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. IPR2016-01577
`Patent 8,242,158
`
`
`DECLARATION OF ALPASLAN YAMAN, PH.D.
`
`
`
`
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1003
`
`

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`TABLE OF CONTENTS
`INTRODUCTION ........................................................................................... 1
`
`I.
`
`II. QUALIFICATIONS & BACKGROUND ...................................................... 3
`
`III.
`
`INFORMATION CONSIDERED ................................................................... 3
`
`IV. THE ‘158 PATENT ......................................................................................... 4
`A.
`Background of the Technology ............................................................. 4
`i.
`History of Dexmedetomidine....................................................... 4
`ii.
`Formulation of Parenteral Drugs ................................................ 5
`iii.
`“Ready to Use” Formulations .................................................... 8
`Scope of the ‘158 Patent ........................................................................ 9
`
`B.
`
`V.
`
`CLAIM CONSTRUCTION ............................................................................ 9
`A. A Person of Ordinary Skill in the Art (POSA) ..................................... 9
`B.
`Broadest Reasonable Interpretation ....................................................10
`C.
`Claim Terms of the ‘158 Patent ..........................................................11
`i.
`“Ready To Use” ........................................................................11
`ii.
`“Dexmedetomidine” .................................................................13
`VI. PRIOR-ART REFERENCES DISCLOSE ALL OF THE ELEMENTS OF
`THE CLAIMS OF THE ‘158 PATENT ........................................................13
`
`A. A Person of Ordinary Skill in the Art Would Have Been
`Motivated to Make the Invention of Claims 1-4 of the ‘158
`Patent by the 2010 Precedex Label in View of Palmgren................... 15
`
`Claim 1 ......................................................................................17
`i.
`Claims 2-3 .................................................................................24
`ii.
`iii. Claim 4 ......................................................................................26
`
`
`
`i
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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page i
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`B. Ground 2: A Person of Ordinary Skill in the Art Would Have
`Been Motivated to Make the Invention of Claims 1-4 of the
`‘158 Patent by U.S. 6,716,867 in view of the 2010 Precedex
`Label and Palmgren .............................................................................27
`
`C. Ground 3: A Person of Ordinary Skill in the Art Would Have
`Been Motivated to Make the Invention of Claims 1-4 of the
`‘158 Patent by the 2010 Precedex Label in View of Giorgi,
`Eichhorn, Palmgren, and the Lavoisier Documents ............................31
`
`VII. CONCLUDING STATEMENTS ................................................................35
`
`ii
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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page ii
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`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. 8,242,158
`
`(“the ‘158 patent”), Ex. 1001, issued on August 14, 2012, and that the ‘158 patent
`
`issued from U.S. Patent Application Serial No. 13/343,672 (“the ‘672
`
`application”), Ex. 1008, filed on January 4, 2012.
`
`4.
`
`I have been asked by counsel for Amneal to explain the technical
`
`subject matter of the ‘158 patent and its background. I have also been asked to
`
`explain whether prior art discloses the compositions claimed in the ‘158 patent.
`
`My opinions are set forth below.
`
`5.
`
`Generally, the ‘158 patent disclosure and claims are directed to a
`
`
`
`1
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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 1
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`ready to use liquid pharmaceutical composition for parenteral administration to a
`
`subject which is comprised of dexmedetomidine (or a pharmaceutically acceptable
`
`salt) at a concentration of about 4 µg/mL and is contained within a sealed glass
`
`container. Ex. 1001, col. 26, ll. 4-8. The liquid pharmaceutical composition may
`
`further comprise sodium chloride at a concentration of between about 0.01 to about
`
`2.0 weight percent and may be formulated as a total volume of 20 mL, 50 mL, or
`
`100 mL. Id. at col. 26, ll. 9-18.
`
`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 1-4 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
`
`claims 1-4 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.
`
`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 1-4 by considering U.S. Patent No. 6,716,867 (“the ‘867 patent”), Ex. 1006,
`
`
`
`2
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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 2
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`in view of the 2010 Precedex Label, Ex. 1007, and Palmgren, Ex. 1017.
`
`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
`
`expertise, and the materials I have reviewed.
`
`III.
`
`INFORMATION CONSIDERED
`
`12.
`
`In forming my opinions, I have reviewed the ‘158 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.
`
`
`
`3
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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1003 – Page 3
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`IV. THE ‘158 PATENT
`
`A.
`
`Background of 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, 11. 55-59. Dexmedetomidine ((S)-4-[1—(2,3-dimethylphenyl)ethyl]—
`
`IH-imidazole), which is
`
`the S-enantiomer of medetomidine
`
`(4-[1-(2,3-
`
`dimethylphenyl)ethyl]—IH—imidazole), has the following structure:
`
`fir
`
`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 separated into two enantiomers, one of which was dexmedetomidine,
`
`in 1988, Ex. 1005, col. 1, 11. 8-43.
`
`15. Additionally, in 2004, the prior art disclosed methods of sedating a
`
`patient by administering dexmedetomidine, or a pharmaceutically acceptable salt
`
`thereof, to the patient. Ex. 1006, col. 1, 11. 10-13. Dexmedetomidine administration
`
`to a patient via parenteral (including intravenous infusion) and oral routes was also
`
`disclosed in the prior art at least as early as 1985. See Ex. 1004 and Ex. 1005.
`
`4
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`16.
`
`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
`17. Parenteral pharmaceutical formulations include a variety of active
`
`ingredients, which may be incorporated into liquids. A given formulation may
`
`require certain formulation or physiochemical parameters such as tonicity,
`
`particular storage material, and active ingredient stability, of which one with
`
`ordinary skill in the field of parenteral drug formulation would routinely select, test
`
`for and analyze. Ex. 1028, “The Keys to RTU Parenterals,” Pharmaceutical
`
`Formulation & Quality, Vol. 11, No. 5, p. 40, September 2009, pp. 2-4.
`
`1. Storage material studies
`18. A pharmaceutical producer has a responsibility to be 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
`
`
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`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 recommended
`
`for clinical use. Id.
`
`19.
`
`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.
`
`
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`2. Tonicity
`20. 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. Ex. 1029,
`
`“Parenteral Preparations,” edited by Kenneth Avis, Chapter 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 intracellular volume of cells in the patient 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, and for these
`
`reasons, such a buffer system is typically chosen for parenteral solutions. Id.
`
`3. The U.S. Food and Drug Administration requires
`stability studies
`
`21. 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.
`
`
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`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
`
`product. Id.
`
`iii. “Ready to Use” Formulations
`It is well known in the art that some drug products intended for
`
`22.
`
`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
`
`(“Pacheco”), and esmolol hydrochloride, Ex. 1033, U.S. Pat. No. 6,310,094
`
`(“Liu”).
`
`23. Historically, RTU medications were proposed as a way to standardize
`
`drug preparation and improve medication safety. Ex. 1020, Gerlach, A., 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, Giorgi, I., et al., “Risk and pharmacoeconomic analyses of the
`
`
`
`8
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`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)
`
`(advocating that the most effective way to reduce microbial contamination and
`
`dilution error is use of ready to use solution) and Ex. 1034, Linden, P., 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 ‘158 Patent
`
`B.
`24. The ‘158 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, amploules, 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
`
`suitable concentrations for the premixed concentrations, including 4 μg/mL. Id. at
`
`col. 7, l. 64 – col. 8, l. 16.
`
`V. CLAIM CONSTRUCTION
`A. A Person of Ordinary Skill in the Art (POSA)
`I have been informed that construction of the terms of a patent claim
`25.
`
`is to be done from the point of view of a POSA at the time of the invention. For
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`purposes of defining a POSA, I have assumed that the time of the invention is the
`
`date of filing of the ‘672 application, namely January 4, 2012.
`
`26.
`
`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
`
`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
`
`who has familiarity with the use of parenteral injection and/or familiarity with
`
`ready to use medications.
`
`B.
`27.
`
`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.
`
`28.
`
`I have also been advised by counsel that patent claims are to be
`
`construed first in the context of the specification, including the plain meaning of
`
`
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`the claims, of the patent. The prosecution history of the patent should also be
`
`considered to the extent that it provides clarification.
`
`29.
`
`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 ‘158
`
`patent.
`
`C. Claim Terms of the ‘158 Patent
`i. “Ready To Use”
`‘158 patent discloses an embodiment of
`30. The
`
`the claimed
`
`pharmaceutical composition as being 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
`
`31. The claims of
`
`the ‘158 patent describe
`
`the claimed
`
`liquid
`
`pharmaceutical composition as being “ready to use” for parenteral administration.
`
`For example, independent claim 1 of the ‘158 patent reads:
`
`A ready to use liquid pharmaceutical composition for parenteral
`administration to a subject, comprising dexmedetomidine or a
`pharmaceutically acceptable salt thereof at a concentration of about 4
`μg/mL disposed within a sealed glass container.
`
`
`
`1 The dependent claims, in my opinion, do not introduce any terms that require
`
`construction.
`
`
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`Ex. 1001, col. 26, ll. 4-8.
`
`32. Also, the specification of the ‘158 patent discloses that the
`
`formulation of dexmedetomidine can be “ready to use.” In particular, the
`
`specification of the ’158 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. 56-63 (emphasis added).
`
`33. 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.
`
`34. 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
`
`to a patient.
`
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`ii. “Dexmedetomidine”
`‘158 patent discloses an embodiment of
`35. 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. 21-45.
`
`
`
`36. The specification of the ‘158 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. 21-24.
`
`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 ‘158 PATENT
`
`37.
`
`In my opinion, and as set forth in the chart below, a POSA would
`
`have had reason to, and would have had a reasonable expectation of success to,
`
`arrive at an embodiment within the scope of claims 1-4 of the ‘158 patent by
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`combining the disclosure of the 2010 Precedex label, Ex. 1007, with the disclosure
`
`of the Palmgren reference, Ex. 1017 (“Ground 1”).
`
`38.
`
`It is also my opinion that a POSA would have had reason to, and
`
`would have had a reasonable expectation of success to, arrive at an embodiment
`
`within the scope of claims 1-4 of the ‘158 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”).
`
`39. Finally, in my opinion, a POSA would have had reason to, and would
`
`have had a reasonable expectation of success to, arrive at an embodiment within
`
`the scope of claims 1-4 of the ‘158 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
`1
`
`35 U.S.C.
`§ 103(a)
`
`Claims
`1-4
`
`2
`
`3
`
`§ 103(a)
`
`§ 103(a)
`
`1-4
`
`1-4
`
`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)
`
`
`40.
`
`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
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`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.
`
`41. 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 as follows: the
`
`2010 Precedex Label, Ex. 1007, was published September of 2010; the Eichhorn
`
`reference, Ex. 1016, was published in Spring 2010 in a Newsletter of the Official
`
`Journal of Anesthesia Patient Safety Foundation; the Palmgren reference, Ex.
`
`1017, was published June 29, 2006 in the European Journal of Pharmaceutics and
`
`Biopharmaceutics; the Product sheet associated with the Lavoisier Documents, Ex.
`
`1018, has a revision date of June 2009; and the ‘867 patent, Ex. 1006, has a
`
`priority date of December 4, 1998. Thus, it is my understanding that each cited
`
`reference qualifies as prior art against the ‘158 patent 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 1-4 of the ‘158 Patent
`by the 2010 Precedex Label in View of Palmgren
`
`42.
`
`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
`
`
`
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`1-4 of the ‘ 158 patent in View of Palmgren, Ex- 1017.
`
`Claim Language
`
`U.S. Patent No. 6,716,867 and The Precedex
`2010 Label
`
`A ready to use liquid
`pharmaceutical composition
`for parenteral administration
`to a subject, comprising
`dexmedetomidine or a
`phannaceutically acceptable
`salt thereof at a concentration
`
`of about 4 /mL
`
`U.S. 6,716,867, Ex. 1006 col. 1, 11. 12-14 and
`28-31; col. 3, 11. 38-42; col. 5, 1. 7; col. 5, ll. 21-
`28; Example 1, col. 5, 11. 53-58.
`
`Precedex 2010 Label, Ex. 1007, Sec. 2.2; Sec.
`2.6, 11, 203-206; Sec. 3, 11, 207-208.
`
`disposed within a sealed glass Precedex 2010 Label, Ex. 1007 Sections 3 and
`container.
`1 6.
`
`Palmgren, Ex. 1017, p. 370, 1113-4; p. 374, right
`col., 112; p. 374, Table 4; p. 374-376.
`
`The ready to use liquid
`pharmaceutical composition
`of claim 1,
`
`See claim 1.
`
`further comprising sodium
`chloride at a concentration of
`
`U.S. 6,716,867, Ex. 1006 Example 1, col. 5, ll.
`53-55.
`
`between about 0.01 and about
`
`2.0 wei o
`
`t ercent.
`
`The ready to use liquid
`pharmaceutical composition
`of claim 2,
`
`wherein the sodium chloride
`is present at a concentration
`of about 0.9 Wei
`t ercent
`
`See claims 1 and 2.
`
`U.S. 6,716,867, Ex. 1006 Example 1, col. 5, 11.
`53-55.
`
`The ready to use liquid
`pharmaceutical composition
`of claim 1,
`
`See claim 1.
`
`U.S. 6,716,867, Ex. 1006 at col. 5, 11. 21-28.
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`Claim Language
`
`U.S. Patent No. 6,716,867 and The Precedex
`2010 Label
`
`and 100 mL.
`
`formulated as a total volume
`
`selected from the group
`consisting of 20 mL, 50 mL
`
`Precedex 2010 Label, Ex. 1007 Sec 2.2; Sec. 2.4.
`
`i. Claim 1
`
`43.
`
`It is my opinion that the 2010 Precedex Label, in View of Palmgren,
`
`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) at a concentration of about 4 ug/mL
`
`disposed within a sealed glass container.
`
`44. A POSA would understand that the 2010 Precedex Label generally
`
`disclosed a Precedexm (dexmedetomidine hydrochloride) product for parenteral
`
`administration via intravenous infusion following dilution. Ex. 1007 at 1.
`
`In
`
`particular, the 2010 Precedex Label taught a liquid pharmaceutical composition,
`
`the Precedexm Concentrate, containing dexmedetomidine at a concentration of
`
`200 mcg/2 mL (i.e., 100 mcg/mL) that is disposed in a sealed glass container. Id. at
`
`Sec. 3, 11. 207-208.
`
`45-
`
`The 2010 Precedex Label
`
`f11rther disclosed the preparation of a
`
`solution containing the Precedexm Concentrate for parenteral administration via
`
`intravenous infusion by diluting 2 mL the Precedexm Concentrate in 48 mL of
`
`0.9% sodium chloride injection to a total of 50 mL. Id. at Sec. 2.4, 11. 175-184. The
`
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`2010 Precedex Label disclosed that the diluted 4 mcg/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).
`
`46.
`
`In my opinion, preparing a “ready
`
`to use” solution of
`
`dexmedetomidine hydrochloride at a concentration of 4 mcg/mL in 48 mL of 0.9%
`
`sodium chloride solution, for parenteral administration to a patient via intravenous
`
`infusion would thus be within this routine 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 “ready to use.” 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.
`
`47. 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)
`
`
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`injection, at the provided, undiluted concentration of 100 mcg/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.
`
`48. 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,
`
`¶ 46.
`
`49. Thus, while the 2010 Precedex Label did not expressly disclose a
`
`ready to use or premixed solution at a concentration of 4 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 1-4 for occasions when dilution, as further described below, is
`
`needed or desired.
`
`50. 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.
`
`51. First, the 2010 Precedex Label only disclosed the use of a glass vial as
`
`the means for storage and handling of the PrecedexTM Concentrate. Id. at Sec. 3
`
`