Exhibit 1022
`
`Coalition For Affordable Drugs XI LLC
`Exhibit 1022
`Coalition For Affordable Drugs XI LLC v Insys Pharma, Inc.
`IPR2015-01800
`
`

`
`Attorney Docket No. INTH-001/01US 308548-2014
`
`PATENT
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In Re Application of: KOTTAYIL,
`George, et al.
`
`S. Confirmation No.2
`
`4756
`
`Serial No.:
`
`11/698,739
`
`Group Art Unit:
`
`1646
`
`Filed:
`
`January 25, 2007
`
`Examiner:
`
`WEGERT, Sandra L.
`
`FOR:
`
`SUBLINGUAL FENTANYL SPRAY
`
`Mail Stop Amendment
`Commissioner for Patents
`P.O. Box 1450
`
`Alexandria, VA 22313-1450
`
`RESPONSE TO OFFICE ACTION
`
`In response to the Official Action dated September 15, 2010, Applicants respectfully
`
`request reconsideration in View of the following Amendments and Remarks.
`
`Amendments to the Claims begin on page 2 of this paper.
`
`Remarks/Arguments begin on page 20 of this paper.
`
`128655 V2/DC
`
`

`
`Attorney Docket No. INTH-001/01US 308548-2014
`Serial No. 11/698,739
`
`AMENDMENTS TO THE CLAIMS
`
`(Currently Amended): A sublingual fentanyl formulation comprising discrete liquid droplets
`
`of an effective amount of fentanyl, a pharmaceutically acceptable salt thereof, or derivative
`
`thereof; in a pharmaceutically acceptable liquid carrier; said droplets having a mean diameter
`
`of at least about 10 microns, wherein said sublingual fentanyl formulation provides a mean
`
`maximum plasma concentration (Cmax) Of fentanyl of about 127 pg/ml to about 213 pg/ml per
`
`100 pg fentanyl after sublingual administration to humans.
`
`(Original): The sublingual fentanyl formulation of claim 1, wherein said liquid droplets have
`
`a mean diameter of at least about 20 microns.
`
`(Original): The sublingual fentanyl formulation of claim 1, wherein said liquid droplets have
`
`a size distribution of from about 5 microns to about 500 microns.
`
`(Original): The sublingual fentanyl formulation of claim 1, wherein said liquid droplets have
`
`a size distribution of from about 10 microns to about 200 microns.
`
`(Withdrawn): The sublingual fentanyl formulation of claim 1, wherein said fentanyl,
`
`pharmaceutically acceptable salt thereof, or derivative thereof is included in said formulation
`
`in a concentration of from about 0.05 mg/ml to about 15 mg/ml.
`
`(Withdrawn): The sublingual fentanyl formulation of claim 1 which provides a mean time to
`
`maximum plasma concentration (Tmax) of fentanyl at from about 5 minutes to about 120
`
`minutes, after sublingual administration to humans.
`
`(Withdrawn): The sublingual fentanyl formulation of claim 1, which provides a mean time to
`
`maximum plasma concentration (Tmax) of fentanyl at from about 10 to about 60 minutes, after
`
`sublingual administration to humans.
`
`(Withdrawn): The sublingual fentanyl formulation of claim 1, which provides a mean time to
`
`maximum plasma concentration (Tmax) of fentanyl at from about 15 to about 35 minutes after
`
`sublingual administration to humans.
`
`128655 V2/DC
`
`

`
`Attorney Docket No. INTH-001/01US 308548-2014
`Serial No. 11/698,739
`
`(Cancelled).
`
`(Original): The sublingual fentanyl formulation of claim 1, which provides a mean maximum
`
`plasma concentration (Cmax) of fentanyl of about 142 pg/ml to about 195 pg/ml per 100 ug
`
`fentanyl after sublingual administration to humans.
`
`(Original): The sublingual fentanyl formulation of claim 1, which provides a mean maximum
`
`plasma concentration (Cmax) of fentanyl of about 158 pg/ml to about 177 pg/ml per 100 ug
`
`fentanyl after sublingual administration to humans.
`
`(Withdrawn): Thc sublingual fcntanyl formulation of claim 1, further comprising an organic
`
`solvent.
`
`(Withdrawn): The sublingual fentanyl formulation of claim 12, wherein said fentanyl,
`
`pharmaceutically acceptable salt thereof, or derivative thereof is dissolved in said organic
`
`solvent.
`
`(Withdrawn): The sublingual fentanyl formulation of claim 1, wherein said fentanyl,
`
`pharmaceutically acceptable salt thereof, or derivative thereof is dispersed in said
`
`pharmaceutically acceptable liquid carrier.
`
`(Withdrawn): The sublingual fentanyl formulation of claim 1, further comprising an
`
`absorption enhancer.
`
`(Withdrawn): The sublingual fentanyl formulation of claim 15, wherein said absorption
`
`enhancer is triacetin.
`
`(Withdrawn): The sublingual fentanyl formulation of claim 15 or 16, wherein said absorption
`
`enhancer is in an amount of from about 0.001 % to about 10 % by weight of the formulation.
`
`10.
`
`ll.
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`17.
`
`128655 v2/DC
`
`

`
`Attorney Docket No. INTH-001/01US 308548-2014
`Serial No. 11/698,739
`
`(Withdrawn): The sublingual fentanyl formulation of claim 1, which is a non-propellant
`
`formulation.
`
`(Withdrawn): The sublingual fentanyl formulation of claim 1, wherein the fentanyl,
`
`pharmaceutically acceptable salt thereof, or derivative thereof does not or substantially does
`
`not enter the lungs of a human patient after sublingual administration.
`
`(Previously Presented): A unit dose of a sublingual fentanyl formulation comprising discrete
`
`liquid droplets of an effective amount of fentanyl, a pharmaceutically acceptable salt thereof,
`
`or derivative thereof; in a pharmaceutically acceptable liquid carrier suitable for sublingual
`
`spray administration; said droplets having a mean diameter of at least about 10 microns,
`
`wherein said unit dose of said sublingual fentanyl formulation provides a mean maximum
`
`plasma concentration (Cmax) of fentanyl of about 127 pg/ml to about 213 pg/ml per 100 ug
`
`fentanyl after sublingual administration to humans.
`
`(Original): The unit dose of claim 20, wherein said liquid spray formulation comprises
`
`droplet particles having a mean diameter of at least about 20 microns.
`
`(Original): The unit dose of claim 20, wherein said liquid spray formulation comprises
`
`droplet particles having a size distribution of from about 5 microns to about 500 microns.
`
`(Original): The unit dose of claim 20, wherein said liquid spray formulation comprises
`
`droplet particles having a size distribution of from about 10 microns to about 200 microns.
`
`(Withdrawn): The unit dose of claim 20, which comprises from about 10 ug to about 10 mg
`
`of said fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof.
`
`(Withdrawn): The unit dose of claim 20, which comprises from about 25 rig to about 5 mg of
`
`said fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof.
`
`(Withdrawn): The unit dose of claim 20, which comprises from about 50 ug to about 1600 pg
`
`of said fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof.
`
`18.
`
`19.
`
`20.
`
`21.
`
`22.
`
`24.
`
`25.
`
`26.
`
`128655 v2/DC
`
`

`
`Attorney Docket No. INTH-001/01US 308548-2014
`Serial No. 11/698,739
`
`27.
`
`28.
`
`29.
`
`30.
`
`31.
`
`32.
`
`33.
`
`34.
`
`35.
`
`(Withdrawn): The unit dose of claim 20, which provides a mean time to maximum plasma
`
`concentration (Tmax) of fentanyl at from about 5 minutes to about 120 minutes, after
`
`sublingual administration to humans.
`
`(Withdrawn): The unit dose of claim 20, which provides a mean time to maximum plasma
`
`concentration (Tmax) of fentanyl at from about 10 to about 60 minutes, after sublingual
`
`administration to humans.
`
`(Withdrawn): The unit dose of claim 20, which provides a mean time to maximum plasma
`
`concentration (Tmax) of fentanyl at from about 15 to about 35 minutes after sublingual
`
`administration to humans.
`
`(Cancelled).
`
`(Original): The unit dose of claim 20, which provides a mean maximum plasma
`
`concentration (Cmax) of fentanyl of about 142 pg/ml to about 195 pg/ml per 100 ug fentanyl
`
`after sublingual administration to humans.
`
`(Original): The unit dose of claim 20, which provides a mean maximum plasma
`
`concentration (Cmax) of fentanyl of about 158 pg/ml to about 177 pg/ml per 100 ug fentanyl
`
`after sublingual administration to humans.
`
`(Withdrawn): The unit dose of claim 20, wherein said formulation is a non propellant
`
`formulation.
`
`(Withdrawn): The unit dose of claim 20, wherein the fentanyl, pharmaceutically acceptable
`
`salt thereof, or derivative thereof does not or substantially does not enter the lungs of a
`
`human patient after sublingual administration.
`
`(Withdrawn): A method of treating pain comprising sublingually administering a liquid spray
`
`formulation in the form of discrete liquid droplets having a mean diameter of at least about
`
`128655 v2/DC
`
`

`
`Attorney Docket No. INTH-001/01US 308548-2014
`Serial No. 11/698,739
`
`10 microns to a human patient experiencing pain, said liquid spray formulation comprising an
`
`effective amount of fentanyl, a pharmaceutically acceptable salt thereof, or derivative thereof,
`
`dispersed in a pharmaceutically acceptable liquid carrier.
`
`(Withdrawn): The method of claim 35, wherein said liquid droplets have a mean diameter of
`
`at least about 20 microns.
`
`(Withdrawn): A method of treating pain comprising sublingually administering a liquid spray
`
`formulation in the form of discrete liquid droplets having a size distribution of from about 5
`
`microns to about 500 microns to a human patient experiencing pain; said liquid spray
`
`formulation comprising an effective amount of fentanyl, a pharmaceutically acceptable salt
`
`thereof, or derivative thereof, dispersed in a pharmaceutically acceptable liquid carrier.
`
`(Withdrawn): The method of claim 37, wherein said size distribution is from about 10
`
`microns to about 200 microns.
`
`(Withdrawn): The method of claim 35 -37, or 38, wherein said fentanyl, pharmaceutically
`
`acceptable salt thereof, or derivative thereof is included in said liquid spray formulation in a
`
`concentration of from about 0.05 mg/ml to about 15 mg/ml.
`
`(Withdrawn): The method of claim 35-37, or 38, wherein said fentanyl, pharmaceutically
`
`acceptable salt thereof, or derivative thereof is administered to said human patient in an
`
`amount of from about 10 ug to about 10 mg.
`
`(Withdrawn): The method of claim 35 -37, or 38, wherein said fentanyl, pharmaceutically
`
`acceptable salt thereof, or derivative thereof is administered to said human patient in an
`
`amount of from about 25 ug to about 5 mg.
`
`(Withdrawn): The method of claim 35-37 or 38, wherein said fentanyl, pharmaceutically
`
`acceptable salt thereof, or derivative thereof is administered to said human patient in an
`
`amount of from about 50 ug to about 1600 ug.
`
`36.
`
`37.
`
`38.
`
`39.
`
`40.
`
`41.
`
`42.
`
`128655 V2/DC
`
`

`
`Attorney Docket No. INTH-001/01US 308548-2014
`Serial No. 11/698,739
`
`(Withdrawn): The method of claim 35-37 or 38, wherein said liquid spray formulation
`
`provides a mean time to maximum plasma concentration (Tmax) of fentanyl at from about 5
`
`minutes to about 120 minutes, after sublingual administration to humans.
`
`(Withdrawn): The method of claim 35 -37 or 38, wherein said liquid spray formulation
`
`provides a mean time to maximum plasma concentration (Tmax) of fentanyl at from about 10
`
`to about 60 minutes, after sublingual administration to humans.
`
`(Withdrawn): The method of claim 35-37 or 38, wherein said liquid spray formulation
`
`provides a mean time to maximum plasma concentration (Tmax) of fentanyl at from about 15
`
`to about 35 minutes after sublingual administration to humans.
`
`(Withdrawn): The method of claim 35 -37 or 38, wherein said liquid spray formulation
`
`provides a mean maximum plasma concentration (Cmax) of fentanyl of about 127 pg/ml to
`
`about 213 pg/ml per 100 ug fentanyl after sublingual administration to humans.
`
`(Withdrawn): The method of claim 35 -37 or 38, wherein said liquid spray formulation
`
`provides a mean maximum plasma concentration (Cmax) of fentanyl of about 142 pg/ml to
`
`about 195 pg/ml per 100 ug fentanyl after sublingual administration to humans.
`
`(Withdrawn): The method of claim 35-37 or 38, wherein said liquid spray formulation
`
`provides a mean maximum plasma concentration (Cmax) of fentanyl of about 158 pg/ml to
`
`about 177 pg/ml per 100 ug fentanyl after sublingual administration to humans.
`
`(Withdrawn): The method of claim 35 -37 or 38, wherein said human patient has cancer
`
`which causes said pain.
`
`(Withdrawn): The method of claim 35-37 or 38, wherein said spray formulation further
`
`comprises an organic solvent.
`
`(Withdrawn): The method of claim 51, wherein said organic solvent is ethanol.
`
`43.
`
`44.
`
`45.
`
`46.
`
`47.
`
`48.
`
`49.
`
`50.
`
`51.
`
`128655 v2/DC
`
`

`
`Attorney Docket No. INTH-001/01US 308548-2014
`Serial No. 11/698,739
`
`(Withdrawn): The method of claim 50, wherein said organic solvent is a cosolvent
`
`comprising ethanol, propylene glycol, polyethylene glycol, labrosol, labrafil, transcutol, or
`
`combination thereof.
`
`(Withdrawn): The method of claim 35-37 or 38, wherein said carrier is water.
`
`(Withdrawn): The method of claim 35-37 or 38, wherein said carrier is miglyol.
`
`(Withdrawn): The method claim 35-37 or 38, wherein said spray formulation further
`
`comprises an absorption enhancer.
`
`(Withdrawn): The method of claim 55, wherein said absorption enhancer is triacetin.
`
`(Withdrawn): The method of claim 5 5, wherein said absorption enhancer is included in said
`
`spray formulation in an amount of from about 0.001 % to about 10 % by weight of the
`
`formulation.
`
`(Withdrawn): The method of claim 35 -37 or 38, wherein none or substantially none of the
`
`liquid spray formulation enters the lungs of the human patient after administration.
`
`(Withdrawn): A method of treating breakthrough pain comprising:
`
`sublingually administering a liquid spray formulation comprising an effective amount of
`
`fentanyl, a pharmaceutically acceptable salt thereof, or derivative thereof, dispersed in a
`
`pharmaceutically acceptable carrier to a human patient who is receiving chronic pain
`
`treatment, and is experiencing breakthrough pain.
`
`(Withdrawn): The method of claim 59, wherein said liquid spray formulation is administered
`
`in the form of discrete liquid droplets having a mean diameter greater than about 10 microns.
`
`(Withdrawn): The method of claim 5 9, wherein said liquid spray formulation is administered
`
`in the form of discrete liquid droplets having a mean diameter greater than about 20 microns.
`
`52.
`
`53.
`
`54.
`
`55.
`
`56.
`
`57.
`
`58.
`
`59.
`
`60.
`
`61.
`
`128655 v2/DC
`
`

`
`62.
`
`63.
`
`64.
`
`65.
`
`66.
`
`67.
`
`68.
`
`69.
`
`Attorney Docket No. INTH-001/01US 308548-2014
`Serial No. 11/698,739
`
`(Withdrawn): The method of claim 59, wherein said liquid spray formulation is administered
`
`in the form of discrete liquid droplets having a size distribution of from about 5 microns to
`
`about 500 microns.
`
`(Withdrawn): The method of claim 59, wherein said liquid spray formulation is administered
`
`in the form of discrete liquid droplets having a size distribution of from about 10 microns to
`
`about 200 microns.
`
`(Withdrawn): The method of claim 59, wherein said fentanyl, pharmaceutically acceptable
`
`salt thereof, or derivative thereof is included in said liquid spray formulation in a
`
`concentration of from about 0.05 mg/ml to about 15 mg/ml.
`
`(Withdrawn): The method of claim 5 9, wherein said liquid spray formulation provides a
`
`mean time to maximum plasma concentration (Tmax) of fentanyl at from about 5 minutes to
`
`about 120 minutes, after sublingual administration to humans.
`
`(Withdrawn): The method of claim 5 9, wherein said liquid spray formulation provides a
`
`mean time to maximum plasma concentration (Tmax) of fentanyl at from about 10 to about 60
`
`minutes, after sublingual administration to humans.
`
`(Withdrawn): The method of claim 59, wherein said liquid spray formulation provides a
`
`mean time to maximum plasma concentration (Tmax) of fentanyl at from about 15 to about 35
`
`minutes after sublingual administration to humans.
`
`(Withdrawn): The method of claim 5 9, wherein said liquid spray formulation provides a
`
`mean maximum plasma concentration (Cmax) of fentanyl of about 127 pg/ml to about 213
`
`pg/ml per 100 ug fentanyl after sublingual administration to humans.
`
`(Withdrawn): The method of claim 5 9, wherein said liquid spray formulation provides a
`
`mean maximum plasma concentration (Cmax) of fentanyl of about 142 pg/ml to about 195
`
`pg/ml per 100 ug fentanyl after sublingual administration to humans.
`
`128655 V2/DC
`
`

`
`70.
`
`71.
`
`72.
`
`73.
`
`74.
`
`75.
`
`76.
`
`77.
`
`78.
`
`79.
`
`Attorney Docket No. INTH-001/01US 308548-2014
`Serial No. 11/698,739
`
`(Withdrawn): The method of claim 59, wherein said liquid spray formulation provides a
`
`mean maximum plasma concentration (Cmax) of fentanyl of about 158 pg/ml to about 177
`
`pg/ml per 100 ug fentanyl after sublingual administration to humans.
`
`(Withdrawn): The method of claim 5 9, wherein said human patient has cancer which causes
`
`said pain.
`
`(Withdrawn): The method of claim 59, wherein said spray formulation further comprises an
`
`organic solvent.
`
`(Withdrawn): The method of claim 72, wherein said organic solvent is ethanol.
`
`(Withdrawn): The method of claim 72, wherein said organic solvent is a cosolvent
`
`comprising ethanol, propylene glycol, polyethylene glycol, labrosol, labraf1l,transcutol, or
`
`combination thereof.
`
`(Withdrawn): The method of claim 5 9, wherein said carrier is water.
`
`(Withdrawn): The method of claim 5 9, wherein said carrier is miglyol.
`
`(Withdrawn): The method of claim 59, wherein said spray formulation is a non-propellant
`
`formulation.
`
`(Withdrawn): The method of claim 59, wherein none or substantially none of the liquid spray
`
`formulation enters the lungs of the human patient after administration.
`
`(Withdrawn): A unit dose or bi-dose device for sublingual administration of a drug
`
`comprising:
`
`a reservoir containing a unit dose or a bi-dose of a liquid formulation comprising an effective
`
`amount of fentanyl, a pharmaceutically acceptable salt thereof, or derivative thereof in a
`
`pharmaceutically acceptable liquid carrier; and
`
`128655 V2/DC
`
`10.
`
`

`
`Attorney Docket No. INTH-001/01US 308548-2014
`Serial No. ll/698,739
`
`the device having an actuator which when actuated delivers the unit dose of the liquid
`
`formulation in the form of liquid droplets having a mean diameter of at least about 10
`
`microns.
`
`(Withdrawn): The unit dose or bi—dose device of claim 79, wherein said delivered unit dose
`
`comprises from about 10 ug to about 10 mg fentanyl, pharmaceutically acceptable salt
`
`thereof, or derivative thereof.
`
`(Withdrawn): The unit dose or bi—dose device of claim 79, wherein said delivered unit dose
`
`comprises from about 25 ug to about 5 mg fentanyl, pharmaceutically acceptable salt thereof,
`
`or derivative thereof.
`
`(Withdrawn): The unit dose or bi—dose device of claim 79, wherein said delivered unit dose
`
`comprises from about 50 ug to about 1600 pg fentanyl, pharmaceutically acceptable salt
`
`thereof, or derivative thereof.
`
`(Withdrawn): The unit dose or bi—dose device of claim 79, the device further comprising a
`
`stopper comprising a material that precludes or substantially precludes the absorption of the
`
`fentanyl, pharmaceutically acceptable salt thereof or derivative thereof.
`
`(Withdrawn): The unit dose or bi—dose device of claim 83, wherein the stopper is a
`
`component of a primary packaging of the device which affects spray characteristics of the
`
`liquid formulation.
`
`(Withdrawn): The unit dose or bi—dose device of claim 83, wherein said stopper has the
`
`following composition and characteristic: a) elastomer: bromobutyl and/or chlorobutyl; b)
`
`reinforcement: inert material: inert mineral; and c) curing system: unconventional.
`
`(Withdrawn): A multi—dose device for sublingual administration of a drug comprising:
`
`a reservoir containing a liquid formulation comprising fentanyl, a pharmaceutically
`
`acceptable salt thereof, or derivative thereof in a pharmaceutically acceptable liquid carrier;
`
`80.
`
`81.
`
`82.
`
`83.
`
`84.
`
`85.
`
`86.
`
`and
`
`128655 V2/DC
`
`ll.
`
`

`
`Attorney Docket No. INTH-001/01US 308548-2014
`Serial No. 11/698,739
`
`the device having an actuator which when actuated delivers a therapeutically effective dose
`
`of the liquid formulation in the form of liquid droplets having a mean diameter of at least
`
`about 10 microns.
`
`87.
`
`88.
`
`89.
`
`90.
`
`91.
`
`92.
`
`94.
`
`(Withdrawn): The multi—dose device of claim 86, wherein said therapeutically effective dose
`
`comprises from about 10 ug to about 10 mg fentanyl, pharmaceutically acceptable salt
`
`thereof, or derivative thereof.
`
`(Withdrawn): The multi—dose device of claim 86, wherein said therapeutically effective dose
`
`comprises from about 25 ug to about 5 mg fentanyl, pharmaceutically acceptable salt thereof,
`
`or derivative thereof.
`
`(Withdrawn): The multi—dose device of claim 86, wherein said therapeutically effective dose
`
`comprises from about 50 ug to about 1600 pg fentanyl, pharmaceutically acceptable salt
`
`thereof, or derivative thereof.
`
`(Withdrawn): The multi—dose device of claim 86, wherein the device further comprises a
`
`gasket comprising a material which precludes or substantially precludes the absorption of the
`
`fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof.
`
`(Withdrawn): The device of claim 86, wherein said gasket has the following composition and
`
`characteristic: a) elastomer: bromobutyl and/or chlorobutyl; b) reinforcement: inert material:
`
`inert mineral; and c) curing system: unconventional.
`
`(Withdrawn): The device of claim 79-90, or 91, wherein said liquid droplets have a mean
`
`diameter of at least about 20 microns.
`
`(Withdrawn): The device of claim 79-90, or 91 , wherein said liquid droplets have a size
`
`distribution of from about 5 microns to about 500 microns.
`
`(Withdrawn): The device of claim 79-90, or 91, wherein said liquid droplets have a size
`
`distribution of about 10 microns to about 200 microns.
`
`128655 V2/DC
`
`12.
`
`

`
`Attorney Docket No. INTH-001/01US 308548-2014
`Serial No. 11/698,739
`
`95.
`
`96.
`
`97.
`
`98.
`
`99.
`
`100.
`
`101.
`
`102.
`
`103.
`
`(Withdrawn): The device of claim 79-90, or 91, wherein said dose provides a mean time to
`
`maximum plasma concentration (Tmax) of fentanyl at from about 5 minutes to about 120
`
`minutes, after sublingual administration to humans.
`
`(Withdrawn): The device of claim 79-90, or 91, wherein said dose provides a mean time to
`
`maximum plasma concentration (Tmax) of fentanyl at from about 10 to about 60 minutes, after
`
`sublingual administration to humans.
`
`(Withdrawn): The device of claim 79-90, or 91, wherein said dose provides a mean time to
`
`maximum plasma concentration (Tmax) of fentanyl at from about 15 to about 35 minutes after
`
`sublingual administration to humans.
`
`(Withdrawn): The device of claim 79-90, or 91, wherein said liquid formulation is a
`
`nonpropellant formulation.
`
`(Withdrawn): The device of claim 79-90, or 91, wherein none or substantially none of the
`
`dose enters the lungs of a human patient after sublingual administration.
`
`(Withdrawn): The device of claim 79, wherein after said unit dose is delivered, said device is
`
`substantially empty.
`
`(Withdrawn): The device of claim 79, wherein said device is disposable after said unit dose
`
`is delivered.
`
`(Withdrawn): The device of claim 86, which contains two doses of said fentanyl,
`
`pharmaceutically acceptable salt thereof, or derivative.
`
`(Withdrawn): The device of claim 102, wherein said device is substantially empty after said
`
`two doses are delivered.
`
`128655 V2/DC
`
`13.
`
`

`
`104.
`
`105.
`
`Attorney Docket No. INTH-001/01US 308548-2014
`Serial No. 11/698,739
`
`(Withdrawn): The device of claim 103, wherein said device is disposable after said two doses
`
`are delivered.
`
`(Withdrawn): The device of claim 86, further including a lock-out mechanism which allows
`
`for the administration of one dose and locks out of further administration for a certain period
`
`of time.
`
`106.
`
`(Withdrawn): A method of treating pain comprising:
`
`utilizing a sublingual spray device comprising a reservoir containing a liquid formulation
`
`comprising fentanyl, a pharmaceutically acceptable salt thereof, or derivative thereof in a
`
`pharmaceutically acceptable liquid carrier; and the device having an actuator which upon
`
`actuation delivers a therapeutically effective amount of liquid droplets to be sprayed from the
`
`device having a mean diameter of at least about 10 microns.
`
`107.
`
`108.
`
`109.
`
`110.
`
`ll].
`
`(Withdrawn): The method of claim 106, wherein said liquid droplets have a mean diameter
`
`greater than about 20 microns.
`
`(Withdrawn); The method of claim 106, wherein said liquid droplets have a size distribution
`
`of from about 5 microns to about 500 microns.
`
`(Withdrawn): The method of claim 106, wherein said liquid droplets have a size distribution
`
`of from about 10 microns to about 200 microns.
`
`(Withdrawn); The method of claim 106, wherein said therapeutically effective amount
`
`comprises from about 10 ug to about 10 mg fentanyl, pharmaceutically acceptable salt
`
`thereof, or derivative thereof.
`
`(Withdrawn): The method of claim 106, wherein said therapeutically effective amount
`
`comprises from about 25 ug to about 5 mg fentanyl, pharmaceutically acceptable salt thereof,
`
`or derivative thereof.
`
`128655 V2/DC
`
`14.
`
`

`
`112.
`
`113.
`
`114.
`
`115.
`
`116.
`
`117.
`
`118.
`
`119.
`
`Attorney Docket No. INTH-001/01US 308548-2014
`Serial No. 11/698,739
`
`(Withdrawn): The method of claim 106, wherein said therapeutically effective dose
`
`comprises from about 50 ug to about 1600 ug fentanyl, pharmaceutically acceptable salt
`
`thereof, or derivative thereof.
`
`(Withdrawn): The method of claim 106, wherein said therapeutically effective amount
`
`provides a mean time to maximum plasma concentration (Tmax) of fentanyl at from about 5
`
`minutes to about 120 minutes, after sublingual administration to humans.
`
`(Withdrawn): The method of claim 106, wherein said therapeutically effective amount
`
`provides a mean time to maximum plasma concentration (Tmax) of fentanyl at from about 10
`
`to about 60 minutes, after sublingual administration to humans.
`
`(Withdrawn): The method of claim 106, wherein said therapeutically effective amount
`
`provides a mean time to maximum plasma concentration (Tmax) of fentanyl at from about 15
`
`to about 35 minutes after sublingual administration to humans.
`
`(Withdrawn): The method of claim 106, wherein said therapeutically effective amount
`
`provides a mean maximum plasma concentration (Cmax) of fentanyl of about 127 pg/ml to
`
`about 213 pg/ml per 100 ug fentanyl after sublingual administration to humans.
`
`(Withdrawn): The method of claim 106, wherein said a liquid formulation is a nonpropellant
`
`formulation.
`
`(Withdrawn): The method of claim 106, wherein none or substantially none of the liquid
`
`droplets enter the lungs of a human patient after sublingual administration.
`
`(Withdrawn): A method of preparing a pharmaceutical composition for sublingual
`
`administration comprising:
`
`preparing a mixture of a therapeutically active agent in a pharmaceutically acceptable carner,
`
`incorporating a sufficient amount of said mixture into a unit dose device to provide at least
`
`one therapeutic dose, said device being capable ofbeing actuated to deliver liquid droplets of
`
`128655 v2/DC
`
`15.
`
`

`
`Attorney Docket No. INTH-001/01US 308548-2014
`Serial No. 11/698,739
`
`said at least one therapeutic dose having a mean diameter of at least about 10 microns to the
`
`sublingual region of a human.
`
`120.
`
`(Withdrawn): A sublingual pharmaceutical formulation comprising discrete liquid droplets of
`
`an effective amount of a therapeutically active agent in a pharmaceutically acceptable liquid
`
`carrier; said droplets having a mean diameter of at least about 10 microns.
`
`121.
`
`(Withdrawn): A unit dose of a sublingual pharmaceutical formulation comprising discrete
`
`liquid droplets of an effective amount of a therapeutically active agent, in a pharmaceutically
`
`acceptable liquid carrier suitable for sublingual spray administration; said droplets having a
`
`mean diameter of at least about 10 microns.
`
`122.
`
`(Withdrawn): A method of treating a human patient comprising sublingually administering a
`
`liquid spray formulation in the form of discrete liquid droplets having a mean diameter of at
`
`least about 10 microns to a human patient, said liquid spray formulation comprising an
`
`effective amount of therapeutically active agent, dispersed in a pharmaceutically acceptable
`
`liquid carrier.
`
`123.
`
`(Withdrawn): A method of treating a human patient comprising sublingually administering a
`
`liquid spray formulation in the form of discrete liquid droplets having a size distribution of
`
`from about 5 microns to about 500 microns to a human patient; said liquid spray formulation
`
`comprising an effective amount of therapeutically active agent, dispersed in a
`
`pharmaceutically acceptable liquid carrier.
`
`124.
`
`(Withdrawn): A unit dose or bi-dose device for sublingual administration of a drug
`
`comprising:
`
`a reservoir containing a unit dose or a bi-dose of a liquid formulation comprising an effective
`
`amount of a therapeutically active agent in a pharmaceutically acceptable liquid carrier; and
`
`the device having an actuator which when actuated delivers the unit dose of the liquid
`
`formulation in the form of liquid droplets having a mean diameter of at least about 10
`
`microns.
`
`128655 V2/DC
`
`16.
`
`

`
`Attorney Docket No. INTH-001/01US 308548-2014
`Serial No. 11/698,739
`
`125.
`
`(Withdrawn): A multi-dose device for sublingual administration of a drug comprising:
`
`a reservoir containing a liquid formulation comprising a therapeutically active agent; and
`
`the device having an actuator which when actuated delivers a therapeutically effective dose
`
`of the liquid formulation in the form of liquid droplets having a mean diameter of at least
`
`about 10 microns.
`
`126.
`
`(Withdrawn): A method of treating a human patient comprising:
`
`utilizing a sublingual spray device comprising a reservoir containing a liquid formulation
`
`comprising a therapeutically active agent in a pharmaceutically acceptable liquid carrier; and
`
`the device having an actuator which upon actuation delivers a therapeutically effective
`
`amount of liquid droplets to be sprayed from the device having a mean diameter of at least
`
`about 10 microns.
`
`127.
`
`128.
`
`129.
`
`130.
`
`131.
`
`132.
`
`(Withdrawn); The fentany formulation of claim 1 wherein upon administration to a human
`
`patient, at least about 90% of the discrete liquid droplets have a mean diameter equal or
`
`greater than about 9 mm.
`
`(Withdrawn): The fentanyl formulation of claim 127 wherein not more than about 5% of the
`
`discrete liquid droplets have a mean diameter less than 9 pm.
`
`(Withdrawn): The fentanyl formulation of claim 127 wherein the formulation provides a
`
`respirable dose of not more than about 5% of the total fentanyl dose contained.
`
`(Withdrawn): The method of treatment of claim 35 wherein upon administration to a human
`
`patient, at least about 90% of the discrete liquid droplets have a mean diameter equal or
`
`greater than about 9 mm.
`
`(Withdrawn): The method oftreatment of claim 35 wherein not more than about 5% ofthe
`
`discrete liquid droplets have a mean diameter less than 9 pm.
`
`(Withdrawn): The method of treatment of claim 35 wherein the formulation provides a
`
`respirable dose of not more than about 5% of the total fentanyl dose contained.
`
`128655 v2/DC
`
`17.
`
`

`
`Attorney Docket No. INTH-001/01US 308548-2014
`Serial No. 11/698,739
`
`133.
`
`134.
`
`135.
`
`136.
`
`137.
`
`138.
`
`139.
`
`(Withdrawn): The device of claim 79 wherein upon administration to a human patient, at
`
`least about 90% of the discrete liquid droplets have a mean diameter equal or greater than
`
`about 9 pm.
`
`(Withdrawn): The device of claim 79 wherein not more than about 5% of the discrete liquid
`
`droplets have a mean diameter less than 9 um.
`
`(Withdrawn): The device of claim 79 wherein the formulation provides a respirable dose of
`
`not more than about 5% of the total fentanyl dose contained.
`
`(Withdrawn): The device of claim 86 wherein upon administration to a human patient, at
`
`least about 90% of the discrete liquid droplets have a mean diameter equal or greater than
`
`about 9 pm.
`
`(Withdrawn): The device of claim 86 wherein not more than about 5% of the discrete liquid
`
`droplets have a mean diameter less than 9 um.
`
`(Withdrawn): The device of claim 86 wherein not more than about 5% of the discrete liquid
`
`droplets have a mean diameter less than 9 um.
`
`(New): A non—propellant sublingual fentanyl formulation comprising discrete liquid droplets
`
`of an effective amount of fentanyl in a pharmaceutically acceptable liquid carrier, wherein
`
`the sublingual fentanyl formulation comprises:
`
`from about 0.001% to about 15% by weight fentanyl free base;
`
`from about 5% to about 90% by weight of ethanol; and
`
`from about 0.1% to about 40% by weight of propylene glycol;
`
`said droplets having a mean diameter of at least about 10 microns, and
`
`wherein said sublingual fentanyl formulation provides a mean maximum plasma
`
`concentration (Cmax) of fentanyl of about 127 pg/ml to about 213 pg/ml per 100 ug fentanyl
`
`after sublingual administration to humans.
`
`128655 V2/DC
`
`18.
`
`

`
`140.
`
`(New): The non-propellant sublingual fentanyl formulation of claim 139, wherein sublingual
`
`Attorney Docket No. INTH-001/01US 308548-2014
`Serial No. 11/698,739
`
`fentan