Exhibit 1026
`
`Coalition For Affordable Drugs XI LLC
`Exhibit 1026
`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, S.
`George, et al.
`
`Confirmation No.:
`
`4756
`
`Serial No.:
`
`11/698,739
`
`Group Art Unit:
`
`1646
`
`Filed:
`
`January 25, 2007
`
`Examiner:
`
`Sandra WEGERT
`
`FOR:
`
`SUBLINGUAL FENTANYL SPRAY
`
`Mail Stop RCE
`Commissioner for Patents
`PO. Box 1450
`
`Alexandria, VA 22313-1450
`
`AMENDMENT/RESPONSE TO OFFICE ACTION
`
`In response to the final Office Action dated November 17, 2011, please amend the above-
`
`identified patent application in the following manner:
`
`Amendments to the Claims are reflected on the listing of the claims which begins on
`
`page 2 of this paper.
`
`Remarks/Arguments begin on page 4 of this paper.
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`Attorney Docket No. INTH—001/01US 308548-2014
`Serial No. 11/698,739
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`IN THE CLAIMS:
`
`Set/brth below in ascending order, with status identifiers, is a complete listing ofall
`
`claims currently under examination. Changes to any amended claims are indicated by
`
`strikethrough and underlining. This listing also reflects any cancellation and/or addition of
`
`claims.
`
`Claims l-143. (Canceled).
`
`144.
`
`(New) A unit dose of a non—propellant sublingual fentanyl formulation comprising
`
`discrete liquid droplets of an effective amount of fentanyl and a pharmaceutically
`
`acceptable liquid carrier, wherein the sublingual fentanyl formulation comprises:
`
`from about 0.1% to about 0.8% by weight of fentanyl or a pharmaceutically
`
`acceptable salt thereof;
`
`from about 20% to about 60% by weight of ethanol; and
`
`from about 4% to about 6% by weight of propylene glycol;
`
`wherein said discrete liquid droplets have a size distribution of from about 5 um
`
`to about 500 um, and a mean diameter of about 20 mm to about 200 tun;
`
`wherein after sublingual administration to a human, said sublingual fentanyl
`
`formulation provides:
`
`a mean maximum plasma concentration (Cmax) of fentanyl of from about
`
`158 pg/ml, to about 177 pg/mL per 100 ug fentanyl;
`
`a mean time to maximum plasma concentration (Tmax) of fentanyl of from
`
`about 10 to about 60 minutes; and
`
`a mean area under the plasma concentration time curve to infinity (AUQD)
`
`of fentanyl of from about 715 pg-hour/mL to about 1061 pg-hour/mL per 100 pg
`
`fentanyl.
`
`145.
`
`(New) The unit dose of claim 144, wherein said discrete liquid droplets have a size
`
`distribution of from about 10 um to about 200 um.
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`146.
`
`(New) The unit dose of claim 144, wherein said discrete liquid droplets have a size
`
`distribution of from about 20 um to about 100 um.
`
`147.
`
`(New) The unit dose of claim 144, wherein said discrete liquid droplets have a size
`
`distribution of from about 30 um to about 70 um.
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`Attorney Docket No. INTH—001/01US 308548-2014
`Serial No. 11/698,739
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`1.
`
`Status of the Claims
`
`REMARKS
`
`Claims 1-143 have been canceled without prejudice to their further prosecution. New
`
`claims 144-147 have been added, and are supported by the originally filed claims and the
`
`specification. Specifically:
`
`“unit dose” is supported at 11 10020];
`
`“non—propellant sublingual fentanyl formulation” is supported at ‘H [0076];
`
`“from about 0.1% to about 0.8% by weight of fentanyl”, “from about 20% to about 60%
`
`by weight of ethanol”, and “from about 4% to about 6% by weight of propylene glycol” are
`
`supported at 1] [0099];
`
`“said discrete liquid droplets have a mean diameter of from about 20 microns to about
`
`200 microns” is supported at 11 [00115];
`
`“said discrete liquid droplets have a size distribution of from about 5 microns to about
`
`500 microns,” “from about 10 pm to about 200 um,” “from about 20 pm to about 100 tun,” and
`
`“from about 30 pm to about 70 um” are supported at 11 [0115];
`
`“a mean maximum plasma concentration (Cum) of fentanyl of from about 158 pg/mL to
`
`about 177 pg/mL per 100 pg fentanyl” is supported at 11 [0079] ;
`
`“a mean time to maximum plasma concentration (Tum) of fentanyl of from about 10 to
`
`about 60 minutes” is supported at 11 [0078] ; and
`
`“a mean areas under the plasma concentration time curve to infinity (AUCa)) of fentanyl
`
`of from about 715 pg-hr/mL to about 1061 pg-hr/mL per 100 ug fentanyl” is supported at 11
`
`[0083].
`
`No new matter is believed to have been added. Claims 144-147 are active.
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`Attorney Docket No. INTI-I-001/01US 308548-2014
`Serial No. 11/698,739
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`II.
`
`Interview of December 21, 2011
`
`Applicants wish to thank Examiners Wegert and Nickol for the courteous and helpful
`
`interview held with Applicants’ representatives (Thomas Blinka and the undersigned), on
`
`December 2l, 2011. During the interview, and as presented herein, Applicants’ representatives
`
`discussed the distinction between the previously pending claims and the cited art, and the further
`
`distinction over the cited art provided by the presently presented new claims. Applicants
`
`continue to respectfully assert that the claims previously presented in the response filed February
`
`15, 2011 are unobvious over US 2006/0062812 (Ross). However, in order to advance
`
`prosecution, Applicants have provided new claims which are believed to further an
`
`unequivocally distinguish over Ross, as discussed herein.
`
`III.
`
`Introduction
`
`The pending claims recite various “compositional” limitations (i.e., amounts of fentanyl,
`
`ethanol, propylene glycol), droplet size limitations (i.e., size distribution and mean droplet size),
`
`and pharmacokinetic (PK) limitations (i.e., mean Cmx, mean Tmax, and mean AUC<n).l As
`
`discussed in the Declaration of Venkat Goskonda, submitted herewith (“the Goskonda
`
`Declaration”), the presently claimed amount of propylene glycol enables the formation of the
`
`presently recited droplet sizes and distributions thereof. For example, as discussed at ‘W 5-6 of
`
`the Goskonda Declaration, propylene glycol affects the rheology (e.g., viscosity, density) of the
`
`present formulation, which in turn affect the spray characteristics of the formulation (c.g., droplet
`
`size and size distribution).
`
`In addition, the present specification states that the “particle/droplet size distribution .
`
`.
`
`.
`
`can affect the delivery of the fentanyl,” “alteration of these parameters could lead to variability in
`
`dosing and absorption,” and that providing the “desired droplet/particle size distribution is an
`
`important factor for the correct performance of the fentanyl product.” Instant specification at ‘W
`
`[00l25]—[00l 26]. In other words, Applicants have found that effective PK and clinical
`
`characteristics depend on both the composition of the fentanyl formulation as well as the manner
`
`1 A functional limitation must be evaluated and considered, just like any other limitation of the claim, for wtat it
`fairly conveys to a person of ordinary skill
`in the pertinent art in the context in which it
`is used. MPEP §
`2l73.05(g).
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`in which the formulation is “presented” to the sublingual mucosa ~ e.g., the mean droplet size
`
`and droplet size distribution. Furthermore, as evidenced by the Declaration of Larry Dillaha,
`
`submitted herewith (“the Dillaha Declaration”), the clinical efficacy and side effect profile of the
`
`presently claimed unit dose depends not only on the composition of the formulation, but also on
`
`the droplet size and droplet size distribution of the unit close when administered to the sublingual
`
`mucosa of a patient. Dillaha Declaration at ‘H 6.
`
`Furthermore, the presently claimed unit dose provides efficacious pain relief at
`
`significantly lower Cmax values relative to other sublingual fentanyl formulations, and provides
`
`distinct clinical benefits. Since the present unit dose provides efficacious pain relief at
`
`significantly lower Cmax values, the incidence of serious, potentially fatal side effects associated
`
`with higher Cmax values is minimized in the presently claimed unit dose relative to other
`
`sublingual fentanyl formulations. Dillaha Declaration at 1] 22.
`
`Finally, the relatively low mean Cmax values provided by the present formulations were
`
`uncxpcctcd in view of the significantly higher mean Cmax values provided by other sublingual
`
`fentanyl formulations. Dillaha Declaration at ‘ll 19.
`
`The cited reference US 2006/0062812 (Ross) is silent with respect to the critical nature of
`
`the composition of the formulation of the present unit dose in forming the presently claimed
`
`droplet sizes and distribution.
`
`In addition, Ross fails to disclose, suggest or recognize the
`
`relationship between droplet size and clinical efficacy. Furthermore, since Ross fails to disclose
`
`or recognize the importance of the formulation composition in the present unit dose, or the
`
`relationship between droplet size and clinical efficacy, Ross cannot recognize the clinical
`
`advantages provided by the present unit dose. Finally, the present formulations provide
`
`efficacious pain relief at unexpectedly low Cum, values, and accordingly, such unexpected results
`
`render the present claims non-obvious. As a result, the present claims are patentable over Ross.
`
`IV.
`
`Rejection Under 35 USC §103 Over Ross
`
`The Examiner has rejected the previously pending claims as obvious over Ross.
`
`In
`
`support of this rejection, the Examiner states that “Ross does not specifically teach a liquid
`
`droplet size of at least about 10 microns, nor a mean Cmax of l27pg/ml to 213 pg/ml”, but that
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`“the broad teachings of Ross” ~ i.e., “several concentrations of the required blood concentrations
`
`of fentanyl” — “cure these deficiencies”, thus concluding that it would have been “prima facie
`
`obvious
`
`to have used the teachings of Ross to optimize the fentanyl formulations and means
`
`of administration in order to achieve
`
`Cmax’s of 127 to 2l3pg/ml of 100 ug fentanyl.” Office
`
`Action at page 4.
`
`Applicants first respectfully submit that the Examiner has somewhat mischaracterized
`
`Ross. Applicants agree that Ross does not teach the claimed liquid droplet size. Indeed, Ross
`
`fails to disclose any droplet size, or even recognize the importance of controlling droplet size or
`
`droplet size distribution. However, Ross do_e§ expressly teach a mean Cmax for a “non-
`
`pressurized pump spray” formulation of 516.3 pg/mL per 200 pg fentanyl (258.15 pg/mL per
`
`100 ug fentanyl) which is substantially larger (i.e., 22% larger than the largest mean Cm, value
`
`described in the present specification, 213 pg/ml per 100 pg fentanyl; see paragraph [0079] of
`
`the present specification) and 45% larger than the maximum mean Cmax value claimed, 177
`
`pg/mL per 100 ug fentanyl. See Ross, Tables l and 2, first column, page 8.2
`
`In addition, Applicants submit that the individual Cum values referred to by the Examiner
`
`(i.e., the individual Cum values found for patients 6-8 of Table 2 of Ross) which fell within the
`
`previously claimed mean Cmax range of about 127-213 pg/mL per 100 pg fentanyl, are, as a
`
`threshold matter, not relevant to the claimed limitation. That is, an individual Cmax is not the
`
`same parameter as a “mean” Cmax because an individual Cmax refers to the maximum plasma
`
`concentration found in a §iggl_e patient, whereas the mean Cmax characterizes the average
`
`maximum plasma concentration found in a population of patients.
`
`As evidenced by the Dillaha Declaration, mean Cmax values and discrete Cmax values are
`
`distinct measurements with distinct clinical significance. For example, individual Cmax values
`
`for individual patients may vary widely as a function of, e.g., patient body weight, differences in
`
`efficiency of metabolism of the compound in question (e.g., fentanyl), consistency of
`
`administration of the drug between patients, etc. Conversely, a mean Cum provides an average
`
`Cmax value for a drug across a patient population. Such an average incorporates both typical Cmax
`
`2 As demonstrated in Table 18 of the present specification, sublingual fentanyl spray formulations having widely
`varying doses of, respectively, 100 pg, 400 pg, and 800 pg, all exhibit roughly similar PK values when normalized
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`values and “outliers” (e. g., those values which are significantly higher or lower than those Cmax
`
`values typically observed) in the patient population, and averages those values to provide a mean
`
`Cmax which is statistically valid and predictive of what Cmax values will be observed across the
`
`majority of a patient population. Thus, a single, individual Cmax value in any single patient and
`
`the mean Cmax value for a patient population provided by a formulation can differ significantly,
`
`and are distinct. See the Dillaha Declaration at ‘H l 1.
`
`Furthermore, Applicants respectfully submit that the selection of particular individual
`
`Cmax values from Ross must be improperly based on hindsight knowledge of Applicants’ claimed
`
`Cmax range. Specifically, Table 2 discloses 12 individual Cmax values, ranging from a low of 273
`
`pg/mL per 200 ug fentanyl to a high of 755 pg/mL per 200 pg fentanyl (respectively, 136.5 and
`
`377.5 pg/mL per 100 ug fentanyl). The Examiner has provided no rationale as to why one would
`
`select any particular individual Cmax value within this wide range as a desirable "target" for a
`
`“modified” mean Cmax. Applicants respectfully submit that any such selection could only be
`
`based on hindsight knowledge of Applicants’ far different mean Cmax range.
`
`Even if it were reasonable to compare individual Cmax values to mean Cm“ values (which
`
`Applicants do not concede), the present claims now recite a mean Cum range (about 158-177
`
`pg/mL per 100 ug fentanyl) which excludes all Cmax values taught in Ross, including mean Cmx
`
`and individual Cmax values.
`
`The Examiner urges that it would be "prima facie obvious" to modify Ross, based on
`
`Ross ’s own teachings, to obtain the claimed invention. However, as discussed above, Ross
`
`expressly teaches a mean Cmax which is far different from the range claimed. Furthermore, one
`
`of skill in the art would not compare individual Cmax values to mean Cmax values, because they
`
`are different parameters. In addition, Ross provides absolutely no suggestion that it would be
`
`desirable to provide a mean Cmax different from the expressly disclosed Cmax value. Even if, in
`
`arguendo, one viewed the disclosure of individual Cmax value as a guide to a hypothetical
`
`modified mean Cmax, there is no direction in Ross as to which individual Cmax value one should
`
`select, and thus this rationale necessarily relies on improper hindsight knowledge of Applicants’
`
`to 100 pg of fentanyl. Accordingly, it is reasonable to normalize the PK parameters of the formulations of Ross to
`the same 100 ug fentanyl basis as in the present claims. See also the Dillaha Declaration at W 11-12.
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`own invention to guide the selection. Finally, the presently claimed Cmax range no longer
`
`includes any individual or mean Cmax values mentioned in Ross.
`
`The Examiner also states that "[s]ince the formulation of Ross comprises the same
`
`ingredients as the instant formulation, produces overlapping Cmax values, is administered
`
`sublingually, and is sprayed into the mouth in the form of liquid droplets, the invention as
`
`claimed is not obviously distinguishable from that of Ross." Thus, the Examiner appears to
`
`argue that due to the similarity of the formulations of Ross to those of the claimed invention,
`
`Ross inherently discloses the PK characteristics of the claimed invention.
`
`Applicants respectfully disagree. It is well established law that an inherent property must
`
`"necessarily" and "inevitably" be present in a single disclosure or embodiment of the prior art.
`
`The fact that a certain result or characteristic may occur or be present in the prior art is not
`
`sufficient to establish the inherency of that result or characteristic.3 However, as discussed
`
`above, Ross expressly discloses mean Cmax values falling_gut_side of the claimed range. Thus, the
`
`disclosure of Ross itself conclusively establishes that the claimed mean Cmax range cannot be
`
`inherently provided by the formulations of Ross, because the formulations of Ross _d_Q_r_1o_t provide
`
`Cmax values within the claimed mean Cmax range.
`
`Applicants also note that Ross fails to disclose formulations which provide the mean
`
`AUCOO range presently claimed, or disclose a single formulation which provides all three PK
`
`parameters presently claimed (mean Cmax, mean Tmax, and mean AUC(x))~ Accordingly, on this
`
`basis alone Ross fails to support primafacie obviousness.
`
`As shown in the present specification and in the Dillaha Declaration, droplet size and
`
`droplet size distribution affect the PK characteristics of the claimed formulation upon
`
`administration. As admitted by the Examiner, Ross fails to disclose the droplet size during
`
`administration, and thus Ross does not recognize the importance of controlling droplet size.
`
`Accordingly, as a matter of well-established law, it would not be obvious to modify the droplet
`
`3 MPEP 21 l2(lV) (citing In re Rzjckaert, 9 F.3d 1531, 1534 (Fed. Cir. 1993)). See also In re Robertson, 169 F.3d
`743, 745 (Fed. Cir. 1999) (“To establish inherency,
`the extrinsic evidence ‘must make clear that the missing,
`descriptive matter is necessarily present in the thing described in the reference, and that it would be so recognized by
`persons of ordinary skill. lnherency, however, may not be established by probabilities or possibilities. The mere fact
`that a certain thing may result from a given set of circumstances is not sufficient”).
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`Attorney Docket No. INTH—001/01US 308548-2014
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`size of the formulations of Ross, as Ross does not recognize that droplet size or droplet size
`
`distribution are result-effective variables. A particular parameter mustfirst be recognized as a
`
`result-ejfective variable, i. e., a variable which achieves a recognized result, before the
`
`determination of the optimum or workable ranges of said variable might be characterized as
`
`routine experimentation.4
`
`Furthermore, the mere disclosure in Ross that sublingual formulations can be dispensed
`
`using different spray devices does not constitute an inherent disclosure of the claimed droplet
`
`size or droplet size distribution. While different spray devices can provide different average
`
`droplet sizes, there is no necessity that any particular spray device will provide the claimed
`
`droplet size range and size distribution, particularly since the droplet size/distribution also
`
`depends in part on the rheological characteristics of the spray composition itself (see, e. g., the
`
`Goskonda Declaration at W 5-7)
`
`Additionally, Applicants note that although Ross mentions the inclusion of various
`
`solvents and other ingredients such as sweeteners, moisturizing agents, penetration enhancers,
`
`etc. (Ross, ‘H11 [0037]-[0056]), the explicitly disclosed formulations of Ross are relatively simple
`
`solutions of fentanyl, ethanol, citrate buffer, saccharine, and menthol. Ross fails to specifically
`
`disclose any formulations containing propylene glycol. As discussed above, and in the
`
`Goskonda Declaration, the claimed amount of propylene glycol modifies the rheological
`
`characteristics (e.g., density, viscosity) of the claimed formulation, and affects the formation of
`
`the claimed droplet size and droplet size distribution, which in turn affects the ultimate PK
`
`characteristics provided upon administration.
`
`Further, the relatively low mean Cmax values provided by the present formulations, and
`
`the observed reduction of breakthrough cancer pain, and associated with the present formulation,
`
`were unexpected in view of the significantly higher mean Cmax values provided by other
`
`sublingual fentanyl dosage forms (e. g. , that described by Ross). Dillaha Declaration atll 19.
`
`Finally, clinical studies5 have established that the presently claimed unit dose comprising
`
`discrete liquid droplets having a size distribution of from about 5 urn to about 500 um, and a
`
`4 MPEP 2l44.05(ll)(B) (citing In re Antonie, 559 F.2d 618 (CCPA 1977), emphasis added).
`5 See Dillaha Declaration at 1111 15-18.
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`mean diameter of about 20 um to about 200 um, and providing a mean Cmax of from about 158
`
`pg/mL to about 177 pg/mL per 100 ug fentanyl, is a safe and efficacious therapy for the
`
`treatment of breakthrough cancer pain episodes, and provides effective pain relief at significantly
`
`lower mean Cmax values than those described in Ross. Dillaha Declaration at 1] 20. Accordingly,
`
`the presently claimed unit dose, which provides efficacious pain relief at significantly lower Cmax
`
`values relative to other sublingual fentanyl formulations, provides distinct clinical benefits
`
`relative to such formulations (e. g., that described by Ross). Since the present unit dose provides
`
`efficacious pain relief at significantly lower Cmax values, the incidence of serious, potentially
`
`fatal side effects associated with higher Cmax values is minimized in the presently claimed unit
`
`dose relative to other sublingual fentanyl formulations such as that of Ross. Dillaha Declaration
`
`at ‘ll 21. Thus, the present unit dose provides clinical advantages which Ross fails to recognize.
`
`In summary, Ross does not disclose the claimed mean Cmax and AUC.,, range, the claimed
`
`amount of propylene glycol, or the claimed droplet size and droplet size distribution. Indeed,
`
`Ross fails to even recognize that formulation components may affect droplet size, much less that
`
`droplet size and droplet size distribution affect the PK characteristics of sublingual fentanyl
`
`spray compositions upon administration. Since Ross fails to disclose or recognize the
`
`importance of the formulation composition in the present unit dose, or the relationship between
`
`droplet size and clinical efficacy, Ross cannot recognize the unexpectedly low Cmax values
`
`provided by the present formulations, nor clinical advantages provided thereby. Thus, Ross
`
`clearly fails to suggest the claimed invention. Accordingly, Applicants respectfully request that
`
`the rejection be withdrawn.
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`CONCLUSION
`
`In View of the foregoing, Applicant respectfully submits that no further impediments
`
`exist to the allowance of this application and, therefore, requests an indication of allowability.
`
`However, the Examiner is requested to call the undersigned if any questions or comments arise.
`
`The Director is hereby authorized to charge any appropriate fees under 37 CPR. §§ 1 .16,
`
`1.17, and 1.21 that may be required by this paper, and to credit any overpayment, to Deposit
`
`Account No. 50-1283.
`
`Dated: Z/'7'/1°’ Z
`COOLEY LLP
`
`ATTN: Patent Group
`
`777 6“‘ Street NW, Suite 1100
`Washington, DC 20001
`
`Tel: (202)728-7127
`Fax: (202) 842-7899
`
`Respectfully submitted,
`COOLEY LLP
`
`BYI
`
`Z E
`_
`
`William E. B
`
`Reg No- 64,209
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`12.