DETAILED ACTION
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 . In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Change of Examiner
This application has been reassigned from Bryan Rego to Brian Gulledge for the remainder of its prosecution. Applicant is advised that future communications should be directed to Brian Gulledge, who can be contacted at 571-270-5756, Monday–Friday from 7:00 am until 4:00 pm.
Previous Rejections
Applicants' arguments, filed 09 June 2025, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. In particular, the indefiniteness rejection is withdrawn in view of the amendment to the claims. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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.
Claims 1-9, 11-12, 16-18, 21, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Cabrera (Nano Lett., 2013, 13(8), pages 3766-3774) in view of Lee (US Patent Application Publication 2018/0049991).
Cabrera teaches quatsomes comprising cholesterol and hexadecyltrimethylammonium bromide [Pg. 3768, Col. 2, Para. 1] that are PEGylated with cholesterol_PEG1000 and other examples containing a cholesterol-PEG-RGD moiety [Figure 1] to bind to the integrin receptors that over expressed in cancer cells to increase cell penetration [Pg. 3769, Col. 2, Para. 2, Ln. 1-10]. Cabrera teaches the quatsomes are spherical unilaminar and have a polydispersion index of around 0.15-0.26 with a diameter from 67-149 nm [Table 1]; reproduced below. Cabrera states that the quatsomes nanoconjugates remained stable for over 5 months that are spherical morphology [Figure 3f].
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Cabrera fails to teach the use of DC-Chol.
Lee teaches the use of a nanoparticle for the deliver miRNA and nucleic acids [0005]. Lee teaches the use of tertiary and quaternary cationic lipids for the improvement in delivery of RNA [0004] and that DC-Chol is a tertiary amine cationic lipid [0024] that are conditionally ionizable and their positive charge is largely regulated by pH which results in the release of the active component allows for the precise controlled release of nucleic acids into the cytosol [0214] and are beneficial for the delivery of therapeutic agents [0195] through the association of the negatively charged therapeutics via electrostatic interaction [0180]. Lee teaches the use of cholesterol as a helper lipid [Claim 17] wherein the amount quaternary amine to cholesterol is 25:20 [Claim 17], which results in a DC-chol in amount 25/55*100% which 55% relative to the total amount of cholesterol.
Lee is not understood to be anticipatory as it fails to teach the use of DC-cholesterol or a non-lipid cationic surfactant in a single example.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to have modified the teachings of Cabrera, to add a cholesterol-PEG-RGD moiety and a quatsomes. One would have been motivated to add cholesterol-PEG-RGD moiety to bind to the integrin receptors that over expressed in cancer cells to increase cell penetration [Pg. 3769, Col. 2, Para. 2, Ln. 1-10] and a quatsomes as they are low cost and stable for long period of times [Abstract].
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to have modified the teachings of Cabrera with Lee, to DC-Cholesterol. One would have been motivated to add DC-cholesterol which results in the release of the active component allows for the precise controlled release of nucleic acids into the cytosol [0214] and are beneficial for the delivery of therapeutic agents [0195] through the association of the negatively charged therapeutics via electrostatic interaction [0180].
It would have been obvious to achieve the desired range of the amount of DC-cholesterol relative to the total amount of sterols. A prima facie case of obviousness exists where the claimed ranges or amounts do overlap with the prior art. See MPEP 2144.05(I). In this case, the general conditions of an DC-sterol in nanovesicles. As such, it would not have been inventive for the skilled artisan to have discovered the optimum or workable ranges of the DC-Sterol.
Regarding claim 1, Lee teaches the use of a nanoparticle for the deliver miRNA and nucleic acids [0005]. Lee teaches the use of tertiary and quaternary cationic surfactants for the improvement in delivery of RNA [0004] and that DC-Chol is a tertiary amine cationic lipid [0024] that are conditionally ionizable and their positive charge is largely regulated by pH which results in the release of the active component allows for the precise controlled release of nucleic acids into the cytosol [0214]
Regarding claim 2, Cabrera teaches quatsomes comprising cholesterol and hexadecyltrimethylammonium bromide [Pg. 3768, Col. 2, Para. 1].
Regarding claim 3, Lee teaches the use of cholesterol as a helper lipid [Claim 17] wherein the amount quaternary amine to cholesterol is 25:20 [Claim 17], which results in a DC-chol in amount 25/55*100% which 55% relative to the total amount of cholesterol.
Regarding claim 4, Lee teaches the use of cholesterol as a helper lipid [Claim 17] wherein the amount quaternary amine to cholesterol is 25:20 [Claim 17], which results in a DC-chol in amount 25/55*100% which 55% relative to the total amount of cholesterol.
Regarding claim 5, Lee teaches the use of cholesterol as a helper lipid [Claim 17] and DC-Chol as a tertiary cationic lipid [0024]. Cabrera teaches quatsomes comprising cholesterol and hexadecyltrimethylammonium bromide [Pg. 3768, Col. 2, Para. 1].
Regarding claim 6, Cabrera teaches quatsomes that are PEGylated with cholesterol_PEG1000 and other examples containing a cholesterol-PEG-RGD moiety [Figure 1] to bind to the integrin receptors that over expressed in cancer cells to increase cell penetration [Pg. 3769, Col. 2, Para. 2, Ln. 1-10].
Regarding claim 7, Cabrera teaches quatsomes that are PEGylated with cholesterol_PEG1000 and other examples containing a cholesterol-PEG-RGD moiety [Figure 1] to bind to the integrin receptors that over expressed in cancer cells to increase cell penetration [Pg. 3769, Col. 2, Para. 2, Ln. 1-10]. This is assumed to read on the required peptide.
Regarding claim 8, Cabrera teaches quatsomes that are PEGylated with cholesterol_PEG1000 and other examples containing a cholesterol-PEG-RGD moiety [Figure 1] to bind to the integrin receptors that over expressed in cancer cells to increase cell penetration [Pg. 3769, Col. 2, Para. 2, Ln. 1-10]. This is assumed to read on the required peptide.
Regarding claim 9, Cabrera teaches quatsomes that are PEGylated with cholesterol_PEG1000 and other examples containing a cholesterol-PEG-RGD moiety [Figure 1] to bind to the integrin receptors that over expressed in cancer cells to increase cell penetration [Pg. 3769, Col. 2, Para. 2, Ln. 1-10]. This is assumed to read on the required peptide.
Regarding claim 11, Cabrera teaches the use of and hexadecyltrimethylammonium bromide [Pg. 3768, Col. 2, Para. 1] which is a non-lipid cationic surfactant.
Regarding claim 12, Cabrera teaches the use of and hexadecyltrimethylammonium bromide [Pg. 3768, Col. 2, Para. 1] which is a non-lipid cationic surfactant.
Regarding claim 16, Cabrera states that the quatsomes nanoconjugates remained stable for over 5 months that are spherical morphology [Figure 3f].
Regarding claim 17, Cabrera teaches the quatsomes have a Polydispersion index of around 0.15-0.26 with a diameter from 67-149 nm [Table 1].
Regarding claim 18, Lee teaches the delivery of nucleic acids [0004].
Regarding claim 21, Lee teaches that the composition should be administered in a pharmaceutically acceptable vehicle [0232] in therapeutically effective amount [0151].
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Cabrera (Nano Lett., 2013, 13(8), pages 3766-3774) and Lee (US Patent Application Publication 2018/0049991) as applied to claim 1 above and further in view of Xie (Int. J. Nanomed., 2012, vol. 7, pages 163-75)
Lee and Cabrera teaches the above limitations of claims 1 and 7.
Lee and Cabrera fails to teach the use of Chol-PEG-Glucose.
Xie teaches the use of Chol-PEG-Glucose for incorporation in nanovesicles which results in improved circulation [Abstract] for delivery to the brain.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to have modified the teachings of Lee and Cabrera in view of Xie, to include Chol-PEG-Glucose. One would have been motivated to add to Chol-PEG-Glucose incorporation into nanovesicles which results in improved circulation [Abstract] for delivery to the brain.
Regarding claim 10, Xie teaches the use of Chol-PEG-Glucose for incorporation into nanovesicles which results in improved circulation [Abstract] for delivery to the brain.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Cabrera (Nano Lett., 2013, 13(8), pages 3766-3774) and Lee (US Patent Application Publication 2018/0049991) as applied to claim 1 and further in view of Grimaldi (Chem. Soc. Reviews, 2016, 45(23), pages 6520-6545)
Lee and Cabrera teaches the above limitations of claims 1 and 12.
Lee and Cabrera fails to teach the use of myristalkonium chloride.
Grimaldi teaches the use of cetrimonium bromide (CTAB), myristalkonium chloride (MKC) and cetylpyridinium chloride (CPC), as quaternary ammonium surfactants [Pg. 6526, Col, 1, Para. 2, Ln. 23-25] and other sterols can be used instead of cholesterol [Pg. 6526, Col, 1, Para. 2].
Grimaldi is not understood to be anticipatory as it fails to teach the above limitations in a single example.
The skilled artisan would have been motivated to have substituted myristalkonium chloride of Grimaldi in place of the CTAB of Cabrera for incorporation in the composition of Cabrera for predictable vesicle formation with a reasonable expectation of success. The simple substitution of one known element (e.g. myristalkonium chloride of Grimaldi) in place of another (e.g. CTAB of Cabrera) in order to achieve predictable results (formation of vesicle) is prima facie obvious. See MPEP 2143, Exemplary Rationale B.
The skilled artisan would have been motivated to have substituted the DC-cholesterol of Lee in place of the cholesterol of Cabrera for incorporation in the composition of Cabrera for predictable vesicle formation with a reasonable expectation of success. The simple substitution of one known element (e.g. DC-cholesterol of Lee) in place of another (e.g. cholesterol of Cabrera) in order to achieve predictable results (formation of vesicle through the use of a sterol and quaternary ammonium surfactant pair [Grimaldi, Pg. 6526, Col, 1, Para. 2] ) is prima facie obvious. See MPEP 2143, Exemplary Rationale B.
Regarding claim 15, Grimaldi teaches the use of myristalkonium chloride as a quaternary ammonium surfactant and other sterols can be used instead of cholesterol [Pg. 6526, Col, 1, Para. 2, Ln. 23-25]. Lee teaches the use of a nanoparticle for the deliver miRNA and nucleic acids [0005]. Lee teaches the use of tertiary and quaternary cationic lipids for the improvement in delivery of RNA [0004] and that DC-Chol is a tertiary amine cationic lipid [0024] that are conditionally ionizable and their positive charge is largely regulated by pH which results in the release of the active component allows for the precise controlled release of nucleic acids into the cytosol [0214]
Claims 19 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Cabrera (Nano Lett., 2013, 13(8), pages 3766-3774) and Lee (US Patent Application Publication 2018/0049991) as applied to claim 1 above and further in view of Men (International Journal of Radiation Oncology, Biology, Physics, 2017, 99(2), E610)
Lee and Cabrera teaches the above limitations of claims 1 and 18.
Lee and Cabrera fails to teach the use of miRnA-323a-3p.
Men is drawn to the use of miRnA-323a-3p and teaches that it inhibits cell proliferation, migration, of cancer cells [Abstract].
Men is not understood to be anticipatory as it fails to teach the above limitations in a vesicle composition.
The skilled artisan would have been motivated to have substituted the MiRnA-323a-3p of Men in place of the miRNA of Lee for incorporation in the composition of Cabrera for predictable anticancer effect with a reasonable expectation of success. The simple substitution of one known element (e.g. miRnA-323a-3p of Men) in place of another (e.g. the composition of Cabrera) in order to achieve predictable results (anticancer effects) is prima facie obvious. See MPEP 2143, Exemplary Rationale B.
Regarding claim 19, Men teaches that it inhibits cell proliferation, migration, of cancer cells [Abstract].
Response to Arguments
The Applicant argues the obviousness rejections are not proper. The Applicant states that the rejection relies upon a substitution of neutral cholesterol molecules for DC cholesterol, which is an additional positively charged molecule. This would increase the charge density of the quatsome. And one of ordinary skill in the art would not expect that such a more charged quatsome would self-assemble, let alone remain stable for extended periods of time. Cholesterol is a helper lipid per the teaching of Lee, and thus these stabilizing lipids, if substituted, would result in a less stable quatsome.
The Applicant also argues that Cabrera is silent as to encapsulating nucleic acids in quatsomes. The quatsomes of Lee are derived from negatively charged phosphate backbones capable of having electrostatic interactions with the cationic lipid. So as Cabrera deals with protein encapsulation in nanovesicles, one of ordinary skill in the art would not look to Lee for nucleic acids.
The Examiner acknowledges the arguments presented, but does not consider them persuasive. The Applicant argues that the substitution of cholesterol for DC cholesterol would not have been obvious. The rejection rationales did not state that such a 1:1 substitution was obvious. The first rationale stated that it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to have modified the teachings of Cabrera, to add a cholesterol-PEG-RGD moiety and a quatsomes. One would have been motivated to add cholesterol-PEG-RGD moiety to bind to the integrin receptors that over expressed in cancer cells to increase cell penetration [Pg. 3769, Col. 2, Para. 2, Ln. 1-10] and a quatsomes as they are low cost and stable for long period of times [Abstract]. This rationale does not rely on the argued substitution.
The second rationale was that it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to have modified the teachings of Cabrera with Lee, to DC-Cholesterol. One would have been motivated to add DC-cholesterol which results in the release of the active component allows for the precise controlled release of nucleic acids into the cytosol [0214] and are beneficial for the delivery of therapeutic agents [0195] through the association of the negatively charged therapeutics via electrostatic interaction [0180]. This too was not based on substitution, but rather addition. Thus, the argument is not found persuasive as it is not based on the rejection as presented.
The Examiner also is not persuaded by the arguments that Cabrera is silent as to encapsulating nucleic acids in quatsomes. Lee teaches that the negatively charged phosphate backbones (of the nucleic acid) are capable of having electrostatic interactions with the cationic lipid. Both references has a cationic lipid present. Thus, the encapsulation of nucleic acid would be obvious, as the required element (cationic lipid) is present for both Cabrera and Lee.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Brian Gulledge/Primary Examiner, Art Unit 1699
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