Exhibit 1017
`
`Coalition For Affordable Drugs XI LLC
`Exhibit 1017
`Coalition For Affordable Drugs XI LLC v Insys Pharma, Inc.
`IPR2015-01800
`
`

`
`IN THE UNITED STATES PATENT
`
`AND TRADEMARK OFFICE
`
`Filed via EFS— WEB
`
`-- PATENT --
`
`Applicants:
`
`S. George Kottayil et al. ’
`
`Docket No.:
`
`50695.0100
`
`Serial No.:
`
`1 1/698,739
`
`Confirmation
`-No.:
`
`4756
`
`Filing Date:
`
`January 25, 2007
`
`Examiner:
`
`Sandra L. Wegert
`
`Title:
`
`SUBLINGUAL FENTANYL
`SPRAY
`
`Art Unit:
`
`1646
`
`RESPONSE TO RESTRICTION REQUIREMENT AND
`PRELIMINARY AMENDMENT
`
`Mail Stop: AMENDMENT
`Commissioner for Patents
`P.O. Box 1450
`
`Alexandria, VA 22313-1450
`
`Sir:
`
`In response to the Examiner's Restriction Requirement dated March 10, 2010, please
`
`accept the following Response to the restriction requirement entered pursuant to 35 U.S.C. § 121
`
`for the above—referenced application.
`
`Amendments to the Claims are reflected in the listing of claims which begin on page 2 of this
`paper.
`
`Remarks directed to Applicants‘ election begin on page 20 of this paper.
`
`506950100/11412200
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`1
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`Serial No. 11/698,739
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`

`
`Amendments to the Claims:
`
`This listing of claims will replace all prior versions, and listings, of claims in the application:
`
`Listing of Claims:
`
`1. (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 (Cm of fentan l of about 127
`
`/ml to about 213
`
`ml er
`
`100 },_lg fentanyl after subling1_1al administration to humans.
`
`2. (Original): The sublingual fentanyl formulation of claim 1, wherein said liquid droplets have
`
`a mean diameter of at least about 20 microns.
`
`3. (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.
`
`4. (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.
`
`5. (Withdrawn): The sublingual fentanyl formulation of claim 1, wherein said fentanyl,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.
`
`6. (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.
`
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`

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`7. (Withdrawn): The sublingual fentanyl formulation of claim 1, which provides a mean time to
`
`maximum plasma concentration (Tum) of fentanyl at from about 10 to about 60 minutes, after
`
`sublingual administration to humans.
`
`8. (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.
`
`9. (Cancelled): The sublingual fentanyl formulation of claim 1, which 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.
`
`10. (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 pg fentanyl after sublingual administration to humans.
`
`11. (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 pg fentanyl after sublingual administration to humans.
`
`12. (Withdrawn): The sublingual fentanyl formulation of claim 1, firrther comprising an organic
`
`solvent.
`
`13. (Withdrawn): The sublingual fentanyl formulation of claim 12, wherein said fentanyl,
`
`pharmaceutically acceptable salt thereof, or derivative thereof is dissolved in said organic
`
`solvent.
`
`14. (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.
`
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`

`
`15. (Withdrawn): The sublingual fentanyl formulation of claim 1, further comprising an
`
`absorption enhancer.
`
`16. (Withdrawn): The sublingual fentanyl formulation of claim 15, wherein said absorption
`
`enhancer is triacetin.
`
`17. (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.
`
`18. (Withdrawn): The sublingual fentanyl formulation of claim 1, which is a non-propellant
`
`formulation.
`
`19. (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.
`
`20. (Currently Amended): A unit dose of a sublingual fentanyl formulation comprising discrete
`
`liquid droplets of an effective amount of fentanyl, a phannaceutically acceptable salt thereof, or
`
`derivative thereof; in a pharrnaceutically 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 §CL() of fentanyl of about 127 pg/ml to about 213 pg/ml per 100 ug fentanyl after
`
`sublingual administration to humans.
`
`21. (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.
`
`22. (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.
`
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`

`
`23. (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.
`
`24. (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.
`
`25. (Withdrawn): The unit dose of claim 20, which comprises from about 25 ug to about 5 mg
`
`of said fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof.
`
`26. (Withdrawn): The unit dose of claim 20, which comprises from about 50 gig to about 1600
`
`pg of said fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof.
`
`27. (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.
`
`28. (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.
`
`29. (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.
`
`30. (Cancelled): The unit dose of claim 20, which 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.
`
`31. (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.
`
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`

`
`32. (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 pg fentanyl after
`
`sublingual administration to humans.
`
`33. (Withdrawn): The unit dose of claim 20, wherein said formulation is a non propellant
`
`formulation.
`
`34. (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.
`
`35. (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
`
`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.
`
`36. (Withdrawn): The method of claim 35, wherein said liquid droplets have a mean diameter
`
`of at least about 20 microns.
`
`37. (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.
`
`38. (Withdrawn): The method of claim 37, wherein said size distribution is from about 10
`
`microns to about 200 microns.
`
`506950100/11412200
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`

`
`39. (Withdrawn): The method of claim 35-37, or 38, wherein said fentanyl, pharrnaceutically
`
`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.
`
`40. (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 pg to about 10 mg.
`
`41. (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.
`
`42. (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.
`
`43. (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.
`
`44. (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.
`
`45. (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.
`
`46. (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.
`
`50695.0lO0/11412200
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`7
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`Serial No. 11/698,739
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`

`
`47. (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 pg fentanyl after sublingual administration to humans.
`
`48. (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.
`
`49. (Withdrawn): The method of claim 35-37 or 38, wherein said human patient has cancer
`
`which causes said pain.
`
`50. (Withdrawn): The method of claim 35-37 or 38, wherein said spray formulation further
`
`comprises an organic solvent.
`
`51. (Withdrawn): The method of claim 51, wherein said organic solvent is ethanol.
`
`52. (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.
`
`53. (Withdrawn): The method of claim 35-37 or 38, wherein said carrier is water.
`
`54. (Withdrawn): The method of claim 35-37 or 38, wherein said carrier is miglyol.
`
`55. (Withdrawn): The method claim 35-37 or 38, wherein said spray formulation further
`
`comprises an absorption enhancer.
`
`56. (Withdrawn): The method of claim 55, wherein said absorption enhancer is triacetin.
`
`50695.0l0O/11412200
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`

`
`57. (Withdrawn): The method of claim 55, 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.
`
`58. (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.
`
`59. (Withdrawn): A method of treating breakthrough pain comprising:
`
`sublingually administering a liquid spray formulation comprising an effective amount of
`
`fentanyl, a pharrnaceutically 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.
`
`60. (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.
`
`61. (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 20
`
`microns.
`
`62. (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.
`
`63. (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.
`
`506950100/11412200
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`

`
`64. (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.
`
`65. (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 5 minutes to about
`
`120 minutes, after sublingual administration to humans.
`
`66. (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 10 to about 60
`
`minutes, after sublingual administration to humans.
`
`67. (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.
`
`68. (Withdrawn): The method of claim 59, 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.
`
`69. (Withdrawn): The method of claim 59, 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.
`
`70. (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.
`
`71. (Withdrawn): The method of claim 59, wherein said human patient has cancer which causes
`
`said pain.
`
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`Serial No. 11/698,739
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`

`
`72. (Withdrawn): The method of claim 59, wherein said spray formulation further comprises an
`
`organic solvent.
`
`73. (Withdrawn): The method of claim 72, wherein said organic solvent is ethanol.
`
`74. (Withdrawn): The method of claim 72, wherein said organic solvent is a cosolvent
`
`comprising ethanol, propylene glycol, polyethylene glycol, labrosol, labrafil, transcutol, or
`
`combination thereof.
`
`75. (Withdrawn): The method of claim 59, wherein said carrier is water.
`
`76. (Withdrawn): The method of claim 59, wherein said carrier is miglyol.
`
`77. (Withdrawn): The method of claim 59, wherein said spray formulation is a non-propellant
`
`formulation.
`
`78. (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.
`
`79. (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
`
`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.
`
`80. (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, pharrnaceutically acceptable salt thereof, or
`
`derivative thereof.
`
`50695.0100/11412200
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`11
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`Serial No. 11/698,739
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`

`
`81. (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.
`
`82. (Withdrawn): The unit dose or bi—dose device of claim 79, wherein said delivered unit dose
`
`comprises from about 50 pg to about 1600 pg fentanyl, pharmaceutically acceptable salt thereof,
`
`or derivative thereof.
`
`83. (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.
`
`84. (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.
`
`85. (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.
`
`86. (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; 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.
`
`87. (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.
`
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`

`
`88. (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.
`
`89. (Withdrawn): The multi-dose device of claim 86, wherein said therapeutically effective
`
`dose comprises from about 50 pg to about 1600 pg fentanyl, pharmaceutically acceptable salt
`
`thereof, or derivative thereof.
`
`90. (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.
`
`91. (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.
`
`92. (Withdrawn): The device of claim 79-90, or 91, wherein said liquid droplets have a mean
`
`diameter of at least about 20 microns.
`
`93. (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.
`
`94. (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.
`
`95. (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.
`
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`

`
`96. (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.
`
`97. (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.
`
`98. (Withdrawn): The device of claim 79-90, or 91, wherein said liquid formulation is a non-
`
`propellant formulation.
`
`99. (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.
`
`100. (Withdrawn): The device of claim 79, wherein after said unit dose is delivered, said device
`
`is substantially empty.
`
`101. (Withdrawn): The device of claim 79, wherein said device is disposable after said unit
`
`dose is delivered.
`
`102. (Withdrawn): The device of claim 86, which contains two doses of said fentanyl,
`
`pharrnaceutically acceptable salt thereof, or derivative.
`
`103. (Withdrawn): The device of claim 102, wherein said device is substantially empty after
`
`said two doses are delivered.
`
`104. (Withdrawn): The device of claim 103, wherein said device is disposable after said two
`
`doses are delivered.
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`105. (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. (Withdrawn): The method of claim 106, wherein said liquid droplets have a mean diameter
`
`greater than about 20 microns.
`
`108. (Withdrawn): The method of claim 106, wherein said liquid droplets have a size
`
`distribution of from about 5 microns to about 500 microns.
`
`109. (Withdrawn): The method of claim 106, wherein said liquid droplets have a size
`
`distribution of from about 10 microns to about 200 microns.
`
`110. (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.
`
`111. (Withdrawn): The method of claim 106, wherein said therapeutically effective amount
`
`comprises from about 25 pg to about 5 mg fentanyl, pharmaceutically acceptable salt thereof, or
`
`derivative thereof.
`
`112. (Withdrawn): The method of claim 106, wherein said therapeutically effective dose
`
`comprises from about 50 ug to about 1600 11g fentanyl, pharmaceutically acceptable salt thereof,
`
`or derivative thereof.
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`113. (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.
`
`114. (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.
`
`115. (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.
`
`116. (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.
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`117. (Withdrawn): The method of claim 106, wherein said a liquid formulation is a non-
`
`propellant formulation.
`
`118. (Withdrawn): W The method of claim 106, wherein none or substantially none of the liquid
`
`droplets enter the lungs of a human patient after sublingual administration.
`
`119. (Withdrawn): A method of preparing a pharmaceutical composition for sublingual
`
`administration comprising:
`
`preparing a mixture of a therapeutically active agent in a pharrnaceutically acceptable
`
`carrier,
`
`incorporating a sufficient amount of said mixture into a unit dose device to provide at
`
`least one therapeutic dose, said device being capable of being actuated to deliver liquid droplets
`
`of said at least one therapeutic dose having a mean diameter of at least about 10 microns to the
`
`sublingual region of a human.
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`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.
`
`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
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`the device having an actuator which when actuated delivers a therapeutically effective
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`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 pharrnaceutically 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.
`
`(Withdrawn): The fentany formulation of claim 1 wherein upon administration to a
`
`human patient, at least about 90%iof the discrete liquid droplets have a mean diameter equal or
`
`greater than about 9 pm.
`
`128.
`
`(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.
`
`129.
`
`(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.
`
`130.
`
`(Withdrawn): The methodiof 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 um.
`
`131.
`
`(Withdrawn): The method of treatment of claim 35 wherein not more than about 5% of
`
`the discrete liquid droplets have a mean diameter less than 9 pm.
`
`132.
`
`(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.
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`133.
`
`(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.
`
`134.
`
`(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.
`
`135.
`
`(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.
`
`136.
`
`(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
`
`I
`
`9 mm.
`
`137.
`
`(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.
`
`138.
`
`(Withdrawn): The device of claim 86 wherein not more than about 5% of the discrete
`
`liquid droplets have a mean diameter less than 9 pm.
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`50695.0100/11412200
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`REMARKS
`
`In response to the Examiner’s restriction requirement, Applicants elect invention IV,
`
`claims 9-11 and 30-32, without traverse, for further examination.
`
`In further response to the
`
`Examiner’s restriction requirement, Applicants have amended claims 1 and 20 and have
`
`cancelled claims 9 and 30.
`
`In addition, Applicants have included additional dependent claims
`
`which further limit the claims elected in response to the restriction requirement.
`
`Reconsideration of the application is earnestly solicited. Should the Examiner wish to
`
`discuss any of the above in greater detail or deem that further amendment should be made to
`
`improve the form of the claims, then the Examiner is invited to telephone the undersigned at the
`
`Examiner's convenience.
`
`Applicants have attached a copy of the claim s