Case 1:15-cv-00697-RGA Document 39-8 Filed 01/29/16 Page 1 of 43 PageID #: 403
`Case 1:15-cv-OO697-RGA Document 39-8 Filed 01/29/16 Page 1 of 43 PagelD #: 403
`
`EXHIBIT 7
`
`EXHIBIT 7
`
`

`

`Case 1:15-cv-00697-RGA Document 39-8 Filed 01/29/16 Page 2 of 43 PageID #: 404
`Case 1:15-cv-OO697-RGA Document 39-8 Filed 01/29/16 Page 2 of 43 PagelD #: 404
`PATHN’I‘
`
`0773 50.0355
`
`Showing ofSupport of Each Claim Limitation
`
`
`. SUPPORT FOR._C'LAIM
`.
`'Lmfl-TATION-IN _
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`.- PRIORITY -
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`
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`
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`CLAIM LIMITATon
`
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`
`-.Sl}l’-P0R7f 'fe‘oft CLAIM '
`LIMm-TIQN'IN THE
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`_ PRESENT;
`' ArPLICATION .
`
`_
`
`
`
`
`
`]. A ready in use liquid
`
`pharmaceutical
`
`emnpesllien
`
`See, for examplepip. 2,
`
`“TE-8; P3319; p- 5.1l25;
`
`v.6.l30;p.11.l50;
`
`
`Examples 1 -6.
`
`
`
`
`
`
`for parenteral
`
`administration to a
`
`I SEerr example, p. 2, W;
`
`f.l,3,fll9;ll.8;.ll37;1311.9-
`
`I See~ for example, pp.
`
`l—2.
`
`3' 1|4; p.3,‘l!19; p. 8.1237; pp.
`
`9—10. “4244; Examples
`lvfi.
`J.———._ .....—_._._.__
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`
`I.
`
`i9; [3. 3, 1H4; pp. 46:
`
`pp. lO~ll,‘;;I1|r46-49;
`
`|23;
`
`subject, comprising
`
`l0. 1|€l42-44_; Examples 1»
`
`(i.
`
`dexmedetomidine 01' a
`
`See, for example. p. 2,
`
`phannaecmieally
`
`acceptable gall the-reel"
`
`W69; 9- 3.. 'lll4; pp 4-1
`l?"-,4.
`
`pp. 10—1 l___ "1|46-49;
`
`
`
`
`
`Examples 1—6.
`Examples '1-6.
`
`
`a1 a concentralion 0|” about
`
`I
`
`l'pr exun‘lple, p. 10,
`
`0.005 Te about 50 jlgflnL
`
`17.46.
`
`dispersed within a sealed
`
`’1
`See, for example, p. 4, 1:6;
`
`glass container.
`
`p.5.%12;p.12;ll57-58;
`
`See, for example. p.
`
`1346.
`
`lU_._
`
`l See, for example. p. 2. 1|6;
`
`p. 2, {1-2; 1). l2; $5158; 1).
`
`p. 13, 'léU; and Examples
`
`13, $60: and Examples 1-6.
`
`See, for example, p. 2.11;;
`'J-
`
`and pp.
`
`3,T13.
`
`I
`
`l lrIl
`
`1—6.
`
`See, for example, p.
`,_‘1
`and p. _.,T|13.
`
`1"7;
`
`2. The read}- te use liquid :
`
`pharmaceutical
`
`composition of claim 1.
`
`wherein the
`
`NYUE.7-'l'.’828.l
`
`58
`
`
`HOSPIRA_00000385HOSPIRA_00000385
`HOSPIRA_00000385
`
`

`

`Case 1:15-cv-00697-RGA Document 39-8 Filed 01/29/16 Page 3 of 43 PageID #: 405
`Case 1:15-cv-00697-RGA Document 39-8 Filed 01/29/16 Page 3 of 43 PagelD #: 405
`PATENT
`07?35l).l_l355
`
`
`
`F".CLA_IM‘-L1MI’1‘ATION.
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`-
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`
`lSUPPORT FORCLAIM l SUPPORT FOR CLAIM"
`LMITATioNINTHE-“q LIMITATION IN
`' PRESENT _
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`'PRI'ORITY'
`- APPLICATIQN
`'_ DOCUMENT _U'._s. SER.
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`example; p.
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`
`$47K
`
`dexmedelomidine 0r
`
`pharmaceutically
`
`acceptable H‘dll lhe-renl'is
`
`at a concentration of about
`
`0.05 to about [5 Lug-“ml...
`
`.H_.__.
`3. The ready—t0 use liquid I’ See, for example, 13.
`
`
`
`pharmaceutical
`
`compusition ol'elaim ].
`
`wherein the
`
`dexmedemmidine or
`
`pharmaceutith
`
`acceptable salt lhereol‘is
`
`at a concentration oi‘aboul
`
`‘
`
`0.5 to about 10 ugf’mL.
`
`4‘ The
`
`lo use liqllid
`
`See, for efimple;
`
`example, p.
`
`l I,
`
`pharmaceutical
`
`$47.
`
`1H?
`
`cmnpusition of claim 1,
`
`wherein lhe
`
`dexmedetomidine or
`
`plwrmaeeulieally'
`acceptable salt thereol‘is
`
`‘I
`
`at a concentration nl‘abuui
`
`l to abnul 7 ugfnll...
`
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`
`NYan-fifllfi 1
`
`59
`
`
`HOSPIRA_00000386HOSPIRA_00000386
`HOSPIRA_00000386
`
`

`

`
`
`5
`
`Case 1:15-cv-00697-RGA Document 39-8 Filed 01/29/16 Page 4 of 43 PageID #: 406
`Case 1:15-cv-00697-RGA Document 39-8 Filed 01/29/16 Page 4 of 43 PagelD #: 406
`Pi-i'l‘liN’l'
`077.150.0355
`
`
`
`CLAIM" LINIJTATION ;
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`l asiiepou'r FOR cmfffi" '"siiiii’ibitffsoiiéigifii—g
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`mogul-343,672:
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`5. The rel-id}! to use liquid ' See, for examine, p. 3,
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`pharmaceutical
`fill: 13. 3,1214; p.12,";!52;
`'13;p. 3.?14; p.1'2,1|5’2; p.
`
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`'l‘hc ready to use liquid I See, for
`6.
`pharmaceutical
`: 1m; 13. 121'352; p. 12,153;
`composition ofelaim 5,
`- Examples 143.
`
`ixir'égeiuifiie; n.3,
`g p. 12,152; p. 12,1155;
`Examples 1~I5.
`
`wherein the sodium
`
`chloride is present at a
`concentration of about 0.9
`
`i7. The ready to use liquid
`
`pharmaceutical
`
`composition ofelaim 1,
`
`wherein the composition
`
`is formulated as a total
`
`Weight percent.
`
`See, for example, 13. 3,
`
`See, for example, p. 2, 1112.;
`
`‘f12; pp. 13444115265;
`
`pp. 13-141flf62—65;
`
`Examples 1-K).
`
`Examples 1-6.
`
`volume selected from the
`
`j
`
`group consisting of 20
`
`rule, 50 mL and 100 mL.
`
`No means plus function claim elements are present in the above claims.
`
`Thus, claims 13 satisfy the requirements of 35 U.S.C. § 112, $1.
`
`mwziznmzsl
`
`(it)
`
`
`HOSPIRA_00000387HOSPIRA_00000387
`HOSPIRA_00000387
`
`3
`
`-
`
`'
`-
`
`E
`
` 1
`
`composition of claim 1,
`
`p. 12.1i‘54—55; Examples
`
`1111315465; Examples l-fi.
`
`further comprising sodium 1-6.
`
`chloride at :1 Concentration -
`
`of between about 0.01 and
`
`about 2.0 weight percent.
`
`
`
`
`
`
`

`

`Case 1:15-cv-00697-RGA Document 39-8 Filed 01/29/16 Page 5 of 43 PageID #: 407
`Case 1:15-cv-OO697-RGA Document 39-8 Filed 01/29/16 Page 5 of 43 PagelD #: 407
`HWESUIBSS
`
`DEXMEDETOMIDINE PREMIX FORM'ULA'I‘H’JN
`
`CROSS-REFE RENCE “[‘9 RE 1.4111131; APPLICATIONS
`
`This application is a. continuation of and claims priority under 35 USC. §120 to
`
`US. Application Serial No. l3i’343,672 tiled January 4, 2012. the contents of which are hereby
`
`incorporated hy reference in its entirety.
`
`I. FIELD OF THE IN‘TNTION
`
`{0001]
`
`The present
`
`invention relates
`
`to patient-read}; premixed toniiulations of
`
`dexmedetomidine, or a pharmaceutically acceptable salt thereof, that can be used. for example,
`
`in periopei‘ative care ofa patient or for sedation.
`
`2. BACKGROUND OF THE INVENTION
`
`[0002]
`
`Racetnic ilull—(2.3—dimethylphenyllethylj—ll-Limidaxole, which is known under
`
`the name medetontidine,
`
`is a selective and potent rig-adi‘enoeeptor agonist. Medeton'iidine has
`
`been used as an autihypertensive agent and as a sedativeeanalgcsie agent.
`
`It has further been
`
`observed that this compound also possesses: anxiolytic ell‘ects and can therefore be used in the
`
`treatment oi‘gcncral anxiety. panic. disorder and various types of withdrawal symptoms.
`
`[0003]
`
`The
`
`d—cnantiomer of medetomidine,
`
`the
`
`generic
`
`name of which
`
`is
`
`destnedctmnidine.
`
`is described in US. Pat. No. 4,910,214 as an ng-adrenoceptor agonist for
`
`general sedationfi'analgcsia and the treatment
`
`01‘ hypertension or anxiety: US. Pat. Nos.
`
`5,344,840 and 5.991.403 discuss dexmedetomidinc in pcriopcratii-e
`
`and epidural
`
`use,
`
`respectively. For example. when used in pet'ioperative care= dextnedetomidine can reduce the
`
`amount of anesthetic necessary to anesthetize a patient. Additionally, US. Pat. No. 5.304.569
`
`discusses the use of demiedetmnidinc in treating glaucoma, and US. Pat. No. 5,712.30]
`
`discusses the use of dexmedetotnidine lor preventing neurodegeneration caused by ethanol
`
`consumption.
`
`li'urtherniore. US. Pat. No. 6,716,867 discloses methods of scdating a patient
`
`while in an intensive care unit by administerng dexmedetomidine, or a pharmaceutically
`
`acceptable salt thereof, to the patient.
`
`7-: WE ' 7-1. -'l 11.32 . I
`
`
`HOSPIRA_00000449HOSPIRA_00000449
`HOSPIRA_00000449
`
`

`

`Case 1:15-cv-00697-RGA Document 39-8 Filed 01/29/16 Page 6 of 43 PageID #: 408
`Case 1:15-cv-OO697-RGA Document 39-8 Filed 01/29/16 Page 6 of 43 PagelD #: 408
`077350. 355
`
`[0004]
`
`Dexrncdetornidine can be administered to a patient
`
`in a variety of was-'3. For
`
`example, US.
`
`Pat. Nos.
`
`4.544.664
`
`and
`
`4,910,214
`
`disclose
`
`the
`
`administration
`
`of
`
`dexmedetomidine via parenteral, intravenous and oral routes. LES. Pat. No. 4,670,455 describes
`
`intramuscular and intravenous administration, while US. Pat. Nos. S,|24,|57 and 5,21?,?13
`
`describe a method and device for administering dexmedetornidnte through the skin. Additionally.
`
`[.33. Pat. No. 5,712,30l states that dexmedetomidine can he administered transmucosally.
`
`[0005]
`
`To date, dca‘medetomidinc 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 deioncdctomidine fonnulation is associated with additional costs and inconvenience, as
`
`well as
`
`the risk of possible contamination or overdose due to human en‘or.
`
`‘l'hos.
`
`a
`
`dexmedetornidine formulation that avoids the expense.
`
`inconvenience, delay and risk of
`
`contamination or overdose would provide significant advantages over currently availabic
`
`concentrated formulations.
`
`3. SUMMARY OF THE INVENTION
`
`[0006}
`
`The present
`
`invention relates to premised pharmaceutical compositions ol'
`
`dcxmedetomidine, or
`
`a phurmaceutically acceptahie salt
`
`thereof,
`
`that are lormulated for
`
`administration to a patient, without the need to reconstitute or diiute the composition prior to
`
`administration. Thus, the compositions of the present invention are formulated as a premixed
`
`composition comprising dcxmedctomidine.
`
`[0007]
`
`In
`
`certain
`
`non-limiting
`
`embodiments:
`
`the
`
`premixed
`
`dcxmedetomidine
`
`composition is a liquid comprising. Ciearncdetomidinc~ or a pharniaceuticaily acceptable salt
`
`thereof. at a concentration of between about 0.05 pghnL and about 15 pgme.
`
`[0008]
`
`In other non~lin1iting embodiments, the premixed dexmedctornidinc composition
`
`is a liquid comprising dexrncdetoinidine at. a concentration of about -'l ugtrnl...
`
`[0009]
`
`In other non—limiting embodiments, the premixed dexmedetomicline composition
`
`comprises dexniedetomidine mixed or dissolved in a sodium chloride saline solution.
`
`[0010]
`
`In certain embodiments. the premixed dexmedetontidine composition is disposed
`
`within a sealed container or vessel
`
`10011]
`
`in certain embodiments:
`
`the dexmedetomidine composition is disposed in a
`
`container or vessel and is t'orrnuiated as a premixture
`
`N ¥"l}32T-143t13. l
`
`l'-J
`
`
`HOSPIRA_00000450HOSPIRA_00000450
`HOSPIRA_00000450
`
`

`

`Case 1:15-cv-00697-RGA Document 39-8 Filed 01/29/16 Page 7 of 43 PageID #: 409
`Case 1:15-cv-OO697-RGA Document 39-8 Filed 01/29/16 Page 7 of 43 PagelD #: 409
`0?. 350.0355
`
`[0012]
`
`In certain embodiments, the premixed dexmedetomidine composition is disposed
`
`within a sealed container as a total volume oi‘about 20 mi, 50 ml... or 100 mi...
`
`[0013]
`
`In
`
`certain
`
`non-limiting
`
`embodiments,
`
`the
`
`premixed
`
`dexniedetomidine
`
`composition of the present
`
`invention comprises dexmedetomidine or a phannaceuticallv
`
`acceptable salt thereof, at a concentration of between about 0.05 ugr'mL and about 15 ugr'mL.
`
`and sodium chloride at a concentration ofhetwoen about 0.01 and about 2.0 weight percent.
`
`[001-4]
`
`In other non-limiting embodiments, the premixed dcxmedetomidine composititm
`
`of the present
`
`inventirm comprises desmedetomidine, or a pharmaceutically acceptable salt
`
`thereof. at a concentration of about 4 ttgr’mL and sodium chloride at a concentration ol‘ about
`
`0.90 weight perc ent.
`
`[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 ol‘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
`
`adrninisrcring a dexmedetomidine composition of the invention
`
`[0017]
`
`in other non~limiting embodiments, the desrnedetomidine compositions oi" the
`
`present
`
`invention can be administered as an ansioivtie analgesic to a patient.
`
`In certain
`
`embodiments, the composition can be administered as a premediearion prior to on 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 dexmedetomidine compositions of the
`
`present invention can be administered as a sedative.
`
`In certain embodiments. the composition is
`
`administered preoperativcly 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 dexrnedetomidine
`
`composition is administered parenterally as
`
`a
`
`liquid] orally:
`
`transderrnally‘
`
`intravenouslv.
`
`intraniuseularly, suhcutaneouslv, or via an implantable pump.
`
`:"J VIEW-1435?” l
`
`
`HOSPIRA_00000451HOSPIRA_00000451
`HOSPIRA_00000451
`
`

`

`Case 1:15-cv-00697-RGA Document 39-8 Filed 01/29/16 Page 8 of 43 PageID #: 410
`Case 1:15-cv-OO697-RGA Document 39-8 Filed 01/29/16 Page 8 of 43 PagelD #: 410
`t}??350.0355
`
`4. DETAILED DESCRIPTION
`
`[0020]
`
`The present
`
`invention is based in part on the. discovery that dcxtncdetoinidinc
`
`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
`
`t‘onnuiations therefore avoid the cost. inconvenience, and risk of contamination or overdose. that
`
`can be associated with reconstituting or diluting a concentrated dexrnedetomidine formulation
`
`prior to administration to a patient.
`
`IUUZI]
`
`For clarity and not by way of limitation, this detailed description is divided into
`
`the following sub-portions:
`
`(4.1) Definitions;
`
`(4.2)
`
`Pharmaceutical terminations; and
`
`{4.3} Methods of using premixed dexmedetomidine composniotts.
`
`4.1 Definitions
`
`[0022]
`
`the terms used in this specification generally have. their ordinary meanings in the
`
`all, within the context of this invention and in the. specific. conth 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 oi the. invention and
`
`how to make and use them.
`
`[0023]
`
`Accordng to the present invention, the icon “dexmedetomidine” as used herein
`
`reters to a substemtiali}r pure, optically active. dcxtrorotary stereoisomcr oi tnedetomidine, as the
`
`free
`
`base
`
`or
`
`pliamiaccutically
`
`acceptable
`
`salt.
`
`in
`
`one,
`
`non—limiting
`
`embodiment,
`
`dexmedeiomidine has
`
`the
`
`formula
`
`(S)~4~ll-(2r3-dimethylpheny|')ethyl]fi3ii—imidazole.
`
`A
`
`pharmaceutically acceptable salt of dexmedctomidine can include inorganic acids such as
`
`hydrochloric acid, lufdrobromic 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 malonie acid. succinic acid, maleic acid. fumaric acid,
`
`tartaric acid, citric acid, benzoic
`
`acid, cimtainic acid, inandelic. acid, methanesulfonic acid‘ ethanesulfonic acid: p-toluencsulftmic
`
`acid, and salicylic acid. Preferably, the dcxmcdetoniidine salt is dexmedetontidine HQ.
`
`in other
`
`non—limiting embodiments, dexmedetomidine comprises the structure depicted below in Formula
`
`I:
`
`ri‘r"{l;‘.T-1'133?..l
`
`
`HOSPIRA_00000452HOSPIRA_00000452
`HOSPIRA_00000452
`
`

`

`Case 1:15-cv-00697-RGA Document 39-8 Filed 01/29/16 Page 9 of 43 PageID #: 411
`Case 1:15-cv-OO697-RGA Document 39-8 Filed 01/29/16 Page 9 of 43 PagelD #: 411
`0773511121353
`
`CH3
`
`CH3
`
`CH3
`
`Formula l
`
`’N
`
`NH
`
`[0024]
`
`The terms “premif or “premixture” as used herein refers to a pharmaceutical
`
`[omiulation that does not require reconstitution or. dilution prior to administration to a patient.
`
`For example,
`
`in contrast
`
`to non-premixed fiiinnutatitms ol' dexmedetomidtne,
`
`the premised
`
`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.
`
`i-‘or example, in certain embodiments,
`
`the compositions of the present invention are "ready to use“ upon realm-drag the compositions
`
`from a sealed container or vessel.
`
`[0026]
`
`in certain embodiments.
`
`the compositions of the present
`
`intention 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 formulatimt.
`
`[0027]
`
`Aecording to the invention, a “subject” or "patient" is a human, a non—human
`
`inartmtal 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,
`
`tag, for the treatment of domesticated species such as canine, feline, and various other pets; farm
`
`animal species suelt as bovine, equine, twine, caprine, porcine, etc; wild animals, ag, in the
`
`wild or in a Zoological garden: and avian species, such as chickens, turkeys, quail. songbirds, etc.
`
`["028]
`
`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.
`
`'IQ'I'IRFJ-l 382-
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`I
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`(1773500355
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`Preferably. purified material substantially free of contaminants is at
`
`least 95% pure; more
`
`preferably, at
`
`least 97% pure, and more preferably still at
`
`least 9991: pure. Purity can be
`
`evaluated, for example, by chromatography or any other methods lQ‘tUWIt in the art.
`
`in a Specific
`
`embodiment, purified means that
`
`the level of contaminants is below a level acceptable to
`
`regulatory authorities for sale administration to a human or non-human animal.
`
`[0029]
`
`The term “pharmaceutically acceptable,” when used in connection with the
`
`pharmaceutical compositions ofthc invention, refers to molecular entities and compositions that
`
`are physiologically tolerable and do not typically produce untoward reactions when administered
`
`to a human. Prelerahly, as used herein. the term “pharmaceutically acceptable" means approx-ed
`
`by a regulatory agency of the Federal or a state government or listed in the US. Pharmacopeia or
`
`other generally recognized pharntacopcia for use in animals, and more particularly in humans.
`
`The term “earner” refers to a diluent. adjuvant, exeipient, 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,
`
`ptu'ticularly
`
`For
`
`injectable
`
`solutions. Suitable
`
`pharmaceutical carriers are described in. for example. “Remington's Pharmaceutical Sciences“
`
`by Philip 1”. Gerbino, 21st Edition (or Previous editions).
`
`£003!”
`
`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 excipienls. A “phannaccutically 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 US. Phannacopoeia or other generally recognised
`
`pharmacopoeia for use in mammals, and more particularly in humans.
`
`[0031]
`
`The term “dosage” is intended to encompass a formulation expressed in tenns of
`
`pgi’kgr’day, ugi’kgi’hr,
`
`Ingi’kgt'day or mgi’kgi’ltr. The dosage is the amount ol' an ingredient
`
`administered in accordance with a particular dosage regimen. A “dose” is an amount oi” an agent
`
`administered to a mammal in a unit volume or mass,
`
`an absolute unit dose expressed in mg
`
`or pg of the agent. The close depends on the concentration oi'the agent in the formulation. e.g.,
`
`in moles per liter (M). mass per volume (mitt), or mass per mass (mi-lint. The two terms are.
`
`closely related, as a particular dosage results from the regimen of administration of a dose or
`
`doses ol‘ the formulation.
`
`‘l'he particular meaning in any case will be apparent from ct'intcxt.
`
`.‘sYDE.’ Eli-1332.1
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`0773500355
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`[0032]
`
`The
`
`terms
`
`“therapeutically
`
`effective
`
`dose,”
`
`“et‘iEctive
`
`amount,"
`
`and
`
`“therapeutically effective amount“ refer to an amount sufficient to produce the desired etTeet.
`
`[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 5094:, 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 {_c.g., a clinician) will recognize as an effective response to the therapy. Thus, a
`
`therapeutic response Will generally be an induction 01‘ a desired effect, such as, for example,
`
`sedation or analgesia.
`
`["035]
`
`The term “about” or “approximate! as used herein means within an acceptable
`
`error range tor the particular value as determined by one oi" ordinary skill in the art, which will
`
`depend in part. on how the value is measured or determined,
`
`i.e.,
`
`the limitations of the
`
`measurement system.
`
`For example, “about” can mean within 3 or more than 3 standard
`
`deviations, per the practice in the art. Alternatively, “about” can mean a range of up to 20%.
`
`preferably up to lO‘i-‘b, more preferably up to in. and more prel'ierably still up to l‘i‘l} of a given
`
`value. Alternatively, particularly with respect to biological systems or processes, the term can
`
`mean within an order oi“ magnitude, preferably within 5~fold, and more preferath within 2-fold,
`
`ofa value.
`
`4.2 .l’harmaeeutieal Com positions
`
`[0036]
`
`The compounds and compositions of the invention may be formulated as
`
`phairnaceutieal compositions by admixture with a phannaceutieally acceptable carrier or
`
`exeipicnt.
`
`In certain non-limiting embodiments, the compounds or compositions are. provided in
`
`a therapeutically ellective amount to an animal, such as a mammal, preferably a human, in need
`
`of treatment therewith for inducing a sedative. anaiolytic, analgesic, or anesthetic effect.
`
`N YD? 'F-l Bill. I
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`Case 1:15-cv-00697-RGA Document 39-8 Filed 01/29/16 Page 12 of 43 PageID #: 414
`Case 1:15-cv-00697-RGA Document 39-8 Filed 01/29/16 Page 12 of 43 PagelD #: 414
`ti??350.0353
`
`[0037]
`
`[11 certain non—linuting embodiments, dexmedetomidine is
`
`formulated as
`
`a
`
`composition, wherein the dexmedetomidine is the only therapeutically active ingredient present
`
`in the composition.
`
`in another nondimiting embodiments, dexmedetomidiue is formulated as a
`
`compositiou, wherein the dexmedetomidine is formulated in combination with at least one or
`
`more other therapeutically active ingredient. The formulation is profitably suitable for parenteral
`
`administration,
`
`including, but not
`
`limited to,
`
`intravenous, subcutaneous,
`
`intramuscular and
`
`intraperitoneal administration; hovvcver, tbrmulations suitable for other routes ot‘ administration
`
`such as oral. intranetsal, mucosal or transdermal are also contemplated.
`
`[0038]
`
`The pharmaceutical formulations suitable for injectable ttse, such as, for example,
`
`intravenous, subcutaneous,
`
`intramuscular and intraperitoneal administration,
`
`include sterile
`
`aqueous solutions or dispersions and sterile powders for the exteinporaneous preparation of
`
`sterile injectablc solutions or dispersion. In all cases, the form can be sterile and can be fluid to
`
`the extent that easy syringability exists. It can be stable under the conditions of manufacture and
`
`storage and can be preserved against the contaminating action of microt‘ngunisms such as
`
`bacteria and Fungi. The carrier can be a solvent or dispersion medium containing, for example,
`
`water, saline, ethanol, polvol (for example, glycerol, propylene glycol, and polyethylene glycol,
`
`and the like), suitable mixtures thereof, and oils. The proper fluidity can be maintained. For
`
`example, by the use eta coating such as lecithin, by the maintenance ofthe required particle size
`
`in the case of dispersion and by the use of surfactants. The preventions ol“ the action of
`
`microorganisms can be. brought about by various antibacterial and antifungal agents,
`
`for
`
`example, parabcns, chlorobutanol, phenol, benzyl alcohol, sorbic acid, and the like.
`
`[0039]
`
`In many cases. it will be preferable to include isotonic agents, for example, sugars
`
`or sodium chloride. Prolonged absorption ofthe injectabie con-rpositions can be brought about by
`
`the use in the compositions of agents delaying absorption, for example, aluminum monosterate
`
`and gelatin. Sterile iuicetable solutions may be prepared by incorporating the dexmedetomidine
`
`in the required amounts in the appropriate solvent with various of the other ingredients
`
`enumerated above, as required, tollowed by filter or terminal sterilization. Generally; dispersions
`
`are prepared by incorporating the various steriliaed active ingredients into a sterile vehicle which
`
`contains the basic dispersion medium and the required other ingredients from those enumerated
`
`above.
`
`In the case of sterile powders for the preparation of sterile 'utjcctable solutions,
`
`the
`
`preferred methods of preparation are vacuum drying and the freeze—drying technique which yield
`
`'.'\'Yt'i2: 3443321
`
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`Case 1:15-cv-00697-RGA Document 39-8 Filed 01/29/16 Page 13 of 43 PageID #: 415
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`077'35011355
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`a powder of the active ingredient plus any additional desired ingredient from previously sterile—
`
`liltered solution thereof.
`
`[0040]
`
`Preferably the formulation may contain an excipient. Pharmaceutically acceptable
`
`exeipients which may be included in the formulation are buffers such as citrate buffer. phosphate
`
`buffer. acetate buffer. and bicarbonate buffer; amino acids; urea; alcohols; ascorbic acid;
`
`phospholipids; proteins. such as serum albumin, collagen. and gelatin; salts such as EDTA or
`
`EGIA. and sodium chloride; liposornes; polyvinylpyrollidone; sugars. such as dextran. i'nannitol.
`
`sorbitol. and glycerol; propylene glycol and polyethylene glycol {'_e.g__. PEG-4000. PEG-6000i;
`
`glycerol; glycine; lipids; preservatives; suspending agents; stabilizers; and dyes. As used herein.
`
`thc term “stabilizer” refers to a compound optionally used in the phannaC-eulical compositions of
`
`the present invention in order to avoid the need for sulphite salts and increase storage life. Non—
`
`limiting examples of stabilizers
`
`include antioxidants.
`
`Buffer systems for use with the
`
`formulations include citrate; acetate; bicarbonate; and phosphate butters
`
`[00-11]
`
`The formulation also may contain a non-ionic detergent. Preferred non-ionic
`
`detergents include l’olysorhate 20. Polysorbate 3t},
`
`'l‘riton X—lllll. Triton X-l l4. Nonidet 13-40.
`
`Octyl a—glucoside. ()ctyl Bsglucoside. Brij 35. Platonic. and 'T'ween 2t}.
`
`[0042]
`
`The parenteral formulations of the present invention can be sterilized. Non-
`
`limiting examples of sterilization techniques include filtration through a bacterial-retaining lilterl
`
`terminal sterilization, incorporation of sterilizing agents. irradiation, and heating.
`
`[0043}
`
`The route of administration may be oral or parenteral.
`
`including intravenous.
`
`subcutaneous.
`
`inner—arterial. intraperitoneal. ophthalmic. intramuscular, buccal. rectal. vaginal.
`
`intraorbita].
`
`intraeerebral.
`
`intradennal.
`
`intraeranial.
`
`intraspinal,
`
`intrat-rentrieular.
`
`intratheeal.
`
`intracistemal.
`
`intracapsular.
`
`intrapultnonary.
`
`intranasal.
`
`transmuc-osal.
`
`transdermal. or via
`
`inhalation.
`
`[0044]
`
`Administration of the above-described parenteral formulations may be by periodic
`
`injections ofa bolus of the preparation. or may be administered by intravenous or intraperitoneal
`
`administration from a reservoir which is external leg. an intravenous bag) or internal (cg. a
`
`bioerodable implant. a biomiticial or tirganl. See, e.g.. US. Pat. Nos. 4.401957 and 5.798.113.
`
`each incorporated herein by reference in their entireties. lntrapulmonary delivery methods and
`
`apparatus are described. for example.
`
`in LLS. Pat. Nos. 5.654.007, 5.780.014. and 5.814.607.
`
`each incomorated herein by reterence in their cutireties. Other useful parenteral delivery systems
`
`NYtll?‘ 1352. l
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`Case 1:15-cv-00697-RGA Document 39-8 Filed 01/29/16 Page 14 of 43 PageID #: 416
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`0??350.0355
`
`include ethylene-vinyl acetate copolymer particles, osmotic pumps,
`
`implantable
`
`infusion
`
`systems, pump delivery, encapsulated cell delivery,
`
`liposornal delivery, needle-deli\-’crcd
`
`injection, needle-less injection, nebulizer. aeorosulizer, electroporation, and transdermal patch.
`
`Needle—less injector devices are described in US. Pat. Nos. 5,379,32?1 5,520,639; 5,846,233 and
`
`5,704,911,
`
`the specifications of which are herein incorporated herein by reference in their
`
`entire-ties. Any otthe Jorrnulations described herein can be. administered in these methods.
`
`[0045]
`
`in yet another non-limiting en'ibodiincnt,
`
`the therapeutic compound can be
`
`delivered in a controlled or sustained release system. For example, a compound or composition
`
`may be administered using, intravenous infusion, an implantable osmotic pump, a transdcrmal
`
`patch,
`
`tiposomes, or other modes of administration. In one embodiment. a pump may be used
`
`(See Scfion, 1987, CRC Crit. Ref. Biontcd. ling, 14:20}: Buchwald et at, 1980, Surgery 8850?;
`
`Saudelt et al., 1985}, N. Engl. J. Med. 331:5?4). In another embodiment, polymeric. materials can
`
`be used {see Langcr and Wise eds, 19?4, Medical Applications of Controlled Release, CRC
`
`Press: Bose Raton, Fla; Smolen and Ball eds, 1984, Controlled Drug Bioax-ailability, Drug
`
`Product Design and Performance, Wiley, N.Y.', Ranger and Peppas, 1983,
`
`.l. Macromol. Sci.
`
`Rev. Macromol, Chem, 23:61; Levy el
`
`1985, Science 328:0)0; During ct £11., 1980, Ann.
`
`Neurol, 25351; Howard et at, 9189,
`
`.lNeurosurg. ?1:105}.
`
`in yet another embodiment, a
`
`controlled release system can be placed in proximity of the therapeutic target, i.e., the brain, thus
`
`requiring only a traction of the systemic dose (see. e-,i'__r_._. Goodson, 1984, in h-iedical Applications
`
`of Controlled Release, Vol. '2, pp. 115—138).
`
`[0046]
`
`In
`
`certain
`
`non~limiting
`
`embodiments,
`
`the
`
`premixed
`
`dexmedetomidine
`
`eon-iposition cornprisr—zs dexmedctomidine, or a pharmaceutically acceptable salt thereof, at a
`
`concentration of between about 0.005 pgr'rnL and about 100 ug.r"inl., or between about 0.005.
`
`ugt’rnL and about 50 rig/niL, or between about 0.005 ugfml, and about '25 ugi’mL, or between
`
`about 0.005 patrol. and about 15 ugt'mL or between about 0.005 ugfntl. and about 10 pitfalls. or
`
`between about 0.005 ugr’mt. and about 7 pgr’mL, or between about 0.005 ugr’rnL. and about 5
`
`pgme, or between about 0.003 ,ugj'nil, and about 4 pgi'ml.., or between about 0.005 pgtmL and
`
`about 3 pgr'mL, or between about 0.005 egg-“mid and about 2 pg/i‘nL, or between about 0.005
`
`pgtml, and about 1 pgh’nL, or between about 00115 pgr'ml, and about 0.5 pgr'iiiL, or between
`
`about 0,005 pgtml, and about 0.05 pg."1ii.l_,.
`
`‘J 3'02 Til-138?.
`
`I
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`—10—
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`Case 1:15-cv-00697-RGA Document 39-8 Filed 01/29/16 Page 15 of 43 PageID #: 417
`Case 1:15-cv-00697-RGA Document 39-8 Filed 01/29/16 Page 15 of 43 PagelD #: 417
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`1110471
`
`In
`
`certain
`
`non-limiting
`
`embodiments,
`
`the
`
`premixed
`
`dexmedetontidinc
`
`composition comprises dexmedetoinidine, or a pharmaceutically acceptable Suit the