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`UTILITY
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`PATENT APPLICATION
`
`077350.0355
`Atrmexaocke'va _
`First In ventor
`Chowdhury et al.
`
`TRANSMITTAL
`
`We
`
`Dexmedelomidine Premix Formulation
`
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`
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`190
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`375
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`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLc — Exhibit 1048 — Page 2
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`

`PTO/SB/14 (11·08)
`Approved for use through 01131/2014. OMB 0651·0032
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`Application Data Sheet 37 CFR 1.76
`
`Attorney Docket Number
`
`077350.0355
`
`Application Number
`
`Title of Invention I
`
`DEXMEDETOMIDINE PREMIX FORMULATION
`
`The application data sheet is part of the provisional or nonprovisional application for which it is being submitted. The following form contains the
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`r
`.pp 1can t I f
`A
`f
`n orma ion:
`Annlicant 1
`Applicant Authority @Inventor I QLegal Representative under 35 U.S.C. 117
`Middle Name
`Prefix Given Name
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`
`Roychowd h ury
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`Address 1
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`100 Marin Center Dr., Apt. 63
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`City
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`94903
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`I CA
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`A
`Cedergren
`Robert
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`310 Cypress Lane
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`EFS Web 2.2.3
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`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1048 – Page 3
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`PTO/5811401418)
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`0773500355
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`DEXMEDETOMIDINE PREMIX FORMULATION
`
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`Remote :Em'a‘ii
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`Application Information:
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`DEXMEDETOMIDINE PREMIX FORMULATION
`
`Attorney Docket Number 0773500355
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`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLc - Exhibit 1048 — Page 4
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`PTOISB/14 (11-08)
`Approved for use lhrough 0113112014. OMB 0651-0032
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`Application Data Sheet 37 CFR 1.76
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`Attorney Docket Number
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`077350.0355
`
`Application Number
`
`Title of Invention
`
`DEXMEDETOMIDINE PREMIX FORMULATION
`
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`I HOSPIRA, INC.
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`Date (YYYY-MM-DD) 2012-07-03
`
`Registration Number
`
`61910
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`Signature ~ / y .---::::::::·
`I Last Name I Bissonnette
`
`First Name
`
`Dennis M.
`
`This collection of information is required by 37 CFR 1.76. The information is required to obtain or retain a benefit by the public which
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`EFS Web 2.2.3
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`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1048 – Page 5
`
`

`

`DEXMEDETOMIDINE PREMIX FORMULATION
`
`077350.0355
`
`CROSS-REFERENCE TO RELATED APPLICATIONS
`
`This application is a continuation of and claims priority under 35 U.S.C. §120 to
`
`U.S. Application Serial No. 13/343,672 filed January 4, 2012, the contents of which are hereby
`
`incorporated by reference in its entirety.
`
`1. FIELD OF THE INVENTION
`
`[0001]
`
`The present invention relates
`
`to patient-ready, premixed formulations of
`
`dexmedetomidine, or a pharmaceutically acceptable salt thereof, that can be used, for example,
`
`in perioperative care of a patient or for sedation.
`
`2. BACKGROUND OF THE INVENTION
`
`[0002]
`
`Racemic 4-(1-(2,3-dimethylphenyl)ethyl]-1 H-imidazole, which is known under
`
`the name medetomidine, is a selective and potent aradrenoceptor agonist. Medetomidine has
`
`been used as an antihypertensive agent and as a sedative-analgesic agent.
`
`It has further been
`
`observed that this compound also possesses anxiolytic effects and can therefore be used in the
`
`treatment of general anxiety, panic disorder and various types of withdrawal symptoms.
`
`[0003]
`
`The d-enantiomer of medetomidine,
`
`the generic name of which 1s
`
`dexmedetomidine, is described in U.S. Pat. No. 4,910,214 as an a.2-adrenoceptor agonist for
`general sedation/analgesia and the treatment of hypertension or anxiety. U.S. Pat. Nos.
`
`5,344,840 and 5,091,402 discuss dexmedetomidine
`
`in perioperative and epidural use,
`
`respectively. For example, when used in perioperative care, dexmedetomidine can reduce the
`
`amount of anesthetic necessary to anesthetize a patient. Additionally, U.S. Pat. No. 5,304,569
`
`discusses the use of dexmedetomidine in treating glaucoma, and U.S. Pat. No. 5,712,301
`
`discusses the use of dexmedetomidine for preventing neurodegeneration caused by ethanol
`
`consumption. Furthermore, U.S. Pat. No. 6,716,867 discloses methods of sedating a patient
`
`while in an intensive care unit by administering dexmedetomidine, or a pharmaceutically
`
`acceptable salt thereof, to the patient.
`
`NY02:744382.1
`
`- 1 -
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1048 – Page 6
`
`

`

`077350.0355
`
`[0004]
`
`Dexmedetomidine can be administered to a patient in a variety of ways. For
`
`example, U.S. Pat. Nos. 4,544,664 and 4,910,214 disclose
`
`the administration of
`
`dexmedetomidine via parenteral, intravenous, and oral routes. U.S. Pat. No. 4,670,455 describes
`
`intramuscular and intravenous administration, while U.S. Pat. Nos. 5,124,157 and 5,217,718
`
`describe a method and device for administering dexmedetomidine through the skin. Additionally,
`
`U.S. Pat. No. 5,712,301 states that dexmedetomidine can be administered transmucosally.
`
`[0005]
`
`To date, dexmedetomidine has been provided as a concentrate that must be
`
`diluted prior to administration to a patient. The requirement of a dilution step in the preparation
`
`of the dexmedetomidine formulation is associated with additional costs and inconvenience, as
`
`well as the risk of possible contamination or overdose due to human error. Thus, a
`
`dexmedetomidine formulation that avoids the expense, inconvenience, delay and risk of
`
`contamination or overdose would provide significant advantages over currently available
`
`concentrated formulations.
`
`3. SUMMARY OF THE INVENTION
`
`[0006]
`
`The present invention relates to premixed pharmaceutical compositions of
`
`dexmedetomidine, or a pharmaceutically acceptable salt thereof, that are formulated for
`
`administration to a patient, without the need to reconstitute or dilute the composition prior to
`
`administration. Thus, the compositions of the present invention are formulated as a premixed
`
`composition comprising dexmedetomidine.
`
`[0007]
`
`In
`
`certain non-limiting
`
`embodiments,
`
`the premixed dexmedetomidine
`
`composition is a liquid comprising dexmedetomidine, or a pharmaceutically acceptable salt
`
`thereof, at a concentration of between about 0.05 µg/mL and about 15 µg/mL.
`
`[0008]
`
`In other non-limiting embodiments, the premixed dexmedetomidine composition
`
`is a liquid comprising dexmedetomidine at a concentration of about 4 µg/mL.
`
`[0009]
`
`In other non-limiting embodiments, the premixed dexmedetomidine composition
`
`comprises dexmedetomidine mixed or dissolved in a sodium chloride saline solution.
`[0010]
`
`In certain embodiments, the premixed dexmedetomidine composition is disposed
`
`within a sealed container or vessel.
`
`[0011]
`
`In certain embodiments, the dexmedetomidine composition 1s disposed in a
`
`container or vessel and is formulated as a premixture.
`
`NY02:744382. 1
`
`- 2 -
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1048 – Page 7
`
`

`

`077350.0355
`
`[0012]
`
`In certain embodiments, the premixed dexmedetomidine composition is disposed
`
`within a sealed container as a total volume of about 20 mL, 50 mL or I 00 mL.
`
`[0013]
`
`In
`
`certain non-limiting embodiments,
`
`the premixed dexmedetomidine
`
`composition of the present invention comprises dexmedetomidine, or a pharmaceutically
`
`acceptable salt thereof, at a concentration of between about 0.05 µg/mL and about 15 µg/mL,
`
`and sodium chloride at a concentration of between about 0.01 and about 2.0 weight percent.
`
`[0014]
`
`In other non-limiting embodiments, the premixed dexmedetomidine composition
`
`of the present invention comprises dexmedetomidine, or a pharmaceutically acceptable salt
`
`thereof, at a concentration of about 4 µg/mL and sodium chloride at a concentration of about
`
`0.90 weight percent.
`
`[0015]
`
`In certain embodiments, the compositions of the present invention are formulated
`
`as a pharmaceutical composition for administration to a subject for sedation, analgesia or
`
`treatment of anxiety or hypertension.
`
`[0016]
`
`The present invention also relates to the perioperative treatment of a patient to
`
`reduce the response of the autonomic nervous system to stimuli during an operation by
`
`administering a dexmedetomidine composition of the invention.
`
`[0017]
`
`In other non-limiting embodiments, the dexmedetomidine compositions of the
`
`present invention can be administered as an anxiolytic analgesic to a patient.
`
`In certain
`
`embodiments, the composition can be administered as a premedication prior to an operation with
`
`or without administration of an amount of an anesthetic effective to achieve a desired level of
`
`local or general anesthesia.
`
`[0018)
`
`In other non-limiting embodiments, the dexrnedetomidine compositions of the
`
`present invention can be administered as a sedative. In certain embodiments, the composition is
`
`administered preoperatively to potentiate the effect of an anesthetic, wherein administration of
`
`the composition reduces the amount of anesthetic required to achieve a desired level of
`
`anesthesia.
`
`[0019]
`
`In certain embodiments of the present invention, the premixed dexmedetomidine
`
`composition is administered parenterally as a liquid, orally, transdermally, intravenously,
`
`intramuscularly, subcutaneously, or via an implantable pump.
`
`NY02:744382. l
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`Amneal Pharmaceuticals LLC – Exhibit 1048 – Page 8
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`077350.0355
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`4. DETAILED DESCRIPTION
`
`[0020]
`
`The present invention is based in part on the discovery that dexmedetomidine
`
`prepared in a premixed formulation that does not require reconstitution or dilution prior to
`
`administration to a patient, remains stable and active after prolonged storage. Such premixed
`
`formulations therefore avoid the cost, inconvenience, and risk of contamination or overdose that
`
`can be associated with reconstituting or diluting a concentrated dexmedetomidine formulation
`
`prior to administration to a patient.
`
`[0021]
`
`For clarity and not by way of limitation, this detailed description is divided into
`
`the following sub-portions:
`
`( 4 .1) Definitions;
`
`( 4.2) Pharmaceutical formulations; and
`
`(4.3) Methods of using premixed dexmedetomidine compositions.
`
`4.1 Definitions
`
`[0022]
`
`The terms used in this specification generally have their ordinary meanings in the
`
`art, within the context of this invention and in the specific context where each term is used.
`
`Certain terms are discussed below, or elsewhere in the specification, to provide additional
`
`guidance to the practitioner in describing the compositions and methods of the invention and
`
`how to make and use them.
`
`[0023]
`
`According to the present invention, the tenn "dexmedetomidine" as used herein
`
`refers to a substantially pure, optically active dextrorotary stereoisomer of medetomidine, as the
`
`free base or pharmaceutically acceptable salt.
`
`In one, non-limiting embodiment,
`
`dexmedetomidine has
`
`the formula (S)-4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole.
`
`A
`
`pharmaceutically acceptable salt of dexmedetomidine can include inorganic acids such as
`
`hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and
`
`organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic
`
`acid, malonic acid, succinic acid, maleic acid, frunaric acid, tartaric acid, citric acid, benzoic
`
`acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic
`
`acid, and salicylic acid. Preferably, the dexmedetomidine salt is dexmedetomidine HCI. In other
`
`non-limiting embodiments, dexmedetomidine comprises the structure depicted below in Formula
`
`I:
`
`NY02:744382.l
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`Amneal Pharmaceuticals LLC – Exhibit 1048 – Page 9
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`077350.0355
`
`CH3
`
`CH3
`
`CH3
`
`Formula I
`
`N
`
`NH
`
`[0024]
`
`The terms “premix” or “premixture” as used herein refers to a pharmaceutical
`
`formulation that does not require reconstitution or dilution prior to administration to a patient.
`
`For example,
`
`in contrast
`
`to non-premixed formulations of dexmedetomidine,
`
`the premixed
`
`compositions provided herein are suitable for administration to a patient without dilution by, for
`
`example, a clinician, hospital personnel, caretaker, patient or any other individual.
`
`[0025]
`
`In 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.
`
`[0026]
`
`In certain embodiments,
`
`the compositions of the present
`
`invention can be
`
`formulated as a “single use dosage,” which refers to a premixed composition that is disposed
`
`within a sealed container or vessel as a one dose per container or vessel formulation.
`
`[0027]
`
`According to the invention, a “subject” or “patient” is a human, a non-human
`
`mammal or a non-human animal. Although the animal subject
`
`is preferably a human,
`
`the
`
`compounds and compositions of the invention have application in veterinary medicine as well,
`
`e. g., for the treatment of domesticated species such as canine, feline, and various other pets; farm
`
`animal species such as bovine, equine, ovine, caprine, porcine, etc; wild animals, e. g., in the
`
`wild or in a zoological garden; and avian species, such as chickens, turkeys, quail, songbirds, etc.
`
`[0028]
`
`The term “purified” as used herein refers to material that has been isolated under
`
`conditions that reduce or eliminate the presence of unrelated materials,
`
`i.e., contaminants,
`
`including native materials from which the material
`
`is obtained. As used herein,
`
`the term
`
`“substantially free” is used operationally, in the context of analytical testing of the material.
`
`NY022744382l
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`Amneal Pharmaceuticals LLc — Exhibit 1048 — Page 10
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`077350.0355
`
`Preferably, purified material substantially free of contaminants is at least 95% pure; more
`
`preferably, at least 97% pure, and more preferably still at least 99% pure. Purity can be
`
`evaluated, for example, by chromatography or any other methods known in the art. In a specific
`
`embodiment, purified means that the level of contaminants is below a level acceptable to
`
`regulatory authorities for safe administration to a human or non-human animal.
`
`[0029]
`
`The term "pharmaceutically acceptable," when used in connection with the
`
`pharmaceutical compositions of the invention, refers to molecular entities and compositions that
`
`are physiologically tolerable and do not typically produce untoward reactions when administered
`
`to a human. Preferably, as used herein, the term "pharmaceutically acceptable" means approved
`
`by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or
`
`other generally recognized pharmacopeia for use in animals, and more particularly in humans.
`
`The term "carrier" refers to a diluent, adjuvant, excipient, dispersing agent or vehicle with which
`
`the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water
`
`and oils. For example, water, aqueous solutions, saline solutions, aqueous dextrose or glycerol
`
`solutions can be employed as carriers, particularly for
`
`injectable solutions. Suitable
`
`pharmaceutical carriers are described in, for example, "Remington's Pharmaceutical Sciences"
`
`by Philip P. Gerbino, 21st Edition (or previous editions).
`
`[0030]
`
`The term "pharmaceutical composition" as used in accordance with the present
`
`invention relates to compositions that can be formulated in any conventional manner using one
`
`or more pharmaceutically acceptable carriers or excipients. A "pharmaceutically acceptable"
`
`carrier or excipient, as used herein, means approved by a regulatory agency of the Federal or a
`
`state government, or as listed in the U.S. Pharmacopoeia or other generally recognized
`
`pharmacopoeia for use in mammals, and more particularly in humans.
`
`[0031]
`
`The term "dosage" is intended to encompass a formulation expressed in terms of
`
`µg/kg/day, µg/kg/hr, mg/kg/day or mg/kg/hr. The dosage is the amount of an ingredient
`
`administered in accordance with a particular dosage regimen. A "dose" is an amount of an agent
`
`administered to a mammal in a unit volume or mass, e.g., an absolute unit dose expressed in mg
`
`or µg of the agent. The dose depends on the concentration of the agent in the formulation, e.g.,
`
`in moles per liter (M), mass per volume (m/v), or mass per mass (m/m). The two terms are
`
`closely related, as a particular dosage results from the regimen of administration of a dose or
`
`doses of the formulation. The particular meaning in any case will be apparent from context.
`
`NY02:744382.1
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`Amneal Pharmaceuticals LLC – Exhibit 1048 – Page 11
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`077350.0355
`
`{0032]
`
`The
`
`terms
`
`"therapeutically effective dose,"
`
`"effective
`
`amount," and
`
`"therapeutically effective amount" refer to an amount sufficient to produce the desired effect.
`
`(0033]
`
`In some non-limiting embodiments, a "therapeutically effective dose" means an
`
`amount sufficient to reduce by at least about 15%, preferably by at least 50%, more preferably by
`
`at least 90%, and most preferably prevent, a clinically significant deficit in the activity, function
`
`and response of the host. Alternatively, a therapeutically effective amount is sufficient to cause
`
`an improvement in a clinically significant condition in the host. These parameters will depend on
`
`the severity of the condition being treated, other actions, such as diet modification, that are
`
`implemented, the weight, age, and sex of the subject, and other criteria, which can be readily
`
`determined according to standard good medical practice by those of skill in the art.
`
`[0034]
`
`In other non-limiting embodiments a therapeutic response may be any response
`
`that a user (e.g., a clinician) will recognize as an effective response to the therapy. Thus, a
`
`therapeutic response will generally be an induction of a desired effect, such as, for example,
`
`sedation or analgesia.
`
`[0035]
`
`The term "about" or "approximately" as used herein means within an acceptable
`
`error range for the particular v