Detailed Action
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-23 are pending. Claims 3-5, 7-9, and 13-23 are withdrawn. Claims 1-2, 6, and 10-12 are rejected.
Information Disclosure Statement
The Information Disclosure Statement from 1/29/2025 has been considered by the Examiner.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-12) and the species:
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, in the reply filed on 7/29/2026 is acknowledged.
Claims 1-2, 6, and 10-12 embrace Applicant’s elected species and are therefore under examination. Applicant’s elected species is free of the prior art. As per MPEP 803.02, “Following election, the Markush claim will be examined fully with respect to the elected species and further to the extent necessary to determine patentability.” Search was expanded to include species recited under 35 USC 103 below. Additionally, claim 6 was searched in full and is free of the prior art.
Claims 3-5, 7-9, and 13-23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claim Objections
Claim 1 is objected to because of the following informalities: The last line should read “or a pharmaceutically acceptable salt thereof.”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 6 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 6 recites the following variables: R14, R15, and R16 that correspond to independent claim 1’s R7, R8 and R12, respectively. Claim 6 recites the following on lines 5 and 6:
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. The referenced “straight-chain or branched alkyl” do not have a specific carbon number associated with them, implying an unlimited or unspecified number. Variables R7 and R12 of claim 1 are limited to C1-C4 alkyl and that of R8 is limited to C1-C8 alkyl, which are narrower than the dependent claim. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 2, 10 and 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stepanek et al. (European Journal of Medicinal Chemistry, 170, 2019, 276-289), in view of Fredholt et al. (Journal of Controlled Release, 63, 2000, 261-273).
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Stepanek teaches that nSMase2 is a key enzyme in ceramide biosynthesis and is a therapeutic target for the treatment of neurological disorders and cancer (see abstract). Stepanek specifically discloses the following as an nSMase2 inhibitor:
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(see Fig. 2). Table 2 shown here indicates the specific IC50 (in μM) values of various nSMase 2 inhibitors studied, including DPTIP, shown supra:
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. Stepanek does not teach the specific R1 groups of the instant claims (R1 of the prior art is hydrogen).
Fredholt discloses a Leu-enkephalin analogue and ester prodrugs thereof (see Fig 1):
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, wherein the phenolic group of Tyr (on the left of figure supra) is modified with an “R” group. For II, III, IV prodrugs shown supra, the “R” group of the prior art corresponds to instant R1 = -C(=O)-R2, wherein R2 = C1-C4 alkyl. “The prodrug principle seems to be a possible way to increase the permeation across biological membranes as the Papp values are higher for the synthesized prodrugs (Papp: 0.682 x 10-6 to 5.210 x 10-6 cm/s). The greatest effect is seen for the pivaloylprodrug that shows a 18 times higher transport compared to the analogue itself. Higher lipophilicities of the prodrugs could explain the improved transport properties of these.” (see p. 272, right column, first para.).
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art does not disclose a single embodiment of a compound of instant formula (I). Additional dependent limitations will be addressed below.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
Regarding instant claims 1 and 2, it would have been obvious to a skilled artisan, starting with the nSMase2 inhibitor of Stepanek, to modify the phenolic group similarly to Fredholt, with a reasonable expectation of success in arriving at nSMase2 inhibitors with improved transport properties. Stepanek’s compound differs from the instant claims in that there is an “H” in the instant “R1” position instead of an “-C(=O)-R2”, wherein R2 may be substituted or unsubstituted C1-C8 straight chain or branched alkyl. Fredholt is analogous prodrug art wherein a phenolic hydrogen was replaced with three different groups, all of the type -C(=O)-alkyl. A skilled artisan would have been motivated to modify Stepanek’s nSMase2 inhibitor similarly to Fredholt’s phenolic modifications in an effort to enhance pharmacokinetics of such inhibitors. Regarding instant claim 10, the modifications described above embrace the “R1” group of both “P3” and “P4”. Regarding instant claim 11, the prior art report IC50 concentrations wherein a skilled artisan would understand that the molarity values were the result of dilutions with an aqueous solution, which is a pharmaceutically acceptable carrier.
Claim(s) 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stepanek et al. (European Journal of Medicinal Chemistry, 170, 2019, 276-289), in view of Fredholt et al. (Journal of Controlled Release, 63, 2000, 261-273), as applied to claims 1, 2, 10 and 11 above, and further in view of Masson et al. (Journal of Controlled Release, 59, 1999, 107-118).
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Stepanek and Fredholt do not disclose a composition with a cyclodextrin.
Masson analyzed cyclodextrins as permeation enhancers (see title). Masson concluded that “cyclodextrins act as permeation enhancers carrying the drug through the aqueous barrier, from the bulk solution towards the lipophilic surface of biological membranes…” (see abstract).
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art does not have a single embodiment of a compound of instant formula (I) in a pharmaceutical formulation with a cyclodextrin.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
Regarding instant claim 12, it would have been obvious to include a cyclodextrin in an obvious pharmaceutical formulation in an effort to enhance permeation of biological membranes. Masson additionally teaches that the “hydrophilic exterior of the cyclodextrin molecules makes them water-soluble, but the hydrophobic cavity provides a microenvironment for appropriate sized non-polar molecules” (see Introduction, p. 107). A skilled artisan would have been motivated to explore the use of cyclodextrins in a wide variety of molecules, with various functional groups and polarities, with a reasonable expectation of success in improving pharmacokinetics of such substances.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MEGHAN C HEASLEY whose telephone number is (571)270-0785. The examiner can normally be reached Monday - Friday 8:30-4:30 PM.
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/MEGHAN C HEASLEY/Examiner, Art Unit 1626
/KAMAL A SAEED/Primary Examiner, Art Unit 1626
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