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 JAMES GORDON CAIN, MD, MBA, FAAP
`
`
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1002
`
`

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`TABLE OF CONTENTS
`
`INTRODUCTION ............................................................................................ 1
`
`
`I.
`
`II. QUALIFICATIONS & BACKGROUND ........................................................ 2
`
`III.
`
`INFORMATION CONSIDERED .................................................................... 3
`
`IV. THE ‘527 PATENT .......................................................................................... 4
`
`A.
`
`B.
`
`State of the Art ...................................................................................... 4
`
`Scope of the ‘527 Patent ........................................................................ 6
`
`V.
`
`CLAIM CONSTRUCTION ............................................................................ 7
`
`A. A Person of Ordinary Skill in the Art (POSA) ..................................... 7
`
`B.
`
`C.
`
`Broadest Reasonable Interpretation ...................................................... 7
`
`Claim Terms of the ‘527 Patent ............................................................ 8
`
`i.
`
`ii.
`
`“Ready To Use” .......................................................................... 8
`
`“Dexmedetomidine” .................................................................10
`
`VI. THE CLAIMED INVENTION IS WELL-KNOWN IN THE ART .............11
`
`A. A POSA Would Have Been Motivated to Make the
`Invention of Claims 1-11 and 13 of the ‘527 by the 2010
`Precedex Label in View of Palmgren .................................................. 11
`
`i.
`
`ii.
`
`Claim 1 ......................................................................................11
`
`Claims 2-5 .................................................................................17
`
`iii. Claims 6-7 .................................................................................18
`
`iv.
`
`v.
`
`Claim 8 ......................................................................................19
`
`Claim 9 ......................................................................................19
`
`
`
`i
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`vi.
`
`Claim 10 ....................................................................................19
`
`vii. Claim 11 ....................................................................................20
`
`viii. Claim 13 ....................................................................................20
`
`B. A POSA Would Have Been Motivated to Make the
`Invention of Claims 1-11 and 13 of the ‘527 by U.S. Patent
`No. 6,716,867 the 2010 Precedex Label and Palmgren ...................... 21
`
`C. A POSA Would Have Been Motivated to Make the
`Invention of Claims 1-11 and 13 of the ‘527 by 2010
`Precedex Label in view of Giorgi, Eichhorn, Palmgren, and
`the Lavoisier Documents ..................................................................... 26
`
`VII. CONCLUDING STATEMENTS ..................................................................27
`
`ii
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`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1002 – Page ii
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`I.
`
`INTRODUCTION
`
`I, James Gordon Cain, MD, MBA, FAAP, 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. Application 13/678,148 (Ex. 1054, “the ’148 application”) filed
`
`on November 15, 2012. The ’148 application was a continuation of U.S.
`
`Application No. 13/541,524 (Ex. 1048, “the ’524 application”), which was filed on
`
`July 3, 2012, and issued as U.S. Patent No. 8,338,470 (Ex. 1053; “the ’470
`
`patent”). The ’524 application, in turn, was a continuation of the U.S. Application
`
`No. 13/343,672 (Ex. 1006), which was filed on January 4, 2012, and issued as U.S.
`
`Patent No. 8,242,158 (Ex. 1047; “the ’158 patent”). Accordingly, the earliest
`
`
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`1
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`possible effective filing date of the ‘470 patent is January 4, 2012.
`
`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 compositions claimed in the ‘527 patent.
`
`My opinions are set forth below.
`
`II. QUALIFICATIONS & BACKGROUND
`5. 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 clinical
`
`anesthesia and sedation, with significant experience with ready-to-use medications.
`
`In particular, I am knowledgeable about the use of dexmedetomidine for sedation
`
`purposes. For the past 24 years, I have accumulated significant training and
`
`experience in these and related fields.
`
`6.
`
`In 1987, I received a B.S. in Biology from the University of Scranton.
`
`In 1992, I received my M.D. from the School of Medicine at the University of
`
`Pittsburgh. From 1992-1993, I attended Yale University as a Primary-Care
`
`Internal Medicine intern. Through the Massachusetts General Hospital at Harvard
`
`University, I completed my Anesthesiology Residency from 1993-1996 and
`
`Critical Care Medicine Fellowship in 1997 as well as my Adult and Pediatric
`
`Cardiac Anesthesiology Fellowship from 1995-1996 at the Massachusetts General
`
`Hospital and Boston Children’s Hospital.
`
`
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`7.
`
`Subsequent to my postgraduate work, I held the position of Instructor
`
`at Harvard University in 1998 and as Assistant and Associate Professor at West
`
`Virginia University from 1998-2005. From 2005 to the present, I have held the
`
`position as Visiting Associate Professor at the University of Pittsburgh.
`
`8.
`
`In addition to my academic appointments, I am currently the Director
`
`of Perioperative Medical Services, Transplant Anesthesiology and Trauma
`
`Anesthesiology as well as the Chief Charge Anesthesiologist at the Children’s
`
`Hospital of Pittsburgh of UPMC. I have been employed as an anesthesiologist
`
`and/or intensivist since 1996 in a number of additional roles, as set forth in my CV,
`
`Ex. A.
`
`9.
`
`Further, from 2000 to the present, I have gained a significant amount
`
`of experience in the field of sedation by studying teaching the effect of
`
`dexmedetomidine on patients. In particular, I am published in the field of
`
`administration of dexmedetomidine and have given a multitude of invited lectures,
`
`as enumerated in my CV, Ex. A.
`
`10.
`
` I am not an attorney or patent agent and can offer no legal opinions.
`
`My opinions here are based on my professional experience, expertise, and the
`
`materials I have reviewed.
`
`III.
`
`INFORMATION CONSIDERED
`
`11.
`
`In forming my opinions, I have reviewed the ‘527 patent, its
`
`
`
`3
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`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.
`
`State of the Art
`
`12.
`
`The medical field has recognized dexmedetomidine as a general
`
`sedation/analgesic agent since 1988. Ex- 1005, US. 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]-1H-imidazole, has the following structure:
`
`13.
`
`Ht”!
`
`Dexmedetomidine
`
`medetomidlne
`
`Ex. 1001, col. 3, 11. 23-50.
`
`14. Medetornidine was first disclosed in 1985, Ex. 1004, US. Pat. No.
`
`4,544,664 (“the ‘664 patent”), col. 19, l. 47 — col. 20, l. 38, and separated into two
`
`enantiomers, one of which was dexmedetomidine, in 1988, Ex. 1005, col. 1, ll. 8-
`
`43.
`
`15. Additionally, no later than 1999 when dexmedetomidine entered the
`
`4
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`U.S. market, articles such as Venn et al., Anaesthesia 54:1136-1142 (1999), Ex.
`
`1024, established that the prior art disclosed methods of sedating a patient while in
`
`an intensive care unit by administering dexmedetomidine, or a pharmaceutically
`
`acceptable salt thereof, to the patient.
`
`16. Thereafter, in 2004, U.S. Patent No. 6,716,867 likewise disclosed
`
`methods of sedating a patient. Ex. 1006, U.S. Pat. No. 6,716,867 (“the ‘867
`
`patent”). The ‘867 patent was issued on April 6, 2004, and therefore constitutes
`
`prior art under the relevant section of the patent code as I have been informed by
`
`counsel.
`
`17. The ‘867 patent specifically relates to a method of sedating a patient
`
`while in the intensive care unit by administering dexmedetomidine or a
`
`pharmaceutically acceptable salt thereof to the patient. Ex. 1006, abstract. The ‘867
`
`patent describes the use of dexmedetomidine that is diluted in 0.9% sodium
`
`chloride solution which is then ready for administration to patients. Id. at col. 7, ll.
`
`60-65.
`
`18. Administration of dexmedetomidine to a patient via parenteral
`
`(including intravenous infusion and intramuscular, Ex. 1021, Dyck et al.,
`
`Anesthesiology 78:813-820 (1993); Ex. 1022, Scheinin, et al., Anesthesiology
`
`78:1065-1075 (1993)), transmucosal (including buccal and intranasal, Ex. 1023,
`
`Yuen et al., Anesth. Analg. 105:374-80 (2007)) and oral routes was within the
`
`
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`5
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`scope of the prior art. See also Ex. 1004 and Ex. 1005.
`
`19.
`
`In the prior art, dexmedetomidine was provided as a concentrate that
`
`directed the user to dilute 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”).
`
`20. The use of premix formulations of parental medications, particularly
`
`those for use in an intensive care unit setting was also well known prior to the
`
`filing date of the Patents-in-Suit. For example, Gerlach, Ex. 1020, proposes the use
`
`of standardized drug preparations to improve medication safety in the ICU. See
`
`also Giorgi, Ex. 1015 (most effective way to reduce microbial contamination in
`
`ICU setting is use of ready-to-use solution). Thus, from at least these prior art
`
`references, one of ordinary skill in the art would have been well aware of the
`
`properties of dexmedetomidine and the benefits of ready to use medications.
`
`Scope of the ‘527 Patent
`
`B.
`21. Generally, the ‘527 patent disclosure and claims are directed relates to
`
`premixed pharmaceutical compositions of dexmedetomidine and methods 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),
`
`
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`VisIV™, polypropylene containers, and CR3 containers,. Id., col. 9, ll. 21–29. The
`
`specification also provides numerous suitable concentrations for the premixed
`
`concentrations, including the claimed concentration ranges of between about 0.005
`
`to about 50 μg/mL. Id., 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 that construction of the terms of a patent claim
`22.
`
`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 invention is the
`
`date of filing of the ‘672 application, namely January 4, 2012.
`
`23.
`
`In formulating my opinions, I have relied upon my review of the
`
`references cited, my experience in the relevant art, and also considered the
`
`viewpoint of a POSA. In my opinion, the POSA at the time of invention would
`
`have held an advanced degree, such as a Ph.D. or MD in the field of drug
`
`development and formulation, or in the alternative would have significant clinical
`
`experience in anesthesia or sedation and would have familiarity with the use of
`
`parenteral injection and/or familiarity with ready-to-use medications, as of January
`
`4, 2012.
`
`B.
`24.
`
`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
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`“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.
`
`25.
`
`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
`
`the claims, of the patent. The prosecution history of the patent should also be
`
`considered to the extent that it provides clarification.
`
`26.
`
`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”
`‘527 patent discloses an embodiment of
`27. 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
`
`1 The dependent claims, in my opinion, do not introduce any terms that require
`
`construction.
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`28. The claims of
`
`the ‘527 patent describe
`
`the claimed
`
`liquid
`
`pharmaceutical composition as being “ready to use” for parenteral administration.
`
`For example, independent claim 1 of the ‘527 patent reads:
`
`A method for 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
`
`container.
`
`Ex. 1001, col. 26, ll. 25-34.
`
`29. 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
`
`
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`removing the compositions from a sealed container or vessel.
`
`
`Ex. 1001, at col. 3, ll. 59-65 (emphasis added).
`
`30. 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.
`
`31. 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.
`
`ii. “Dexmedetomidine”
`‘527 patent discloses an embodiment of
`32. 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:
`
`
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`Ex. 1001, col. 3, ll. 24-50.
`
`
`
`33. 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. 24-29.
`
`34. 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. THE CLAIMED INVENTION IS WELL-KNOWN IN THE ART
`A. A POSA Would Have Been Motivated to Make the Invention of
`Claims 1-11 and 13 of the ‘527 by the 2010 Precedex Label in
`View of Palmgren
`
`35.
`
`I have been asked to opine whether the 2010 Precedex Label would
`
`have motivated a POSA to make the invention of claims 1-11 and 13 of the ‘527
`
`patent in view of Palmgren.
`
`i. Claim 1
`It is my opinion that a POSA would be motivated by the prior art to
`
`36.
`
`provide sedation to a patient in need thereof by administering to the patient an
`
`
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`11
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`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, and wherein the composition is a ready to use
`
`liquid pharmaceutical composition for parenteral administration to the patient
`
`disposed within a sealed glass container.
`
`37. First, the method of providing sedation to a patient in need by
`
`administering an effective amount dexmedetomidine parenterally was well known
`
`to a POSA at the time of invention.
`
`38. For example, the 2010 Precedex Label disclosed a method of
`
`providing “sedation of initially intubated and mechanically ventilated patients
`
`during treatment in an intensive care setting.” Ex. 1007, Sec 1.1. The
`
`administration of dexmedetomidine has been a routine method for providing
`
`sedation to a patient since 1999. Ex. 1024.
`
`39. Further, it is my opinion that in view of the routine nature of medical
`
`practice to choose the appropriate amount and concentration of drug to be
`
`administered under particular set of circumstances, it would have been obvious for
`
`a POSA to prepare a ready to use solution of dexmedetomidine hydrochloride at a
`
`concentration of about 0.005 to about 50 μg/mL.
`
`40. For example, the 2010 Precedex Label directed a POSA to prepare a 4
`
`μg/mL solution of Precedex for parenteral administration via intravenous infusion
`
`
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`by diluting 2 mL of Precedex in 48 mL of 0.9% sodium chloride injection to a total
`
`of 50 mL.
`
`41. Additionally, in my experience, dosages in “ready to use” form are
`
`commonly used and have been for a number of decades.
`
`42. With respect to the concept of “ready to use,” I understand that during
`
`prosecution of the related ‘524 application, Applicants submitted arguments to
`
`overcome an obviousness rejection over the Precedex Draft Label. Ex. 1049,
`
`Office Action Response, mailed Sept. 17, 2012, U.S. Application No. 13/541,524.
`
`43. Specifically, the applicants argued that the Precedex Label failed to
`
`suggest or describe a premixture composition comprising about 0.005 to about 50
`
`μg/mL of dexmedetomidine disposed within a sealed glass container that is ready
`
`to use without dilution. Id. at p. 5.
`
`44. The applicants argued
`
`that “upon withdrawing
`
`the claimed
`
`composition from a sealed glass container, an artisan of ordinary skill can
`
`administer the composition directly to a subject” whereas the Precedex Label
`
`composition would be “not suitable for administering to a patient upon
`
`withdrawing the composition from a sealed container.” Id. at p. 6.
`
`45.
`
`In my opinion, the undiluted Precedex® solution disclosed in the 2010
`
`Label is ready to use for parenteral administration to a patient in some
`
`circumstances.
`
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`46. Based on my experience, dexmedetomidine is routinely administered
`
`parentally (primarily intramuscularly) and transmucosally to patients in the
`
`undiluted concentration of 100 mcg/mL directly from the vial as described in the
`
`2010 Precedex Label and demonstrates successful results. For example, undiluted
`
`intranasal administration has become a prime method of sedation for pediatric
`
`patients at the Children’s Hospital of Pittsburgh.
`
`47.
`
`In fact, as part of my usual practice, I, and our sedation team in
`
`general, administer PrecedexTM to patients at the provided, undiluted concentration
`
`of 100 μg/mL, directly from the glass vial. In my opinion, the undiluted
`
`concentration of PrecedexTM, without dilution, is ready to use, just as effective as
`
`the diluted formulation and the preferred concentration for intramuscular and
`
`transmucosal administration. This 100 mcg/cc concentration of ready to use
`
`dexmedetomidine is typically used for preoperative premedication and procedural
`
`sedation either as a solo agent or an adjunct with medications such as midazolam
`
`and ketamine. See also Ex. 1039, G. DiSilvio, M. Jacoby, D. Weiner, A.
`
`Broussard, P. Callahan, and J. Cain, “Intranasal Dexmedetomidine & Midazolam:
`
`A Novel Sedation Technique for Infant PFT,” Society for Pediatric Anesthesia,
`
`Phoenix, Arizona (March 2015).
`
`48. Furthermore, and in contrast to some medications which require
`
`central venous administration unless diluted (e.g. dopamine, potassium and
`
`
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`parenteral nutrition), insofar as I can ascertain there is no documented harm in
`
`administration of intravenous dexmedetomidine at 100mcg/ml other than the
`
`inconvenience of its relatively small volume.
`
`49. Dexmedetomidine is also routinely administered in the diluted
`
`concentration of 4 mcg/mL by following the dilution instructions set forth by the
`
`1999 Precedex package insert and the 2010 Precedex Label. As noted above, the
`
`2010 Precedex Label directed a POSA to prepare a 4 μg/mL solution of Precedex
`
`for parenteral administration via intravenous infusion by diluting 2 mL of Precedex
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`in 48 mL of 0.9% sodium chloride injection to a total of 50 mL.
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`50. Differential dilution is routine and necessary in medical practice in
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`order to tailor the appropriate amount and concentration of drug to be administered
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`under particular sets of circumstances, such as for pediatric patients, to maintain
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`osmolality, to avoid phlebitis and/or to avoid fluid overload. See Ex. 1040, Neu et
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`al., Crit. Care Med. 10:610-12 (1982); Ex. 1041, Potts et al., Pediatrics 113:59-62
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`(2004); Ex. 1042, Merry et al., Pediatric Anesthesia 21:743-753 (2011); Ex. 1043,
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`Rodriguez-Gonzalez et al., J. Am. Med. Info. Assoc. 1:72-78 (2012).
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`Additionally, many locations, including Children’s Hospital of Pittsburgh, have
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`discontinued nearly all ICU bedside differential dilutional preparations and moved
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`them to sterile preparation by pharmacy. See Ex. 1038.
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`51.
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`In fact, prior to January 4, 2012, I asked our pharmacy to prepare 10
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`mL premixed syringes of dexmedetomidine at a diluted concentration of 4 mcg/mL
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`for use as an anesthetic. Ex. 1035.
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`52. Since 2005 our pharmacy has been preparing these syringes in a
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`sterile environment. They determined that per their review of literature and
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`customary treatment of other medications they routinely dilute, that a shelf life of 7
`
`days was acceptable. I am unaware of any adverse events attributable to this
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`practice since it began.
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`53. Given the routine use and general acceptance of “ready to use” in the
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`industry, and as shown in the prior art, a POSA would have been motivated to
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`create an embodiment that falls within the scope of claims 1-11 and 13 based on
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`available prior art.
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`54. Finally, in the Declaration of Dr. Yaman, which I have reviewed, he
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`states that as evidenced by Palmgren, it was well known in the art that certain
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`drugs, including medetomidine, interact with plastics found in infusion bags and
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`intravenous tubing, which can lead to drug loss in treatment failure, and thus a
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`POSA would have selected glass as the preferred container. Ex. 1017, p. 370. Ex.
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`1003, ¶52.
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`55. Therefore, it is my opinion that a POSA would have been motivated
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`to parenterally administer a
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`ready-to-use solution of dexmedetomidine
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`hydrochloride at a concentration of 4 μg/mL (or any other appropriate
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`concentration) that is disposed within a sealed glass container.
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`ii. Claims 2-5
`I understand that Claims 2-5 each depend from claim 1 and further
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`56.
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`recite narrower concentration ranges of the dexmedetomidine or pharmaceutically
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`acceptable salt
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`thereof. Claim 2 recites
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`that “the dexmedetomidine or
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`pharmaceutically acceptable salt thereof is at a concentration of about 0.05 to about
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`15 μg/mL;” claim 3 recites that “the dexmedetomidine or pharmaceutically
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`acceptable salt thereof is at a concentration of about 0.5 to about 10 μg/mL;” and
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`claim 4 recites that “the dexmedetomidine or pharmaceutically acceptable salt
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`thereof is at a concentration of about 1 to about 7 μg/mL;” and claim 5 recites that
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`“the dexmedetomidine or pharmaceutically acceptable salt thereof is at a
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`concentration of about 4 μg/mL.”
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`57. As I noted above, the Precedex 2010 Label directed a POSA to
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`prepare a 4 mcg/mL [i.e., 4 μg/mL]) solution of Precedex® for administration to
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`patients, a concentration encompassed by the ranges recited in claims 2 -5 of
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`the ’527 patent. (Ex. 1007, Sec. 2.4.)
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`58. And because dilution is routine and necessary in medical practice to
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`tailor the appropriate amount and concentration of drug to be administered under
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`particular sets of circumstances, it would have been obvious to a POSA to prepare
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`a ready-to-use solution of dexmedetomidine hydrochloride at a concentration of 4
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`
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`µg/mL, for parenteral administration to a patient, e.g., via intravenous infusion,
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`because the 2010 Precedex Label directed a POSA to do so. Ex. 1007, Sec. 11, ll.
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`457-458.
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`59. Accordingly, the 2010 Precedex Label disclosed all of the added
`
`features of claims 2-5.
`
`iii. Claims 6-7
`I understand that claim 6 depends from claim 1 and recites that “the
`
`60.
`
`composition is administered perioperatively.” Claim 7 depends from claim 6 and
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`recites that “the composition is administered before or after surgery.”
`
`61. The Precedex 2010 Label discloses in Section 1.2 that “Precedex is
`
`indicated for sedation of non-intubated patients prior to and/or during surgical and
`
`other procedures.” Exhibit 1007, Sec. 1.2 (emphasis added).
`
`62. Based on my experience, a POSA would understand that perioperative
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`administration recited in claim 6 comprises administering Precedex before, during,
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`or after surgery. Ex. 1061.
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`63. A POSA would also understand that administration can occur to a
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`patient in an intensive care unit. Ex. 1024; Ex. 1061.
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`64. Accordingly, the 2010 Precedex Label also discloses all of the added
`
`features of claim 6 and claim 7. Thus, the added limitations do not overcome the
`
`obviousness established for claim 1 over the Precedex label and Palmgren.
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`
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`iv. Claim 8
`I understand that claim 8 depends from claim 1, and recites that “the
`
`65.
`
`composition is administered to the patient in an intensive care unit.”
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`66.
`
`In numerous places, the 2010 Precedex Label discloses that Precedex
`
`is indicated for treatment “in an intensive care setting.” See, e.g., Ex. 1007, 1.1, ll.
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`144-149.
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`67. Accordingly, the 2010 Precedex Label also discloses all of the added
`
`features of claim 8, and the added limitations do not overcome the obviousness
`
`established for claim 1 over the Precedex label and Palmgren.
`
`v. Claim 9
`I understand that claim 9 depends from claim 1, and recites that “the
`
`68.
`
`patient is non-ventilated or intubated.”
`
`69. The Precedex 2010 Label discloses in Section 1.1 that “Precedex has
`
`been continuously infused in mechanically ventilated patients prior to extubation,
`
`during extubation, and postextubation.” Ex. 1007, 1.1, ll. 148,149.
`
`70. Accordingly, the 2010 Precedex Label also discloses all of the added
`
`features of claim 9.
`
`vi. Claim 10
`I understand that claim 10 depends from claim 1 and recites that “the
`
`71.
`
`patient is critically ill.”
`
`72. The 2010 Precedex Label discloses that Precedex is used in “an
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`intensive care setting.” Regardless of the meaning of “critically ill”, a person
`
`having ordinary skill in the art would understand that an individual that is
`
`“critically ill” encompasses the type of illness that may be treated in an intensive
`
`care setting.
`
`73. Further, it was known in the art at the time of filing that
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`“[d]exmedetomidine is a sedative with a unique mechanism of action that became
`
`available in the United States in 1999 for sedation of critically ill patients.” Ex.
`
`1020, Gerlach at 2 (emphasis added).
`
`74. Accordingly, the 2010 Precedex Label, by itself or in combination
`
`with Gerlach, also discloses all of the added features of claim 10.
`
`vii. Claim 11
`I understand that claim 11 depends from claim 1 and recites that “the
`
`75.
`
`composition is administered by intravenous infusion.”
`
`76. The 2010 Precedex Label discloses in multiple sections, including
`
`Section 17, that “Precedex is indicated for short-term intravenous sedation.”
`
`Accordingly, the 2010 Precedex Label also discloses all of the added features of
`
`claim 11, and the added limitations do not overcome the obviousness established
`
`for claim 1 over the Precedex label and Palmgren.
`
`viii. Claim 1