Exhibit 1019
`
`Coalition For Affordable Drugs XI LLC
`Exhibit 1019
`Coalition For Affordable Drugs XI LLC v Insys Pharma, Inc.
`IPR2015-01799
`
`

`
`INSl0763P0009lUS
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re Application of:
`
`S. George Kottayil
`
`Serial No.:
`
`13/895,124
`
`Filed: May 15, 2013
`
`)
`)
`)
`)
`)
`)
`)
`
`Sublingual Fentanyl Spray
`
`Examiner:
`
`Robert S Landsman
`
`Group Art Unit:
`
`1647
`
`Confirmation No.:
`
`3808
`
`AMENDMENT
`
`Commissioner for Patents
`P.O. Box 1450
`
`Alexandria, VA 22313 -1450
`
`Madam:
`
`Responsive to the Office Action mailed January 10, 2014, please amend the above-
`
`identified application as indicated below.
`
`If any fees are incurred as a result of the filing of this paper, authorization is given to
`
`charge Deposit Account No. 23-0785.
`
`Amendments to the Specification begin on page 2 of this paper.
`
`Listing of the Claims begin on page 8 of this paper.
`
`Remarks begin on page 9 of this paper.
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`Page 1 of 14
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`

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`Response to Office Action mailed January 10, 2014
`Serial No. 13/895,124
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`AMENDMENTS TO THE SPECIFICATION
`
`Please replace paragraph [0005] with the following paragraph:
`
`[0005] Fentanyl is currently available in injectable fonn, as a lozenge (e.g. Actiq®; fentanyl
`
`citrate; Actig is a registered trademark of Ancsta, LLC), and as a transdcrmal patch (c.g.
`
`Duragesic® 25, 50, 75, and 100 ug of fentanyl per hour; Duragesic is a registered trademark of
`
`Johnson & Johnson Corporation). Duragesic® provides continuous systemic delivery of fentanyl
`
`for approximately 72 hours. Duragesic® is indicated in the management of chronic pain in
`
`patients requiring continuous opioid analgesia for pain that is not optimally managed with lesser
`
`means such as acetaminophen—opioid combinations, non—steroidal analgesics, or pm (as needed)
`
`dosing with short-acting opioids. Duragesic® is typically not suitable for patients experiencing
`
`acute pain due to the delay in absorption of the fentanyl through the patch, or postoperative pain
`
`because serious or life-threatening hypoventilation could result.
`
`Please replace paragraph [0094] with the following paragraph:
`
`[0094] In certain embodiments, the compositions comprise a CH alcohol such as propylene
`
`glycol, or a polyethylene glycol and/or polypropylene glycol of an average molar weight of 200
`
`to 4000, or a mixture thereof, in addition to the organic solvent described above. The C2_g
`
`alcohol may act as a cosolvent in combination with the organic solvent. Polyethylene glycols
`
`commercially available as Carbowax®®(Carbowax is a registered trademark of Union Carbide
`
`Corporation; e. g., Carbowax@ 300 of a molar weight of 300), can be used.
`
`Please replace paragraph [00134] with the following paragraph:
`
`[00134] Droplet size distribution can be determined by utilizing any reliable method known to
`
`one of skill in the art. One such method uses laser diffraction devices, such as, for example, the
`
`Malvern® [Malvern is a registered trademark of Malvern Instruments Limited[ Spraytec® with
`
`RT Sizer Software. A Malvemg Mastersizer® §Mastersizer is a registered trademark of Malvern
`
`Instruments Limited] S, by Malvern@ Instruments Limited (U.K.), device may also be used to
`
`determine size distribution. A Malvern@ Mastersizer® S is a modular particle size
`
`analyzer offering measurement versatility. It can measure spray droplet size as well as wet and
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`Page 2 of 14
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`Response to Office Action mailed January 10, 2014
`Serial No. 13/895,124
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`dry samples. Particles from sub-micron to a few millimeters may be measured with the
`
`Malvern@ Mastersizer@ S.
`
`Please replace paragraph [00135] with the following paragraph:
`
`[00135] Further, automated actuation stations for comparative in vitro bioequivalence tests or
`
`other testing to decrease the variability associated with manual actuation may also be used when
`
`determining the droplet size distribution. Any such automated actuation stations known to one of
`
`skill may be applicable in practicing the present invention. An example of one such device is the
`
`MightyRunt Actuation Station by Innova Systems, Inc. In a preferred embodiment, a
`
`MightyRunt is equipped with an exhaust fan attachment. In a further embodiment, the
`
`MightyRunt is further equipped with a Mettler Toledo® (Mettler Toledo is a registered trademark
`
`of Mettler—Toledo AG) balance Model AT201.
`
`Please replace the paragraph titled Preparation of Formulations (Examples 1 - 5) which follows
`
`Table 5 with the following paragraph:
`
`Preparation of Formulations §Examples 1-51
`
`1. Calculated amount of Fentanyl base or Fentanyl citrate was weighed in a tared glass
`
`container.
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`2. Calculated amount of alcohol was added to the container and mixed to dissolve fentanyl.
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`3. Propylene glycol was weighed and added to the fentanyl solution.
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`4. Water or Buffer or Miglyol® gMiglyol is a registered trademark of Cremer Oleo GmbH &
`
`Co. KG Limited Liability Partnership) was weighed, added to the fentanyl solution and
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`mixed for 2 mm.
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`5.
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`Inactive ingredients (Mannitol, Triacetin, or TW80) were added at the end and mixed
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`well.
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`6. The final solution was vortexed for 3 min. After mixing, the formulations were stored in
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`refrigerator for further studies.
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`Page 3 of 14
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`Response to Office Action mailed January 10, 2014
`Serial No. 13/895,124
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`Please replace paragraph [00188] with the following paragraph:
`
`[00188] The EpiOral tissues, grown on cell culture inserts with Teflon§(Teflon is a registered
`
`trademark of E.I. Du Pont De Nemours and Company) backing membrane, were shipped by
`
`MatTek Corp on Monday for delivery on Tuesday morning. All the tissues were used in the
`
`permeability experiments within 72 hours of shipment. The inserts containing the tissues were
`
`rinsed with distilled water before the start of permeation experiments. The tissue area for the
`
`ORL-100 is 0.6 cn12.
`
`Please replace Table 20 with the following table:
`
`EXAMPLE #*
`
`CONC. OF
`
`FENTANYL ;:L($)0H0L
`
`BASE
`
`"
`
`5%)
`
`"
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`1,}/4[S)LY0L
`
`"
`
`Q %
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`PERMEATED
`
`IN 2 HOURS
`
`Fentanyl
`Basc
`
`Fentanyl
`Basc
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`Fentanyl
`Citrate
`
`Fentanyl
`Citrate
`
`
`
`0.646 mg/ml
`
`1 mg/ml
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`(b)-buffer, (w)-water
`
`Please replace paragraph [00195] with the following paragraph:
`
`[00195] In Example 12, several ingredients including hydroxypropyl beta cyclodextrin
`
`(HPBCD), mannitol, polyvinyl pyrrolidone (PVP), propylene carbonate (PC), sodium
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`glycocholate (SG), sodium lauryl sulphate (SLS), triacetin, triethyl citrate and tween Tween® 80
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`(Tween is a registered trademark of Unig ema Americas LLC; TW 80) were added to the
`
`formulations either individually or in combination and studied for their effect on permeability
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`and solution stability. Table 24 to 36 summarizes the formulations and permeation results of
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`buffered and water formulations containing the above excipients.
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`Please replace paragraph [00196] with the following paragraph:
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`Page 4 of 14
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`Response to Office Action mailed January 10, 2014
`Serial No. 13/895,124
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`[00196] The results in Table 24 indicate that all the buffered formulations had similar
`
`permeability characteristics as that of control formulations except the buffered formulation
`
`containing 0.3% Twccn@ 80 which showed lower pcrmcability. All water formulations cxhibitcd
`
`lower permeability than buffered formulations.
`
`Please replace paragraph [00197] with the following paragraph:
`
`[00197] The results indicate that addition of individual excipients including HPBCD (Table 25),
`
`PVP (Table 27), PC (Table 28), Triethyl citrate (Table 31) and Tween® 80 (Table 32) to the
`
`formulation decreased the permeability of fentanyl across MatTek buccal membranes
`
`irrespective of excipient concentration. As shown in Table 26 and Table 30, formulations
`
`containing 0.3% Mannitol and 0.5% Triacetin showed similar permeability characterisitics as
`
`that of control formulation but the permeability decreased as the concentrations of these
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`individual excipients were increased in the formulations. Stability studies indicated that a
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`minimum of 0.45% and 0.5% mannitol concentration should be added to buffer and water
`
`formulations, respectively, to keep them stable. In case of Triacetin, formulations containing
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`0.5% or higher concentrations of triacetin were found to be stable.
`
`Please replace paragraph [00199] with the following paragraph:
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`[00199] The results of fentanyl pcrmcation across MatTcl<-buccal tissues from formulations
`
`containing combination of excipients are shown in Tables 33-36. Addition of Labrasol@
`
`]Labrasol is a registered trademark of Gattefosse SAS[ to the formulation improved the stability
`
`but decreased fentanyl permeation across MatTek buccal tissues. Similar results were observed
`
`with formulations containing -labraselLabrasol® and SLS. Among all the formulations containing
`
`combination of excipients, two formulations, Example l2—uu (0.l5% mannitol, 0.4% triacetin)
`
`and Example 12-bbb (0.2% mannitol, 0.2% TW80), showed higher permeability compared to
`
`control formulation. We observed that the presence of mannitol in triacetin formulations did not
`
`show any improvement in the permeation. Hence, the formulation containing 0.5% triacetin
`
`(Table 30) was selected for further studies. Though the formulation, Example 12-bbb, showed
`
`good permeability mannitol concentration was increased to 0.3% to improve the stability of the
`
`product.
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`Page 5 of 14
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`Response to Office Action mailed January 10, 2014
`Serial No. 13/895,124
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`Please replace paragraph [00200] with the following paragraph:
`
`[00200] Both fentanyl citrate and fentanyl basc formulations were stable at all temperatures
`
`studied. The data from in-vitro tissue permeation studies, as shown in Table 3, showed that
`
`permeation of fentanyl from fentanyl base formulations was about 10-fold higher than from
`
`fentanyl citrate formulations. Water and buffer formulations did not show any significant
`
`difference in fentanyl base permeation across buccal tissue. Our studies also showed that
`
`fentanyl base formulation containing Miglyol® had very low permeability. Among the
`
`excipients, triacetin at 0.5% and mannitol at 0.3% in combination with 0.2% TW 80 showed
`
`good permeability and stability.
`
`Please replace paragraph [00203] with the following paragraph:
`
`[00203] The formulation was sprayed using a 0.10 ml multidose nasal spray pump by Pfeiffer®
`
`of America, Princeton, N.J. [Pfeiffer is a registered trademark of Ing. Erich Pfeiffer GmbH[ and
`
`the droplets were measured using a Malvem® Mastersizer@ S device, by Malvem® Instruments
`
`Ltd. A single depression of the sublingual spray pump generated a plume which was then
`
`analyzed for spray particles. The sample size for the dose volume, spray pattern, and droplet size
`
`distribution was 25 sprays.
`
`Plcasc rcplacc paragraph [00209] with the following paragraph:
`
`[00209] The formulation was sprayed using a 0.10 ml multidose nasal spray pump by Pfeiffer@
`
`of America, Princeton, N.J. and the droplets were measured using a Malvern® Mastersizer® S
`
`device, by Malvem@ Instruments Ltd. A single depression of the sublingual spray pump
`
`generated a plume which was then analyzed for spray particles. The sample size for the dose
`
`volume, spray pattern, and droplet size distribution was 25 sprays.
`
`Please replace paragraph [00214] with the following paragraph:
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`[00214] The equipment and supplies utilized in this process included an HPLC system equipped
`
`with a pump, variable wavelength detector, and autosampler, or equivalent, a Waters Symmetry
`
`HPLC column (C18, 4.6><75 mm, 3.5 um particle size), 0.45 mm, 47 mm nylon filters (Gelman
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`%=l»a~fle® Nylaflo® P/N 66608 or equivalent; Nylaflo is a registered trademark of Membrana
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`Page 6 of 14
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`

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`Response to Office Action mailed January 10, 2014
`Serial No. 13/895,124
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`Inc.), acetonitrile (HPLC Grade), potassium phosphate monobasic (ACS Grade), phosphoric acid
`
`(ACS Grade), deionized water, alcohol (ethanol, absolute), and fentanyl base reference standard.
`
`Please replace paragraph [00230] with the following paragraph:
`
`[00230] In Example 16 the method for determination of droplet size distribution by laser
`
`diffraction for fentanyl sublingual spray using the Spraytec device by Malvem@ was performed.
`
`Please replace paragraph [00234] with the following paragraph:
`
`[00234] Samples were prepared using Pfeiffer® unit dose glass vials, Pfeiffer® unit dose VI
`
`stoppers, Pfeiffer@ vial holder, and Pfeiffer@ unit dose applicator. The instrumentation utilized in
`
`the study include a Spraytec with 200 mm lens by Malvem® Instruments, Inc, a MightyRunt
`
`Actuation Station by Innova Systems Inc. equipped with an exhaust fan attachment, and a
`
`Mettler Toledo@ balance Model AT201.
`
`Please replace paragraph [00266] with the following paragraph:
`
`[00266] The HPLC process was consistent with the process described in Example 15 above. The
`
`materials and supplies utilized in the study included acetonitrile (HPLC Grade), potassium
`
`phosphate monobasic (ACS Grade), phosphoric acid (ACS Grade), deionized water, alcohol
`
`(ethanol, absolute), Short Stack Andersen Cascade Impactor set-up consisting of a 5-liter
`
`expansion chamber, induction port, stages 0, 1, 2, and after filter, a vacuum source, in-line flow
`
`meter (Sierra Top-Track or equivalent), VWR® §VWR is a registered trademark of VWR
`
`International, Inc.) Sterile sampling bags, glass fiber filter, 8.1 cm, external calibrated flow meter
`
`(Dry—Cal Flow Meter or equivalent), and a pneumatic actuator (Innova Systems Mighty Runt or
`
`equivalent).
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`Page 7 of 14
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`

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`Response to Office Action mailed January 10, 2014
`Serial No. 13/895,124
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`LISTING OF THE CLAIMS
`
`1.
`
`(Original) A sublingual fentanyl formulation comprising discrete liquid droplets of an
`
`effective amount of fentanyl, a free base or a pharmaceutically acceptable salt thereof, or
`
`derivative thereof, in a pharrnaceutically acceptable liquid carrier; said droplets having a mean
`
`diameter of at least about 10 microns.
`
`2.
`
`(Withdrawn) A method of treating pain comprising sublingually administering a liquid
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`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 free base or a pharrnaceutically acceptable salt thereof, or
`
`derivative thereof, dispersed in a pharrnaceutically acceptable liquid carrier.
`
`3.
`
`(Withdrawn) A multi-dose device for sublingual administration of a drug comprising:
`
`a reservoir containing a liquid formulation comprising fentanyl, a free base or a
`
`pharrnaceutically acceptable salt thereof, or derivative thereof in a pharrnaceutically
`
`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.
`
`4.
`
`(Original) 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 50% to about 60% 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.
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`Page 8 of 14
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`

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`Response to Office Action mailed January 10, 2014
`Serial No. 13/895,124
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`REMARKS
`
`I. Specification
`
`The specification has been amended to properly respect the proprietary nature of the
`trademarks contained therein.
`
`2. Claims
`
`Claims 1 and 4 are pending. Claims 2 and 3 have been withdrawn from consideration as
`
`drawn to a non-elected invention/species without an allowable generic claim or linking claim.
`
`35 U.S.C. §112 Rejections
`
`Claim 1 stands rejected under 35 U.S.C. § 112, first paragraph, as failing to comply with
`
`the enablement requirement because the specification “does not reasonably provide enablement
`
`for sublingual formulations comprising ‘derivatives thereof”. The Office Action admits that the
`
`specification is enabling for sublingual formulations comprising fentanyl.
`
`Applicants respectfully traverse the rejection. The specification limits the type of
`
`derivatives to sufentanil, carfentanil, lofentanil, alfentanil or the like (para.[0043]). All of these
`
`derivatives are structural and functional analogues of fentanyl. Each of these analogues possesses
`
`the same N-Phenyl-N-(4-piperidinyl)propanamide backbone as fentanyl and differ only slightly
`
`in the substituents of that backbone. All of these analogues and their effective amounts are well
`
`known in the art. What is not well known in the art are sublingual formulations of fentanyl or
`
`these analogues that have discrete liquid droplets having a mean diameter of at least about 10
`
`microns. This slight variation in the identity of the substituents that are attached to the backbone
`
`should have little to no effect on the ability to form these discrete liquid droplets. Thus, taking
`
`any of the sublingual fentanyl formulations from the specification, which the Office Action
`
`admits are enabling, and replacing an effective amount of fentanyl with an effective amount of
`
`one of these analogues would not impose undue experimentation on a person having ordinary
`
`skill in the art (“PHOSITA”).
`
`Claims 1 and 4 are provisionally rejected under 35 U.S.C. § 112, first paragraph, as
`
`failing to enable a PHOSITA to make effective formulations as claimed except for the sublingual
`
`formulations comprising 20% ETOH and 5% PG and 5mg/ml fentanyl base (~ 10 microns-e.g.
`
`Page 9 of 14
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`

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`Response to Office Action mailed January 10, 2014
`Serial No. 13/895,124
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`Tables 48 and 49), which are able to achieve the desired pain management (e.g. Cmax, Tmax,
`
`half-life, AUC). The provisional nature of this rejection is based on the Applicants successfully
`
`overcoming the prior art rcjcctions bclow.
`
`Applicants respectfully and anticipatorily traverse this provisional
`
`rejection.
`
`A
`
`PHOSITA based on his or her knowledge at the time of filing the application would be able to
`
`determine an effective amount of fentanyl, a free base or pharrnaceutically acceptable salt
`
`thereof, or derivative thereof as an effective amount of each was well known in the art. A
`
`PHOSITA would not have been able to determine the composition comprising discrete liquid
`
`droplets having a mean diameter of at least 10 microns. The sublingual fentanyl formulations
`
`from the specification, which the Office Action admits are enabling, result in discrete liquid
`
`droplets having a mean diameter of at least 10 microns. Varying the given amounts of ETOH
`
`and PG in these formulations or replacing these with disclosed or known equivalents to produce
`
`sublingual fentanyl formulations comprising discrete liquid droplets having a mean diameter of
`
`at least 10 microns would not impose undue experimentation on a PHOSITA because sufficient
`
`guidance has been given.
`
`Claim 1 stands rejected under 35 U.S.C. § 112, first paragraph, as containing subject
`
`matter which was not described in the specification in such a way to reasonably convey to a
`
`PHOSITA that the inventors, at the time the application was filed, had possession of the claimed
`
`invention.
`
`Specifically,
`
`the Office Action asserts that the specification and claims do not
`
`indicate what distinguishing (i.e. common structural) attributes are shared by the derivatives.
`
`Applicants respectfully traverse this rejection. As stated above, the specification limits
`
`the type of derivatives to sufentanil, carfentanil, lofentanil, alfentanil or the like (para.[0043]).
`
`All of these derivatives are structural and functional analogues of fentanyl. Each of these
`
`analogues possesses the same N-Phenyl-N-(4-piperidinyl)propanamide backbone as fentanyl and
`
`differ only slightly in the substituents of that backbone. This backbone provides the common
`
`structural attribute among the derivatives. A PHOSITA reading the claim in light of the
`
`specification would reasonably conclude that a sufficient number of species are disclosed to
`
`describe the genus which is limited to sufentanil, carfentanil, lofentanil, alfentanil or the like.
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`Page 10 of 14
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`Response to Office Action mailed January 10, 2014
`Serial No. 13/895,124
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`Claims 1 and 4 are provisionally rejected under 35 U.S.C. § 112, first paragraph, as
`
`failing to describe in the specification in such a way as to reasonably convey to a PHOSITA that
`
`the inventors, at the time the application was filed, had possession of the claimed invention. The
`
`Office Action asserts that the specification describes only sublingual formulations comprising
`
`20% ETOH and 5% PG and 5 mg/ml fentanyl (~ 10 microns-e.g. Tables 48 and 49), which are
`
`able to achieve the desired pain management
`
`(e.g. Cmax, Tmax, half-life, AUC).
`
`The
`
`provisional nature of this rejection is based on the Applicants successfully overcoming the prior
`
`art rejections below.
`
`Applicants respectfully and anticipatorily traverse this provisional
`
`rejection.
`
`The
`
`specification describes more than one sublingual fentanyl formulation (see examples 1-5).
`
`Examples 3-5 in addition to ETOH and PG contain mannitol, Tween® 80, triacetin, buffer and
`
`mioglyol. Example 6 provides Cmax, Tmax, half-life and AUC values for Examples 1-5. These
`
`examples along with the 20% ETOH, 5% PG and 5 mg/ml fentanyl example are sufficient to
`
`reasonably convey to a PHOSITA that the inventors, at the time the application was filed, had
`
`possession of the claimed invention.
`
`In summary, claims 1 and 4 meet the requirements of written description and enablement
`
`set forth in 35 U.S.C. § 112, first paragraph. Accordingly, the Applicants respectfully request
`
`withdrawal of these rejections.
`
`35 U.S.C. § 102/103 Rejections
`
`Claims 1 and 4 are rejected under 102(e) as anticipated by or, in the alternative under
`
`103(a) as obvious over McCarty (US 2007/0071806). The Office Action asserts that McCarty
`
`teaches sublingual fentanyl formulations which comprise ETOH and PG. The Office Action
`
`admits that McCarty does not teach droplet sizes of at least about 10 microns. The Office Action
`
`asserts that the burden is on the Applicants to show a novel or unobvious difference between the
`
`claimed product and the product of the prior art, citing In re Best, 562 F.2d 1252 (CCPA 1977).
`
`Applicants respectfully traverse this rejection. In In re Best, the court found that the later
`
`filed application was anticipated and obvious over an earlier patent despite the fact that the
`
`application’s claims had an additional element not taught by the earlier patent, namely a cooling
`
`rate. The court found that removing the heat source would necessarily lead to the cooling rate
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`Response to Office Action mailed January 10, 2014
`Serial No. 13/895,124
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`claimed and that the applicants failed to show that normal cooling rates were not sufficient for
`
`the process described in the application.
`
`In re Best, does not apply to the instant application because the situation is not analogous.
`
`The additional element claimed in the instant application’s claim 1, namely discrete droplets
`
`having a mean diameter of at least 10 microns, does not necessarily result from the product
`
`taught in McCarty. McCarty teaches that a fentanyl formulation could contain ethanol and
`
`propylene glycol. However, McCarty does not teach that these formulations are limited to those
`
`that are capable of forming discrete droplets having a mean diameter of at least 10 microns. Any
`
`fentanyl formulation containing ethanol and propylene glycol will not necessarily result in
`
`discrete droplets having a mean diameter of at least 10 microns. Additionally, McCarty does not
`
`teach the concentration ranges described in claim 4 of the instant application. Furthermore, all of
`
`McCarty’s examples teach sublingual/buccal tablets.
`
`The Office Action contends that even if McCarty does not meet the limitations of the
`
`instant invention under 10[2], it would still have been obvious at the time of the instant invention
`
`to have optimized the conditions to provide a formulation with a rapid/desired onset of action to
`
`reduce pain quickly as possible. The Office Action further notes that there is no upper limit to
`
`the droplet size, so any droplets taught by McCarty would meet the instant claims.
`
`McCarty does not teach or suggest that a fentanyl formulation of any particular droplet
`
`size would be useful for treating pain. Thus, a PHOSITA would not have found it obvious to
`
`optimize the conditions taught in McCarty, namely sublingual/buccal tablets,
`
`to provide the
`
`instantly claimed invention of a sublingual fentanyl spray with discrete liquid droplets having a
`
`mean diameter of at least 10 microns. McCarty mentions, although does not teach, the possible
`
`use of nasal sprays. However, nasal sprays are likely to have droplet sizes with a mean diameter
`
`of less than 10 microns so that the dose does not drip back through the nasal openings. Thus,
`
`even the liquid spray formulations mentioned by McCarty would not necessarily result in or
`
`make obvious droplet sizes with a mean diameter of at least about 10 microns.
`
`Claims 1 and 4 are rejected under 35 U.S.C. 102(b) as anticipated by or alternatively
`
`under
`
`l03(a) as obvious over Ross
`
`(US 2003/0190290)
`
`(“Ross 2003”) or Ross
`
`(US
`
`2006/0062812) (“Ross 2006”). The Office Action asserts that Ross 2003 and Ross 2006 teach
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`Response to Office Action mailed January 10, 2014
`Serial No. 13/895,124
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`sublingual fentanyl formulations as claimed. The Office Action admits that Ross 2003 and Ross
`
`2006 are silent as to droplet size. The Office Action asserts that the burden is on the Applicants
`
`to show a novel or unobvious difference between the claimed product and the product of the
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`prior art citing In re Best.
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`Applicants respectfully traverse this rejection.
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`In re Best, does not apply to the instant
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`application because the situation is not analogous. The additional element claimed in the instant
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`application’s claim 1, namely discrete droplets having a mean diameter of at least 10 microns,
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`does not necessarily result from the product taught in Ross 2003 or Ross 2006. Ross 2003 and
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`Ross 2006 each teach a fentanyl formulation containing ethanol and propylene glycol. However,
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`neither Ross 2003 nor Ross 2006 teach that this formulation is limited to that which is capable of
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`forming discrete droplets having a mean diameter of at
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`least 10 microns. Any fentanyl
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`formulation containing ethanol and propylene glycol will not necessarily result
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`in discrete
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`droplets having a mean diameter of at least 10 microns. Additionally, neither Ross 2003 nor
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`Ross 2006 teach the concentration ranges described in claim 4 of the instant application.
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`Furthermore none of Ross 2006’s examples contain both ethanol and propylene glycol.
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`The Office Action contends that even if Ross 2003 or Ross 2006 do not meet the
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`limitations of the instant invention under 10[2], it would still have been obvious at the time of the
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`instant invention to have optimized the conditions to provide a formulation with a rapid/desired
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`onset of action to reduce pain quickly as possible. The Office Action further notes that there is
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`no upper limit to the droplet size, so any droplets taught by Ross 2003 or Ross 2006 would meet
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`the instant claims.
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`Neither Ross 2003 nor Ross 2006 teach or suggest that a fentanyl formulation of any
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`particular droplet size would be useful for treating pain. Thus, a PHOSITA would not have
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`found it obvious to optimize the conditions taught in Ross 2003 or Ross 2006 to provide the
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`instantly claimed invention of a sublingual fentanyl spray with discrete liquid droplets having a
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`mean diameter of at least 10 microns.
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`Double Patenting
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`The Office Action rejected claims 1 and 4 on the ground of nonstatutory obviousness-
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`type double patenting over claims 1-3 of U.S. Patent No. 8,486,973 and/or claims 1-20 of U.S.
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`Page 13 of 14
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`

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`Response to Office Action mailed January 10, 2014
`Serial No. 13/895,124
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`Patent No. 8,486,973. The Office Action also provisionally rejected claims 1 and 4 on the
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`ground of nonstatutory obviousness-type double patenting over claims 1-3 of co-pending
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`Application No. 13/895,111.
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`In response, Applicants respectfully request that this rejection be held in abeyance until
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`the instant application is deemed to have allowable subject matter but for the double—patenting
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`rejection.
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`Conclusion
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`None of McCarty, Ross 2003 or Ross 2006 teaches or makes obvious a sublingual
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`fentanyl spray having discrete droplets having a mean diameter of at least about 10 microns.
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`Applicants respectfully submit that the pending claims 1 and 4 are patentable. Accordingly,
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`reconsideration of the rejections and allowance of the application are requested. Should the
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`Examiner have any questions concerning the above, he is respectfully requested to contact the
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`undersigned at the telephone number listed below.
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`Respectfully submitted,
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`Date: March 6, 2014
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`/Steven F. Weinstocld
`Steven F. Weinstock, Registration No. 30,117
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`WOOD, PHILLIPS, KATZ,
`CLARK & MORTIMER
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`500 West Madison Street, Suite 1130
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`Chicago, IL 60662-2511
`Tel.: (312) 876-2110
`Fax.: (312) 876-2020
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`Page 14 of 14