liquid pharmaceutical composition
`
`for parenteral
`
`administration
`
`that
`
`comprises dexmedetomidine
`
`(or
`
`a
`
`pharmaceutically acceptable salt thereof) disposed within a sealed glass container,
`
`where the liquid pharmaceutical product, when stored in the glass container for at
`
`least five months, exhibits no more than about 2% decrease in the concentration of
`
`dexmedetomidine, as set forth in the claim chart below.
`
`45.
`
`I note that Claim 1 of the ’106 patent does not recite a limitation
`
`directed to concentration of dexmedetomadine. Accordingly, claim 1 broadly
`
`includes any concentration of medetomidine suitable for parenteral administration.
`
`46. The 2010 Precedex Label further disclosed the preparation of a
`
`solution containing the PrecedexTM Concentrate for parenteral administration via
`
`intravenous infusion by diluting 2 mL the PrecedexTM Concentrate in 48 mL of
`
`0.9% sodium chloride injection to a total of 50 mL. Id. at Sec. 2.4, ll. 175-184. The
`
`2010 Precedex Label disclosed that the diluted 4 μg/mL solution of the PrecedexTM
`
`Concentrate is “ready to use” for administration to patients. Id. at Sec. 2.4, ll. 175-
`
`176, and Sec. 11, ll. 457-458 (“Precedex (dexmedetomidine hydrochloride)
`
`injection is a sterile, nonpyrogenic solution suitable for intravenous infusion
`
`following dilution.”) (emphasis added).
`
`47.
`
`In my opinion, preparing a “ready
`
`to use” solution of
`
`dexmedetomidine hydrochloride at a desired concentration, for parenteral
`
`
`
`17
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`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 17
`
`
`
`administration to a patient via intravenous infusion would thus be within this
`
`routine clinical practice, particularly because the 2010 Precedex Label explicitly
`
`directs a person of skill in the art to prepare that exact solution. Also, one of
`
`ordinary skill in the art would appreciate that dilution is a routine step prior to
`
`administration of parenteral drugs and would consider the concentrated solution
`
`disclosed in the 2010 Precedex label as such a “ready to use” product. Ex. 1029, p.
`
`1469. It is routine medical practice to choose the appropriate amount and
`
`concentration of drug to be administered under particular sets of circumstances to a
`
`particular patient. Id.
`
`48. Furthermore, the 2010 Precedex Label itself discloses that the
`
`PrecedexTM Concentrate is ready to use under certain circumstances. In the
`
`Declaration of Dr. James Gordon Cain, which I have reviewed, he states that he
`
`routinely administers PrecedexTM to patients parenterally via intramuscular (IM)
`
`injection, at the provided, undiluted concentration of 100 μg/mL, directly from the
`
`glass vial. Ex. 1002, ¶¶ 43-44. Dr. Cain based his opinion on his own routine
`
`administration of dexmedetomidine to patients parenterally, via intramuscular (IM)
`
`injection, at the provided, undiluted concentration of 100 μg/mL, and directly from
`
`the glass vial. Ex. 1002, ¶¶44-45. Parenteral administration of undiluted
`
`dexmedetomidine is a common practice in the field of anesthesiology. Ex. 1002,
`
`¶¶44-45.
`
`
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`18
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`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 18
`
`
`
`49.
`
`In this broadest sense, then, the PrecedexTM Concentrate itself is
`
`“ready to use” without dilution. Id.
`
`50. Also, the use of “ready to use” products for parenteral administration
`
`is well-known in the art as an advantageous means of administration. See supra,
`
`¶ 47.
`
`51. Thus, while the 2010 Precedex Label did not expressly disclose a
`
`ready to use or premixed solution (because the Label requires dilution prior to
`
`administration to a patient), a POSA would be motivated to likewise prepare a
`
`“ready to use” liquid pharmaceutical composition as disclosed in claims 1-9 for
`
`occasions when dilution, as further described below, is needed or desired.
`
`52. As noted above, the 2010 Precedex Label also disclosed that
`
`PrecedexTM is a sterile solution provided “in a glass vial.” Ex. 1007, Sec. 3, ll. 207-
`
`208, and Sec. 16, ll. 698-699. In my opinion, to the extent that the diluted
`
`PrecedexTM solutions are not ready to use without dilution, a person of skill in the
`
`art would have known to prepare, store, or handle the diluted PrecedexTM solutions
`
`in sealed glass containers toward the preparation of a product with an established
`
`shelf-life.
`
`53. First, the 2010 Precedex Label disclosed only a glass vial as the
`
`means for storage and handling of the PrecedexTM Concentrate. Id. at Sec. 3 and
`
`16. Further, the 2010 Precedex Label disclosed that PrecedexTM has a “potential for
`
`
`
`19
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`Petition for Inter Partes Review of US 8,6