Exhibit 1014
`
`Coalition For Affordable Drugs XI LLC
`Exhibit 1014
`Coalition For Affordable Drugs XI LLC v Insys Pharma, Inc.
`IPR2015-01800
`
`

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`Attorney Docket No. INSl0763P00090US
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`PATENT
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In Re Application of: KOTTAYIL, S.
`George, et al.
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`Confirmation No.: 4756
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`Serial No.:
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`11/698,739
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`Group Art Unit:
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`1646
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`Filed:
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`January 25, 2007
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`Examiner:
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`Sandra WEGERT
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`FOR: SUBLINGUAL FENTANYL SPRAY
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`Commissioner for Patents
`P.O. Box 1450
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`Alexandria, VA 22313-1450
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`AMENDMENT/RESPONSE
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`In response to the Office Action dated June 8, 2012, please amend the above-identified
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`patent application in the following manner:
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`Amendments to the Claims are reflected on the listing of the claims which begins on
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`page 2 of this paper.
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`Remarks/Arguments begin on page 4 of this paper.
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`Page 1 of 7
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`

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`Response to Office Action mailed June 8, 2012
`Serial No. 11/698,739
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`Amendments to the Claims:
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`Set forth below in ascending order, with status identifiers, is a complete listing of all
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`claims currently under examination. Changes to any amended claims are indicated by
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`strikethrough and underlining. This listing also reflects any cancellation and/or addition of
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`claims.
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`Claims 1-143. (Cancelled).
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`144.
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`(Currently Amended) A unit dose of a non-propellant
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`sublingual
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`fentanyl
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`formulation comprising discrete liquid droplets of an effective amount of fentanyl
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`and a pharmaceutically acceptable liquid carrier, wherein the sublingual fentanyl
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`formulation comprises:
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`from about 0.1% to
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`about 0.8% by weight of
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`fentanyl or
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`a
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`pharmaceutically
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`acceptable salt thereof;
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`from about 20% to about 60% by weight of ethanol; and
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`from about 4% to about 6% by weight of propylene
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`glycol;
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`
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`wherein after sublingual administration to a human, said sublingual fentanyl
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`formulation provides[:—}
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` m
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`%&p
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`a mean time to maximum plasma concentration (Tmax) of fentanyl of
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`from about 10 to about 60 minutes;—and
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`Page 2 of 7
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`

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`Response to Office Action mailed June 8, 2012
`Serial No. 11/698,739
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`
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`145.
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`(Previously Presented) The unit dose of claim 144, wherein said discrete liquid
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`droplets have a size distribution of from about 10pm to about 200 pm.
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`146.
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`(Cancelled).
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`147.
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`(Cancelled)
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`148.
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`(New) The unit dose of claim 144 wherein after sublingual administration to a
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`human, the sublingual fentanyl formulation provides a mean time to masimurn
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`plasma concentration (Tmax) of fentanyl from about 5 to 120 minutes.
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`Page 3 of 7
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`

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`Response to Office Action mailed June 8, 2012
`Serial No. 11/698,739
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`REMARKS/ARGUMENTS
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`I.
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`Status of the Claims
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`Claims 144-145 are pending. Claim 144 has been amended and claim 148 has been
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`added to reflect "time-to-onset—of-action" in terms of the formulation and Tmax as
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`supported by the Application (pages 3 and 5 and the original claims) and by the
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`Declaration of Dr. Larry Dillaha submitted herewith. No new matter has been added.
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`II.
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`The Claims
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`The pending claims recite various "compositional" limitations (i.e., amounts of
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`fentanyl, ethanol, propylene glycol), and pharmacokinetic (PK) limitations. These claims
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`recite a unique formulation which has unique characteristics and efficacy as mentioned
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`herein.
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`As evidented by the Declaration of Dr. Larry Dillaha submitted herewith,
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`the
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`clinical efficacy has clear advantages which are neither predictable or expected.
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`In
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`particular, when compared to placebo and all commercial transmucosal immediate release
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`fentanyl formulations, the claimed unit dose provides statistically significant relief as early
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`as 5 minutes whereas the competitive products do not begin relief until at least 10-15
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`minutes for breakthrough pain in cancer patients. This is significant and critical.
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`The cited reference US 2006/0062812 (Ross)
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`is
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`inferior with respect
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`to the
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`composition of the formulation of the present unit dose and does not disclose, suggest or
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`recognize the importance of the composition. Furthermore, Ross fails to disclose clinical
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`efficacy better than a 30 minute onset. Accordingly, the compositional differences and such
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`unexpected results render the present claims non-obvious. As a result, the present claims are
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`patentable over Ross.
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`Page 4 of 7
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`

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`Response to Office Action mailed June 8, 2012
`Serial No. 11/698,739
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`III.
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`Rejection Under 35 ‘USC §103 Over Ross
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`The Examiner has rejected the pending claims as prima facie (pf) obvious over
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`Ross. The Examiner states that Ross discloses a sublingual fentanyl formulation having
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`the same ingredients and similar pharmacokinetics. Further, the Examiner has stated that
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`the Applicants have not provided evidence to overcome p.f. obviousness; that is,
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`the
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`Applicants have not provided unexpected results.
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`Ross neither discloses the claimed formulations with propylene glycol, achieves the
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`quick onset of action that such formulations provide and at best achieves a mean time to
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`maximum plasma concentration (Tmax) of fentanyl no better than 30 minutes. Further,
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`there is no direction or clear suggestion to add propylene glycol or achieve such Trnax or
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`quick onset which is
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`so desperately needed for cancer patients who experience
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`breakthrough pain.
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`The Examiner has stated that Ross comprises the same ingredients as the instant
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`formulation. Applicants respectfully disagree. Applicants’ formulation includes propylene
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`glycol. Although mentioned in a prior Ross application (US 2003/0190290), now
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`abandoned, it does not suggest how to use it, what quantities to use or how it will effect the
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`outcome, Tmax or quicker onset. Furthermore, just because Ross discloses a fentanyl
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`sublingual spray and there are similarities of the formulations of Ross to those of the
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`claimed invention, does not mean that Ross inherently discloses pharmacokinetic (PK)
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`characteristics of the claimed invention.
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`It
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`is well established law that an inherent property must “necessarily” and
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`inevitably” be present
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`in a single disclosure or embodiment of the prior art. MPEP
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`2112(lV) (citing In re Rzjckaert, 9 F.3d 1531, 1534 (Fed. Cir. 1993)). See also In re
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`Robertson, 169 F.3d 743, 745 (Fed. Cir. 1999) (“To established inherency, the extrinsic
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`evident must make clear that the missing descriptive matter is necessarily present in the
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`thing described in the reference, and that it would be so recognized by persons of ordinary
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`skill.
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`lnherency, however, may not be established by probabilities or possibilities. The
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`mere fact that a certain thing may result from a given set of circumstances is not
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`Page 5 of 7
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`

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`Response to Office Action mailed June 8, 2012
`Serial No. 11/698,739
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`sufficient.”).
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`As shown in the present specification and in the Declaration of Dr. Larry Dillaha,
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`the claimed formulation including propylene glycol results in PK characteristics and Tmax,
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`in particular, and onset of action far beyond expected and superior to all commercial
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`transmucosal immediate release fentanyl formulations despite the fact that Ross was filed 8
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`years ago and many competitors have tried but failed to accomplish such quick onset.
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`Although Ross states it is preferably to have a composition that has a time to—onset—
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`of~action less than 30 or 15 or 10 or even 5 minutes, Ross only provides plasma
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`concentrations with a Tmax of 30 minutes. So it seems that Ross did not recognize the
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`value of propylene glycol as a result-effective variable. A particular parameter must first
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`be recognized as a result-effective variable, i.e., a variable which achieves a recognized
`result, before the determination of the optimum or workable ranges of said variable might
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`be characterized as routine experimentation. MPEP 2l44.05(II)(B) (citing In re Antonie,
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`559 F.2d 618 (CCPA 1977), emphasis added).
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`In summary, Ross does not disclose the claimed Tmax or the claimed amount of
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`propylene glycol.
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`Since Ross fails to disclose or recognize the importance of the
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`formulation composition in the present unit dose, or the relationship to clinical efficacy,
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`Ross cannot recognize the unexpected Tmax values provided by the present formulations,
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`nor the clinical advantages provided. Most importantly, Ross does not teach, suggest or
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`disclose how to get the unexpected and statistically significant result of 5 minutes to onset-
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`of-action that the claimed unit doses/formulations do. Thus, Ross clearly fails to suggest
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`the claimed invention. Accordingly, Applicants respectfully request that the rejection be
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`withdrawn.
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`IV.
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`CONCLUSION
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`In View of the foregoing, Applicant respectfully submits that no further impediments
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`Page 6 of 7
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`

`
`Response to Office Action mailed June 8, 2012
`Serial No. 11/698,739
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`exist
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`to the allowance of this application and,
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`therefore,
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`requests an indication of
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`allowability. However, the Examiner is requested to call the undersigned if any questions or
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`comments arise,
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`The Director is hereby authorized to charge any appropriate fees under 37 C.F.R.
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`§l .16, 1.17, and 1.21 that may be required by this paper, and to credit any overpayment, to
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`Deposit Account No. 23-0785.
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`Respectfully submitted,
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`/Steven F. Weinstock/
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`Steven F. Weinstock, Registration No. 30,1 17
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`WOOD, PHILLIPS, KATZ,
`CLARK & MORTIMER
`500 West Madison Street, Suite 1130
`Chicago, IL 60662-251 1
`Tel.: (312) 876-2112
`Fax.: (312) 876-2020
`
`Page 7 of 7