Exhibit 1024
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`Coalition For Affordable Drugs XI LLC
`Exhibit 1024
`Coalition For Affordable Drugs XI LLC v Insys Pharma, Inc.
`IPR2015-01800
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`

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`Attorney Docket No. INTH-001/01US 308548-2014
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`PATENT
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`In Re Application of:
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`KOTTAYIL, S.
`George, et al.
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`Confirmation No.1
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`4756
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`Application No.:
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`1 1/698,739
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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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`WEGERT, Sandra L.
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`FOR:
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`SUBLINGUAL FENTANYL SPRAY
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`Mail Stop AMENDMENT
`Commissioner for Patents
`P . O. Box 145 0
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`Alexandria, VA 22313 -1450
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`REPLY UNDER 37 C.F.R. § 1.111
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`SIR:
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`Responsive to the non—final Office Action mailed May 2, 2011, Applicants respectfully
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`request reconsideration of the present application in View of the following remarks.
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`Remarks begin on page 2 of this paper.
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`

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`Attorney Docket No. INTII-001/01US 308548-2014
`Application No. ll/698,739
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`REMARKS
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`1.
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`Status of the Claims
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`Claims 1-8, 10-29 and 31-143 are pending in the present application. Claims 5-8, 12-19,
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`24-29 and 33-138 are withdrawn.
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`II.
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`Rejection Under 35 USC § 112, Second Paragraph
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`Claims 1-4, 10, 11, 20-23, 31, 32 and 139-143 are rejected under 35 U.S.C. § 112, second
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`paragraph, as allegedly being indefinite for failing to particularly point out and distinctly claim
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`the subject matter which applicant regards as the invention. Office Action at pp. 3-4. Applicants
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`respectfully traverse on the ground that the present claims are in no way unclear or indefinite,
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`and describe explicitly the metes and bounds of the claimed invention.
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`The Examiner alleges that “the independent claims recite that the discrete liquid droplets
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`must have a mean diameter of at least about 10 microns. Additional claims recite ‘2O microns,’
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`‘5-500 microns,’ or ‘l0-200 microns.’ The claims are indefinite in that it is unclear how to
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`achieve that particle size using the formulation specified. Similarly, the claims are indefinite in
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`that it is unclear how the recited particle size relates to the effective concentrations recited, or
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`how a particular droplet size contributes to a particular recited Cmax.” Office Action at p. 4.
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`With regard to the Exarniner’s assertion that “[t]he claims are indefinite in that it is
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`unclear how to achieve [the recited] particle size using the formulation specified” (supra),
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`Applicants respectfully submit that the present specification explicitly and exhaustively describes
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`how to achieve the presently claimed droplets sizes, and provides examples of various droplet
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`sizes, size distributions as a function of various parameters, and measurement and validation of
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`the same, etc. See, e. g., Examples 13 and 14 at paragraphs [0233]-[O243]; see also paragraphs
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`[0266]-[O297]. Accordingly, it is not clear how the present claims can be construed as indefinite
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`in View of the extensive disclosure of how to generate the claimed droplet sizes, explicit
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`examples of generating the claimed droplet sizes, and development and Validation of methods for
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`measuring droplet sizes.
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`

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`Attorney Docket No. INTH-001/01US 308548-2014
`Application No. 11/698,739
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`With regard to the Examir1er’s assertion that “the claims are indefinite in that it is unclear
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`how the recited particle size relates to the effective concentrations recited, or how a particular
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`droplet size contributes to a particular recited Cmax,” it is not clear how this rejection, or the
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`proffered rationale for such a rejection relates to 35 U.S.C. § 112, second paragraph.
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`MPEP § 2171 instructs:
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`“There are two separate requirements set forth in [35 U.S.C. § 112, second
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`paragraph]:
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`(A)
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`the claims must set forth the subject matter that applicants regard as
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`their invention; and
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`(B)
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`the claims must particularly point out and distinctly define the metes
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`and bounds of the subj ect matter that will be protected by the patent grant.
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`The first requirement is a subjective one because it is dependent on what
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`the applicants for a patent regard as their invention. The second requirement is an
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`objective one because it
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`is not dependent on the views of applicant or any
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`particular individual, but
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`is evaluated in the context of whether the claim is
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`definite —
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`i. e., whether the scope of the claim is clear to a hypothetical person
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`possessing the ordinary level ofskill in the pertinent art.” Emphasis added.
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`Applicants submit that the present claims explicitly recite clear, well defined limitations
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`which are measurable and readily appreciable by one of ordinary skill in the art, as required by
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`35 U.S.C. § 112, second paragraph. For example, the present claim 1 recites certain explicit
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`limitations, namely:
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`(i) discrete liquid droplets of...fentanyl...in a pharmaceutically acceptable liquid
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`carrier; said droplets having a mean diameter of at least about 10 microns; and
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`(ii) wherein the sublingual fentanyl formulation provides a mean maximum plasma
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`concentration (Cm(1X) offentanyl of about 127pg/ml to about 213 pg/ml per 100 pgfentanyl
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`after sublingual administration to humans. See claim 1 of the present application; emphasis
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`added.
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`Each of limitations (i) and (ii) above are readily measurable, and accordingly, definite.
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`Similarly, independent claims 20 and 139 each recite limitations which are both definite and
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`3.
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`

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`Attorney Docket No. INTH-001/01US 308548-2014
`Application No. 11/698,739
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`readily ascertained by one skilled in the art. Accordingly, the present claims are definite, and the
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`scope thereof is clear to a hypothetical person possessing the ordinary level of skill in the
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`pertinent art, as required by 35 U.S.C. § 112, second paragraph.
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`Furthermore, Applicants respectfully submit that the present specification contains
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`explicit disclosure regarding the relationship between droplet size and drug absorption. See, e.g.,
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`paragraph [0017] of the present specification (“[l]iquid droplets or particles having a diameter of
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`less than about 5 microns have the potential to enter into the lungs of a human upon
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`administration. Such entry into the lungs could lead to an increase in patient to patient variability
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`in absorption of the fentanyl. Further, absorption of fentanyl in the lungs could lead to an
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`increased absorption and increased side effects, including respiratory depression which may be
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`fatal.). In addition, the present specification provides explicit Examples wherein the respirable
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`amount of a dose of the presently claimed formulations was determined. See, e.g., paragraphs
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`[0298]-[0326] of the present specification. Furthermore, the present specification is replete with
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`examples wherein the presently claimed formulations produce the presently claimed Cmax values.
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`See, e.g., paragraphs [0183]-[0199] of the present specification.
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`Thus, Applicants respectfully submit that the present claims are clear, and each claimed
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`limitation is not only definite and readily measurable, but also explicitly described and
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`exemplified in the present specification. Accordingly, the metes and bounds of the present
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`claims are readily ascertainable by one skilled in the art, as required by 35 U.S.C. § 112, second
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`paragraph. As a result, the present rejection is improper, and should be withdrawn.
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`III.
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`Rejection Under 35 USC §103
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`Claims 1-4, 10, 11, 20-23, 31, 32 and 139-143 are rejected under 35 U.S.C. lO3(a) as
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`allegedly being unpatentable over U.S. Pat. Appl. Pub. No. 2006/0062812 (Ross). Office Action
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`at p. 5. Applicants traverse on the grounds that Ross fails to disclose or suggest all of the
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`limitations of the present claims. As a result, the Examiner has failed to satisfy the requirements
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`for establishing a finding ofprima facie obviousness. Further, the Examiner’s rationale for the
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`present rejection ignores the plain language of the present claims, and contradicts the explicit
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`teachings of Ross. Finally, it would not be obvious to modify the formulations of Ross to
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`Attorney Docket No. INTH-001/OIUS 308548-2014
`Application No. 11/698,739
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`provide the claimed invention, because Ross fails to recognize the importance of droplet size. As
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`a result, the present rejection is improper, and the present claims are patentable over Ross.
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`Each of the present independent claims 1, 20 and 139 recite that the claimed formulation
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`comprises “droplets having a mean diameter of at least about 10 microns.” Ross is silent with
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`respect to droplet size, an explicit limitation required by the present claims. The Examiner concurs,
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`stating “Ross does not specifically teach a liquid droplet size of at least about 10 microns.” Office
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`Action at p.6. Thus, Ross fails to disclose all of the limitations of the present claims, and accordingly
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`necessarily fails to support a finding ofprimafacie obviousness.
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`Furthermore, Applicants note that a droplet size below the claimed range can undesirably
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`increase patient to patient variability in the delivery of fentanyl (see e. g., present specification at page
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`25, paragraph [00115]).
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`Since Ross does not recognize the importance of droplet size on the
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`therapeutic effect of fentanyl compositions, Applicants respectfully submit that it would not be
`obvious to modify the formulations of.Ross to provide the claimed range of droplet size (see MPEP
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`2144.05 (11) (13)).
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`The Examiner further alleges that “[s]ince the formulation of Ross comprises the same
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`ingredients as the instant formulation, and produces the same Cmax, the invention as claimed is not
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`structurally distinguishable from that of Ross.” Ia’.
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`Applicants emphatically disagree. Not only does Ross does not produce “the same Cmax”,
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`but Ross actually teaches formulations which provide quite different and higher mean Cmax values.
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`Applicants respectfully submit that the Examiner appears to have disregarded the explicit language of
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`the present claims, and the explicit disclosure of Ross. The present claims require that the claimed
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`formulations “provide[] a 11% maximum plasma concentration (Cmax) of fentanyl of about 127
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`pg/ml to about 213 pg/ml per 100 ug fentanyl after sublingual administration to humans” (see the
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`present claims 1, 20 and 139; emphasis added). While the Examiner asserts that Ross discloses
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`“Cmax values of about l27pg/ml to 2l3pg/ml per 100 pg of fentanyl after sublingual administration
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`of the formulation (for example, 370pg/ml per 200 pg of fentanyl is the same as l85pg/ml per 100 ug
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`of fentanyl- Table 1)” (Office Action at p. 5), Applicants note that the cited value which purportedly
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`falls within the presently claimed range is a single discrete value, and not a mean value.
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`Furthermore, Ross does expressly disclose mean Cmax values which fall outside the presently
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`claimed range (see, e.g., Tables 1 and 2 of Ross, which report mean Cmax values significantly higher
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`5.
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`

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`Attorney Docket No. INTH—001/01US 308548-2014
`Application No. 11/698,739
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`than the claimed range). Accordingly, the Examiner appears to have disregarded the explicit
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`language of claim 1, and the explicit teachings ofRoss, to support this ground of rejection.
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`Furthermore, even assuming arguendo one were to select one of the discrete values reported
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`by Ross in each of Tables 1 and 2, the Examiner has provided no articulated reasoning as to why one
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`would select a lower Cmax value which falls within the presently claimed mean Cmax range, rather
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`than a higher Cmax value (e. g., Table 1, entry 6 of Ross, which reports a Cmax of 760 pg/mL per
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`200 pg of fentanyl, which is 380 pg/ml per 100 pg of fentanyl, and fall outside the presently claimed
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`mean Cmax range).
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`In fact, Applicants submit that the disclosure of Ross suggests the selection of
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`higher Cmax values, because Ross explicitly teaches that “in order for the opioid analgesic to have a
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`pain-relieving effect, a plasma concentration of between 250 pg/ml and 2 ng/ml is required.” Ross at
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`paragraph [0080]. Thus, even if one were to ignore the plain language of the present claims (which
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`require a mean plasma concentration of about 127 pg/1nL to about 213 pg/mL per 100 pg fentanyl),
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`and disregard the explicit disclosure of % plasma concentration taught by Ross (which fall well
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`outside the presently claimed range), and select a single discrete plasma concentration value from
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`Tables 1 or 2 of Ross which falls within the presently claimed range of mean plasma concentrations
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`as suggested by the Examiner (supra), Ross explicitly teaches plasma concentrations of at least 250
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`pg/mL (see paragraph [0080] of Ross). Accordingly, Ross expressly teaches away from plasma
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`concentrations lower than 250 pg/mL and thus, the Examiner’s assertion that one of ordinary skill in
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`the art would select a discrete plasma concentration value which falls within the presently claimed
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`mean plasma concentration range (e.g., l85pg/ml per 100 pg of fentanyl; Office Action at p. 5, citing
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`Table l of Ross) contradicts the explicit teaching of Ross.
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`In summary, Applicants respectfully submit
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`that Ross fails to disclose all of the
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`limitations of the present claims (i.e., droplet size and mean Cmax), and thus cannot support a
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`finding of primafacie obviousness. Furthermore, since Ross fails to disclose or recognize the
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`effect of droplet size on therapeutic effect, it would not be obvious to modify the formulations of
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`Ross to provide the claimed droplet size. Moreover, the Examiner’s reasoning in support of the
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`present obviousness rejection ignores the plain language of the present claims, and contradicts
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`the explicit teachings of Ross. That is, Ross expressly teaches fentanyl formulations which
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`provide different and higher mean Cmax values, which would therefore reasonably provide quite
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`different pharmacological effects. As a result, Ross fails to render obvious the present claims.
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`Accordingly, Applicants respectfully request reconsideration and withdrawal of the present
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`Attorney Docket No. INTH-001/01US 308548-2014
`Application No. l l/698,739
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`rejection.
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`IV.
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`Conclusion
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`Applicants respectfully submit that the claims are now in condition for allowance, early
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`notice of which would be appreciated. Should the Examiner disagree, Applicants respectfully
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`request a telephonic or in-person interview with the undersigned to discuss any remaining issues
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`and to expedite the eventual allowance of the claims.
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`Except
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`for
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`issue fees payable under 37 C.F.R. 1.18,
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`the Commissioner is hereby
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`authorized by this paper to charge any additional fees during the entire pendcncy of this
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`application including fees due under 37 C.F.R. 1.16 and 1.17 which may be required, including
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`any required extension of time fees, or credit any overpayment to Deposit Account 50-1283.
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`This paragraph is intended to be a CONSTRUCTIVE PETITION FOR EXTENSION OF
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`TIME in accordance with 37 C.F.R. l.136(a)(3).
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`Respectfully submitted,
`COOLEY LLP
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`
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`;_,='\
`i
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`*
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`Reg. No. 64,209
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`Dated:
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`
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`COOLEY LLP
`ATTN: Patent Group
`777 6*“ Street NW, Suite 1100
`Washington, DC 20001
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`Tel: (202) 842-7127
`Fax: (202) 842-7899
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`B511
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