UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEALS BOARD
`
`
`AMNEAL PHARMACEUTICALS LLC
`Petitioner
`
`v.
`
`HOSPIRA, INC
`Patent Owner
`
`
`Inter Partes Review No. IPR2016-01579
`Patent 8,455,527
`
`
`DECLARATION OF ALPASLAN YAMAN, PH.D.
`
`
`
`
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 1
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEALS BOARD
`
`
`AMNEAL PHARMACEUTICALS LLC
`Petitioner
`
`v.
`
`HOSPIRA, INC
`Patent Owner
`
`
`Inter Partes Review No. IPR2016-01579
`Patent 8,455,527
`
`
`DECLARATION OF ALPASLAN YAMAN, PH.D.
`
`
`
`
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 1
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION ........................................................................................... 4
`
`II. QUALIFICATIONS & BACKGROUND ...................................................... 6
`
`III.
`
`INFORMATION CONSIDERED ................................................................... 7
`
`IV. THE ‘527 PATENT ......................................................................................... 7
`A.
`Background of the Technology ............................................................. 7
`
`History of Dexmedetomidine....................................................... 7
`i.
`Formulation of Parenteral Drugs ............................................... 8
`ii.
`“Ready to Use” Formulations ..................................................12
`iii.
`Scope of the ‘527 Patent ......................................................................13
`
`B.
`
`V.
`
`CLAIM CONSTRUCTION ..........................................................................13
`A. A Person of Ordinary Skill in the Art (POSA) ...................................13
`
`B.
`
`C.
`
`Broadest Reasonable Interpretation ....................................................14
`
`Claim Terms of the ‘527 Patent ..........................................................15
`
`“Ready To Use” ........................................................................15
`i.
`“Dexmedetomidine” .................................................................17
`ii.
`VI. PRIOR-ART REFERENCES DISCLOSE ALL OF THE ELEMENTS
`OF THE CLAIMS OF THE ‘527 PATENT.................................................. 17
`
`A. A Person of Ordinary Skill in the Art Would Have Been
`Motivated to Perform the Invention of Claims 1-11 and 13 of the ‘527
`Patent by the 2010 Precedex Label in View of Palmgren .............................19
`
`i.
`
`Claim 1 ......................................................................................20
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 2
`
`
`
`Claims 2-5 .................................................................................27
`ii.
`iii. Claims 6-11 and 13 ...................................................................28
`B. Ground 2: A Person of Ordinary Skill in the Art Would Have
`Been Motivated to Make the Invention of Claims 1-11 and 13 of the
`‘527 Patent by U.S. 6,716,867 in view of the 2010 Precedex Label and
`Palmgren ........................................................................................................32
`
`C. Ground 3: A Person of Ordinary Skill in the Art Would Have
`Been Motivated to Make the Invention of Claims 1-11 and 13 of the
`‘527 Patent by the 2010 Precedex Label in View of Giorgi, Eichhorn,
`Palmgren, and the Lavoisier Documents .......................................................38
`
`VII. CONCLUDING STATEMENTS ................................................................43
`
`
`
`
`
`3
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 3
`
`
`
`I.
`
`INTRODUCTION
`
`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
`
`proceeding, I have no other interest in its result. I also expect to be reimbursed for
`
`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. 8,455,527
`
`(“the ‘527 patent”), Ex. 1001, issued on June 4, 2013, and that the ‘527 patent
`
`issued from U.S. Patent Application Serial No. 13/678,148 (“the ‘148
`
`application”), Ex. 1054, filed on November 15, 2012. The ‘148 application is a
`
`continuation of U.S. Application No. 13/541,524, Ex. 1048, now U.S. Patent No.
`
`8,338,470 (“the ‘470 patent”), Ex. 1053, which is a continuation of U.S.
`
`Application No. 13/343,672, Ex. 1008, now U.S. Patent No. 8,242,158 ( “the ‘158
`
`patent”), Ex. 1047, which was filed on January 4, 2012. Accordingly, the earliest
`
`possible effective filing date of the ‘527 patent is January 4, 2012.
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 4
`
`
`
`4.
`
`I have been asked by counsel for Amneal to explain the technical
`
`subject matter of the ‘527 patent and its background. I have also been asked to
`
`explain whether prior art discloses the methods claimed in the ‘527 patent. My
`
`opinions are set forth below.
`
`5.
`
`Generally, the ‘527 patent disclosure and claims are directed to
`
`premixed pharmaceutical compositions of dexmedetomidine and methods of use of
`
`the premixed compositions for sedation. Ex. 1001, col. 2, ll. 3-9, col. 10, ll. 1-
`
`25. The specification provides suitable containers including glass vials, ampoules,
`
`syringes, and plastic flexible containers, such as polyvinyl chloride (PVC),
`
`VisIV™, polypropylene, and CR3 containers. Id. at col. 9, ll. 21-29. The
`
`specification also provides numerous suitable concentrations for the premixed
`
`concentrations, including the claimed concentration range of between about 0.005
`
`to about 50 μg/mL. Id. at col. 7, l. 44 – col. 8, l. 19.
`
`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 1-11 and 13 by combining the disclosure of the 2010 Precedex label, Ex.
`
`1007, in view of the Palmgren reference, Ex. 1017, with a reasonable expectation
`
`of success.
`
`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
`
`
`
`5
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 5
`
`
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`claims 1-11 and 13 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 1-5 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
`
`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
`
`which included pre-mix bags of 50 and 100 mL in addition to their accompanying
`
`20 mL glass vial concentrate solution, which was used either to make a diluted
`
`solution or could be used directly as a ready to use solution.
`
`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
`
`
`
`6
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`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 6
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`
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`expertise, and the materials I have reviewed.
`
`Il.
`
`INFORMATION CONSIDERED
`
`12.
`
`In forming my opinions,
`
`I have reviewed the ‘527 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 ‘527 PATENT
`
`A.
`
`Backgroundof the Technology
`
`i. History ofDexmedetomidine
`
`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, Il. 55-59. Dexmedetomidine ((S)-4-[ 1-(2,3-dimethylpheny])ethy]]-
`
`1H-imidazole), which is
`
`the S-enantiomer of medetomidine
`
`(4-[1-(2,3-
`
`dimethylphenyl)ethyl]|-7H-imidazole), has the following structure:
`
`rey 6
`
`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
`
`7
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`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC — Exhibit 1003 — Page 7
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`
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`dexmedetomidine, in 1988, Ex. 1005, col. 1, ll. 8-43.
`
`15. Administration of dexmedetomidine
`
`to a patient parenterally,
`
`including by intravenous bolus or infusion, intramuscular injection, intranasal and
`
`buccal, as well as oral routes was also disclosed in the prior art. Ex. 1002, ¶18. See
`
`Ex. 1004; Ex. 1005; Ex. 1021, Dyck et al., Anesthesiology 78:813-820 (1993); Ex.
`
`1022, Scheinin et al., Anesthesiology 78:1065-1075 (1993); Ex. 1023, Yuen, et al.,
`
`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 pharmaceutically
`
`acceptable salt thereof, to the patient. Ex. 1024, Venn et al., Anaesthesia 54:1136-
`
`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.
`
`Dexmedetomidine formulations for sedation were commercially available in the
`
`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
`
`
`
`8
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`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 8
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`
`
`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.
`
`1026, “Pharmaceutical dosage forms, parenteral medications,” edited by Kenneth
`
`E. Avis et al., 2nd Edition, p. 161 (1992). Typical formulation studies include
`
`storing, in various glass and plastic containers, prepared admixtures at a desired
`
`concentration of the active pharmaceutical ingredient. Id. at 162. Samples are
`
`periodically withdrawn from the containers as a function of time and evaluated for
`
`potency, pH, color and particulate matter. Id. The container in which essentially
`
`no potency change is observed, from the initial potency that is measured, is then
`
`
`
`9
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`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 9
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`
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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
`
`pharmaceutical products.” Id. at 3. Glass containers are generally classified
`
`according
`
`to
`
`their degree of chemical resistance by
`
`the United States
`
`Pharmacopeia. Id. at 7.
`
`2. Tonicity
`21. For solutions intended for parenteral administration or application to
`
`mucous membranes, it is well known in the art that patient discomfort (and even
`
`injury) is often minimized by adjusting the pharmaceutical solution to include a
`
`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
`
`osmotic pressure equal to that of the patient’s cells. Id. Consequently, the
`
`
`
`10
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`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 10
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`
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`intracellular volume stays constant because the osmotic pressure on the cell
`
`membrane due to the parenteral solution is equalized. Id. It is well known that a
`
`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,
`
`“The Tonicity-Volume Relations for Systems Containing Human Red Cells and
`
`the Chlorides of Monovalent Cations,” The Journal of General Physiology, 398
`
`(1949). Furthermore, it is known in the art that human red cells are least fragile in
`
`isotonic NaCl solutions. Id. For at least these reasons, 0.9% sodium chloride
`
`buffer solutions are typically chosen for parenteral solutions. Ex. 1029, p. 1469.
`
`3. The U.S. Food and Drug Administration requires
`stability studies
`
`22. Pharmaceutical formulation studies typically include investigations
`
`about how the quality of a drug substance or drug product varies with time under
`
`the influence of a variety of environmental factors, such as temperature, humidity,
`
`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,
`
`among other characteristics, the stability of all new pharmaceutical drug products.
`
`21 C.F.R. § 211.166. The testing program must be based on the same container-
`
`closure system in which the drug product is to be marketed and the results are used
`
`to determine the appropriate storage conditions and expiration dates of the drug
`
`
`
`11
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`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 11
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`
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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, “The Keys to RTU Parenterals,” Pharmaceutical Formulation &
`
`Quality, Vol. 11, No. 5, p. 40, September 2009. 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 (“Pacheco”), and esmolol hydrochloride, Ex. 1033, U.S. Pat.
`
`No. 6,310,094 (“Liu”).
`
`24. Historically, RTU medications were proposed as a way to standardize
`
`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
`
`also Ex. 1015, I. Giorgi et al., “Risk and pharmacoeconomic analyses of the
`
`injectable medication process in the paediatric and neonatal intensive care units,”
`
`International Journal for Quality in Health Care, Vol. 22, No. 3, 170-178 (2010)
`
`
`
`12
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`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 12
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`
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`(advocating that the most effective way to reduce microbial contamination and
`
`dilution error is use of ready to use solution) and Ex. 1034, P. Linden et al.,
`
`“Ready-to-use injection preparations versus conventional reconstituted admixtures:
`
`economic evaluation in a real-life setting,” PharmacoEconomics, Vol. 20, No. 8,
`
`529-536 (2002) (citing substantial cost savings in using RTU pharmaceutical
`
`products compared to conventional admixtures).
`
`Scope of the ‘527 Patent
`
`B.
`25. The ‘527 patent generally discloses premixed, or ready to use,
`
`pharmaceutical compositions of dexmedetomidine and methods of use of the
`
`premixed compositions for sedation. Ex. 1001, col. 2, ll. 3-9, col. 10, ll. 1-25. In
`
`particular, the specification discloses that suitable containers include glass vials,
`
`amploules, syringes, and plastic flexible containers, such as polyvinyl chloride
`
`(PVC), VisIV™, polypropylene, and CR3 containers. Id. at col. 9, ll. 21-29. The
`
`specification also discloses numerous suitable concentrations for the premixed
`
`concentrations, including the claimed concentration ranges of between about 0.005
`
`to about 50 μg/mL. Id. at col. 7, l. 44 – col. 8, l. 19.
`
`V. CLAIM CONSTRUCTION
`A. A Person of Ordinary Skill in the Art (POSA)
`I have been informed by counsel that construction of the terms of a
`26.
`
`patent claim is to be done from the point of view of a POSA at the time of the
`
`invention. For purposes of defining a POSA, I have assumed that the time of the
`13
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`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 13
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`invention is the date of filing of the ‘672 application, namely January 4, 2012.
`
`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, Pharm.D. or
`
`Ph.D. in Pharmacy (Pharmaceutics), Chemistry or Engineering with relevant
`
`experience in the field of drug development and formulation. With respect to
`
`clinical drug use, the POSA would have an M.D. with significant clinical
`
`experience in anesthesia or sedation and who has familiarity with the use of
`
`parenteral injection and/or familiarity with ready to use medications.
`
`B.
`28.
`
`Broadest Reasonable Interpretation
`I have been advised by counsel that in an inter partes review
`
`proceeding before the USPTO, like this one, a patent claim term is to receive the
`
`“broadest reasonable interpretation” in light of the specification of the patent in
`
`which it appears. I have also been advised that, at the same time, patent claim
`
`terms are generally given their ordinary and customary meanings as would be
`
`understood by a POSA.
`
`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
`
`
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`14
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`also be considered to the extent that it provides clarification.
`
`30.
`
`I have kept in mind these claim construction principles in the analysis
`
`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 ‘527
`
`patent.
`
`C. Claim Terms of the ‘527 Patent
`i. “Ready To Use”
`31. The ‘527 patent discloses an embodiment of the claimed methods as
`
`administering a “ready to use” liquid pharmaceutical 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
`
`32. The claims of the ‘527 patent describe the liquid pharmaceutical
`
`composition as being “ready to use” for parenteral administration. For example,
`
`independent claim 1 of the ‘527 patent reads:
`
`A method of providing sedation to a patient in need thereof, the
`method comprising administering to the patient an effective amount
`of
`a
`composition, wherein
`the
`composition
`comprises
`dexmedetomidine or a pharmaceutically acceptable salt thereof at a
`concentration of about 0.005 to about 50 μg/mL, wherein the
`composition is a ready to use liquid pharmaceutical composition for
`parenteral administration to the patient disposed within a sealed glass
`
`
`1 The dependent claims, in my opinion, do not introduce any terms that require
`
`construction.
`
`
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`15
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`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 15
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`container.
`
`Ex. 1001, col. 25, ll. 25-32.
`
`33. Also, the specification of the ‘527 patent discloses that the
`
`formulation of dexmedetomidine can be “ready to use.” In particular, the
`
`specification of the ‘527 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.
`
`Ex. 1001, at col. 3, ll. 59-65 (emphasis added).
`
`34. Additionally, the term “ready to use” is a well-known term of art in
`
`the medical and pharmaceutical industry. See, e.g., Ex. 1044, “Injectable
`
`medicines,” WHO Collaborating Centre
`
`for Pharmaceutical Pricing and
`
`Reimbursement Policies, http://whocc.goeg.at/Glossary/PreferredTerms
`
`(last
`
`visited August 9, 2016). It is my opinion that one of skill in the art would
`
`understand the term “ready to use” to mean “requiring no further dilution or
`
`reconstitution before transfer to an administration device.” Id.
`
`35. Based on these descriptions, and my understanding of how this term is
`
`used 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 no further dilution or reconstitution before administration
`16
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`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 16
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`
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`to a patient.
`
`ii. “Dexmedetomidine”
`‘527 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. 24-50.
`
`
`
`37. The specification of the ‘527 patent defines dexmedetomidine as a
`
`“substantially pure, optically active dextrorotary stereoisomer of medetomidine, as
`
`the free base or pharmaceutically acceptable salt.” Ex. 1001, col. 3, ll. 24-27.
`
`Therefore, it is my opinion that the broadest reasonable interpretation of
`
`“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 ‘527 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
`17
`
`
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 17
`
`
`
`embodiment within the scope of claims 1-11, and 13 of the ‘527 patent by
`
`combining the 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 arrive at an embodiment within the scope of
`
`claims 1-11 and 13 of the ‘527 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 1-11 and 13 of the ‘527 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
`Prior Art References
`1-11, 13 2010 Precedex Label (Ex. 1007) in view of
`Palmgren (Ex. 1017)
`
`§ 103(a)
`
`1
`
`2
`
`3
`
`§ 103(a)
`
`1-11, 13
`
`§ 103(a)
`
`1-11, 13
`
`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
`
`
`
`18
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 18
`
`
`
`Ground 35 U.S.C. Claims
`
`Prior Art References
`Documents (Ex. 1018)
`
`
`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 Perform the Invention of Claims 1-11 and 13 of the
`‘527 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 perform the method of claims 1-11, 13 of the
`
`‘527 patent if its teaching were considered in view of Palmgren, Ex. 1017.
`
`
`
`19
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 19
`
`
`
`i. Claim 1
`It is my opinion that the 2010 Precedex Label, in view of Palmgren,
`
`44.
`
`would have led a POSA to perform a method of parenterally administering a ready
`
`to use liquid pharmaceutical composition that comprises dexmedetomidine (or a
`
`pharmaceutically acceptable salt thereof) at a concentration of about about 0.005 to
`
`about 50 μg/ml disposed within a sealed glass container, as set forth in the claim
`
`chart below.
`
`45. A POSA would understand that the 2010 Precedex Label generally
`
`disclosed a method of parenterally administering PrecedexTM (dexmedetomidine
`
`hydrochloride) product for sedation of patients via intravenous infusion following
`
`dilution. Ex. 1007, Sec. 1.1. In particular, the 2010 Precedex Label taught
`
`administering a liquid pharmaceutical composition, the PrecedexTM Concentrate,
`
`containing dexmedetomidine at a concentration of 200 μg/2 mL (i.e., 100 μg/mL)
`
`that is disposed in a sealed glass container. Id. at Sec. 3, ll. 207-208.
`
`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 of 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-
`
`
`
`20
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 20
`
`
`
`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 concentration of about 0.005 to about 50
`
`μg/mL in 0.9% sodium chloride solution for parenteral 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 a solution of dexmedetomidine hydrochloride at a concentration
`
`of 4 μg/mL in 48 mL of 0.9% sodium chloride solution, which falls within that
`
`range. 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)
`
`
`
`21
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 21
`
`
`
`injection, at the provided, undiluted concentration of 100 μg/mL, directly from the
`
`glass vial. Ex. 1002, ¶¶ 43-44. In this broadest sense, then, the PrecedexTM
`
`Concentrate itself is “ready to use” without dilution. Id.
`
`49. 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.
`
`50. Thus, while the 2010 Precedex Label did not expressly disclose a
`
`ready to use or premixed solution at a concentration of about 0.005 to about 50
`
`µg/mL (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 1-11 and 13 for occasions when
`
`dilution, as further described below, is needed or desired.
`
`51. 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 Preced
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