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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/14/2025 has been entered.
Restriction/Election
Amended claims 1, 15-19, 21, 22, 28, 29, 31, 34, 36, 37, 50, 53, 56-57 as well as new claims 58-62 are pending, and claims 36, 37 and 50 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/21/2023.
Thus claims 1, 15-19, 21, 22, 28, 29, 31, 34, 53, 56-57 and 58-62 of elected Group I and species of carbamate alkylene linker, TLR9, HPV related antigen, DOPC and cholesterol are considered here.
Priority
The claim to benefit to U.S. Provisional 62/507591, filed on 05/17/2017, via its PCT filing of PCT/US2018/03320005, filed on 05/17/2018 is recognized.
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. U.S. Provisional 62/507591, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. There is no support for limitations of claim 1 and the new claims, including the genus of 1) carbamate alkylene dithiolate linker, along with limitations of Antigen-NH-C(O)-O-C2-5alkyelene-S-S-alkylene-oligonucleotide; antigen-NH-C(O)-O-CH2-Ar-S-S-C2-7alkylene-Oligonucleotide (recognize NDEC/SPDP figure on pg. 14, understand alkylene to be broader than the species indicated in pg. 14 figure); 2) also there is no support for the broader in scope “associative moiety” (recognize Cholesterol in fig. of pg. 16); since claim 1 lacks support, all its dependent claims will also lack support.
Thus all the examined claims will enjoy the benefit of 05/18/2018 and will be the date used for search purposes.
35 U.S.C. 112(b):
Rejection of claim 29 is withdrawn, the claim has deleted “about”.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 58 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 58 recites the limitation "the carbamate alkylene dithiolate linker" in line 2. There is insufficient antecedent basis for this limitation in the claim. There are two different carbamate alkylene dithiolate linkers recited in claim 1. It is uncertain if the cl. 58 linker is referring to cl. 1(i) linker or cl. 1(ii) linker. In the interest of compact prosecution, claim 58 will be interpreted that both limitations of cl. 1 (i) and cl. 1(ii) are recited in a disjunctive manner (i.e. with an “or”) in cl. 58.
Claim Rejections - 35 USC § 103
Rejection of claims 1, 15-19, 21, 22, 28, 29, 31, 34, 53, 56 and 57 in view of Radovic-Moreno et al. (WO2015187966, pub. 12/10/2015, referred as Radovic-Moreno, in IDS) and Low et al. (WO2013126797, pub. date 08/29/2013, referred as Low) is withdrawn because a better art was found in the updated search.
Thus upon further consideration, the examined claims are rejected as noted below.
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 (i.e., changing from AIA to pre-AIA ) 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.
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.
103 Rejection – Skakuj and Suma references:
Claims 1, 15-19, 21, 22, 28, 29, 31, 34, 36, 37, 50, 53, 56-57 and 58-60 are rejected under 35 U.S.C. 103 as being unpatentable over Skakuj et al. (1/2018, J. Am. Chem. Soc. 140, 1227-1230, in IDS, referred as Skakuj).
The applied reference has a common co-inventors (Skakuj, Wang, Mirkin) with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(1).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Regarding instant cl. 1, Skakuj discloses in Fig. 1, a SNA with nanoparticle (pg. 1227-1228), with adjuvant DNA, which is CpG B oligonucleotides (pg. 1227), gp100 antigen (pg. 1227) linked with various linkers, including NDEC, understood as NH-C(O)-O-C2alkylene-S-S-C-oligonucleotide (see Fig. 1B excerpt below of NDEC). NDEC linker comprises carbamate alkylene (NH-C(O)-O-(CH2)2) and dithiolate groups.
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Instant cl. 1 (cl. 1(i) and cl. 1(ii)) recites carbamate alkylene linkers that are a bit distinct from NDEC as drawn. NDEC has total of three CH2 group, while instant claim 1(i) needs minimum of four CH2 groups; a difference of one CH2 group. MPEP 2144.09 (II) provides that compounds which are position homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2-groups) have generally sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. NDEC and the claimed structure are sufficiently close structural similarity and possess similar properties. Thus the recited carbamate linker 1(i) is an obvious variant/homolog of disclosed NDEC or are not patentably distinct. Thus, cl. 1 is obvious.
Regarding instant cl. 15, Skakuj discloses gp-100 antigen is a human melanoma-specific antigen (pg. 1227).
Regarding instant cl. 16, Skakuj discloses gp-100 is a melanoma specific antigen (pg. 1227).
Regarding instant cl. 17, Skakuj discloses SNAs were synthesized using liposomal core (pg. 1227).
Regarding instant cl. 18, Skakuj discloses liposome comprises DOPC (pg. S3).
Regarding instant cl. 19, Skakuj discloses associative moiety is cholesterol (pg. S3, 1227).
Regarding instant cl. 21, 56, Skakuj discloses Fig. 1 illustrates an additional oligonucleotide, “gp-100-DNA conjugate types, 1-3, made with DNA complementary to the CpG adjuvant” (pg. 1227).
Regarding instant cl. 22, Skakuj discloses additional oligo is DNA (pg. 1227).
Regarding instant cl. 28, Skakuj discloses the liposomes underwent consecutive extrusion filtration from 200 nm to 50 nm polycarbonate filters, but its z-avg. hydrodynamic diameter is of 83.7 nm (pg. 1228, Fig. 1D). Here, under MPEP 2144.05, although the claimed diameter and disclosed diameter do not overlap they are close and therefore there is a prima facie case of obviousness.
Regarding instant cl. 29, Skakuj discloses the duplexes were added at a 75:1 ratio to liposomes (pg. 1227).
Regarding instant cl. 31, Skakuj discloses the SNAs-duplex were diluted with 1X PBS (pg. S3).
Regarding instant cl. 34, Skakuj discloses immunostimulatory SNA is considered a vaccine or that gp-100 antigen activates T-cells and proliferation is considered a cancer-vaccine (pg. 1227).
Regarding instant cl. 53, Skakuj discloses SNA also has an oligonucleotide, which is single-stranded, prior to duplex formation (pg. 1227).
Regarding instant cl. 57, Skakuj discloses a first strand of ds oligo comprises the associative moiety (cholesterol) for association with the nanoparticle and a second strand of the ds oligo comprises the antigen bound by a linker and are complementary (see Fig. 1, pg. 1227 and 1228).
Regarding instant cl. 58, 59, Skakuj discloses antigen linked to DNA using various linkers, including NDEC, a NH-C(O)-O-C2alkylene-S-S-C-oligonucleotide (see Fig. 1 above). There is a difference of a single CH2 group between claimed structure and NDEC, but despite their difference the structures are sufficiently structural similar and is presumed to possess similar properties, and thus claimed structure is an obvious variant/homolog of NDEC. Cl. 58 and 59 are obvious.
Regarding instant cl. 60, there is a difference of three CH2 groups between NDEC and the claimed structure of cl. 60 (C2-4alkylene-CH(X)-S-S-CH(Y)C2-6alkylene). As noted above, the claimed structure is an obvious variant/homolog of NDEC and is presumed to possess similar properties. Thus, cl. 60 is an obvious.
Claims 61 and 62 are rejected under 35 U.S.C. 103 as being unpatentable over Skakuj et al. (1/2018, J. Am. Chem. Soc. 140, 1227-1230, referred as Skakuj, in IDS,) as applied to claims 1, 15-19, 21, 22, 28, 29, 31, 34, 53, 56 and 57-60 above, and further in view of Suma et al. (3/2017, J. Am. Chem. Soc., 139, 4009-4018, referred as Suma, in IDS of 6/8/22).
The disclosure of Skakuj relevant to instant cl. 1, 56-60 is noted above.
Skakuj does not disclose an Antigen-NH-C(O)-O-CH2-Ar-S-S-C2-7alkylene-Oligonucleotide (cl. 61) nor Antigen-NH-C(O)-O-CH2-Ar-S-S-CHXC2-6alkylene-Oligonucleotide (cl. 62); specifically the “Ar” group, which is the recited meta- or para-substituted phenyl group.
Suma (3/2017, J. Am. Chem. Soc., 139, 4009-4018) discloses testing various types of proapoptotic peptide nanoparticles (PPNs) composed of pro-apoptotic KLAK-peptides cross-linked to PEG-moieties via various types of linkers (pg. 4009, 4012). Suma discloses that the cross-linking chemistry is based on linkers comprising disulfide and carbamate alkylene groups (pg. 4009-4010). Suma tested three linkers: NDBC (“B-PPN”, has a phenyl group), NDEC (“E-PPN”)and SPDP (“S-PPN”), (see Fig. 2 below, left panel; pg. 4010). Suma discloses the disassembly to be tunable based on the linkers used (pg. 4009, see right panel of a figure from abstract: Cleavage fragmentation (slow), Cleavage fragmentation (fast) and Cleavage and no fragmentation).
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Suma demonstrates that in culture cells, treatment with B-PPN or E-PPN significantly reduced cell viability and cytotoxicity of PPNs was higher than free peptides; and comparing B-PPN and E-PPN, B-PPN induced a greater reduction in cell viability (pg. 4013, see Fig. 2a, b, relevant to instant cl. 61-62; both B-PPN and E-PPN comprise carbamate alkylene dithiolate linkers; B-PPN comprises a phenyl group (i.e. “Ar” and E-PPN comprises a C2 alkylene group relevant to instant cl. 61, 62)). Further, the E-PPN and B-PPN disassemble into native-state peptides, i.e. the peptides are traceless (pg. 4009). Suma disclose that KLAK peptide with portion of linker group possibly reduces their cytotoxicity properties, “thus regeneration of pristine KLAK peptides are of significant interest” (pg. 4014). Although, both NDEC and NDBC is one or two CH2 short of the required alkylene length of instant cl. 61, 62, as provided by MPEP, additional homolog groups (i.e. CH2 group) are considered to be structurally similar that there is a presumed expectation that such compounds possess similar properties.
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have modified SNA with double-stranded CpG oligonucleotide linked to gp-100 antigen via a NDEC linker of Skakuj in view of Suma and arrive at the claimed invention with a reasonable expectation of success. Based on success of Skakuj use of NDEC linker for improved immunostimulatory activity compared to cleavable linker (SPDP) and non-cleavable linker (BMPS), and Suma demonstration that B-PPN containing NDBC linkers and E-PPN containing NDEC linkers have similar cytotoxicity activity, a skilled artisan would expect reasonable success substituting NDBC linkers of Suma for NDEC linker of Skakuj for similar immune activity. Thus, cl. 61 and 62 are obvious.
103 Rejection – Radovic-Moreno, Kramer, and Suma references
Claims 1, 15-19, 21, 22, 28, 29, 31, 34, 53, and 56-62 are rejected under 35 U.S.C. 103 as being unpatentable over Radovic-Moreno et al. (WO2015187966, pub. 12/10/2015, referred as Radovic-Moreno, in IDS) and Kramer et al. (2017, Molecular Ther., 25, pg. 62-70, referred as Kramer) and Suma et al. (3/2017, J. Am. Chem. Soc., 139, 4009-4018, referred as Suma, in IDS of 6/8/22).
Regarding instant cl. 1, 18, 56-62, Radovic-Moreno discloses liposomal SNA with the following: an embodiment with oligonucleotides designated as "CpG 1826" (relevant (rel.) instant cl. 1), that were 3'- modified with alpha-tocopherol (i.e. “an associative moiety”, rel. instant cl. 1) and incorporated into the vesicles composed of DOPC (Figure 1) (pg. 41, rel. instant cl. 18); in an another embodiment, these structures were further conjugated with ovalbumin, a model protein antigen via Watson-Crick type hybridization of an ovalbumin-oligo construct, where the oligo portion (i.e. the second strand) was complementary to CpG 1826 (Figure 2, see below) (pg. 41, relevant to instant cl. 56-62).
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Radovic-Moreno discloses the antigen is linked indirectly to the oligonucleotide shell through a linker (the oligonucleotide shell is comprised entirely of oligonucleotides); discloses oligonucleotides maybe linked to the liposomal core and linked to an antigen via a linker (pg. 18); the linkers can be saturated and unsaturated amide derivatives of C8-C22 fatty acids; amide functional group include a carbamate functional group, the C8-C22 fatty acid is an alkylene. Thus, Radovic-Moreno discloses an oligonucleotide, a CpG 1826 oligonucleotide, that associates with the liposome nanoparticle, i.e. the DOPC, via the alpha-tocopherol linker; and has a complementary strand (i.e. the second strand) forming a duplex that has an antigen, OVA antigen via linker, which maybe an amide derivative (relevant to instant cl. 1, 18, 56-62). Radovic-Moreno demonstrates, amongst other things, that OVA antigen-conjugated liposomal nanostructure via externally-facing oligonucleotide “provokes unexpectedly more potent induction of immune stimulatory effects in vitro (Fig. 10, pg. 29).
Radovic-Moreno does not disclose carbamate alkylene dithiolate linker.
Kramer (2017, Molecular Ther., 25, pg. 62-70) discloses testing various cleavable, disulfide containing linkers to demonstrate that conjugation of a vaccine adjuvant (CpG oligos) to an antigen (ovalbumin peptide, OVA) enhances anti-tumor immune response (abstract, see Table 1 below).
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Kramer discloses that direct chemical conjugation may limit the processing of adjuvant-antigen complex by the antigen-presenting cells for immune stimulation (abstract). Thus introducing a disulfide group will result in cleavage “by an intracellular trigger [i.e. glutathione (GSH)] to release antigen” from the CpG adjuvant (abstract, pg. 62). Kramer demonstrates that cleavable, disulfide containing linkers “induces a greater anti-tumor immune response in vivo compared to stable conjugate and a conjugate that is cleaved by extracellular GSH concentrations. This indicates that direct stable conjugation of antigen to adjuvant may restrict processing of the antigen by the APCs” (pg. 67). Kramer discloses disulfide containing linkers of various length comprising alkylene groups linking the CpG oligo to the antigen (relevant to alkylene linkers of claimed invention).
Radovic-Moreno and Kramer do not disclose the recited carbamate alkylene dithiolate linker.
Suma (3/2017, J. Am. Chem. Soc., 139, 4009-4018) discloses testing various types of proapoptotic peptide nanoparticles (PPNs) composed of pro-apoptotic KLAK-peptides cross-linked to PEG-moieties via various types of linkers (pg. 4009, 4012). Suma discloses that the cross-linking chemistry is based on linkers comprising disulfide and carbamate alkylene groups (pg. 4009-4010). Suma tested three linkers: NDBC (“B-PPN”, has a phenyl group), NDEC (“E-PPN”)and SPDP (“S-PPN”), (see Fig. 2 below, left panel; pg. 4010). Suma discloses the disassembly to be tunable based on the linkers used (pg. 4009, see right panel of a figure from abstract: Cleavage fragmentation (slow), Cleavage fragmentation (fast) and Cleavage and no fragmentation).
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Suma demonstrates that in culture cells, treatment with B-PPN or E-PPN significantly reduced cell viability and cytotoxicity of PPNs was higher than free peptides, while the S-PPN resulted in a negligible reduction in cell viability; and comparing B-PPN and E-PPN, B-PPN induced a greater reduction in cell viability (pg. 4013, see Fig. 2a, b, relevant to instant cl. 58-62; both B-PPN and E-PPN comprise carbamate alkylene dithiolate linkers; B-PPN has a phenyl group (i.e. “Ar” relevant to instant cl. 61, 62) and E-PPN has a C2 alkylene group, relevant to instant cl. 59, 60). Further, the E-PPN and B-PPN disassemble into native-state peptides (pg. 4009). Suma disclose that following disassembly of KLAK peptide with portion of linker group possibly reduces their cytotoxicity properties, “thus regeneration of pristine KLAK peptides are of significant interest” (pg. 4014).
Although, both NDEC and NDBC have up to three CH2 short of the required alkylene length of instant recited carbamate dithiolate linkers, as provided by MPEP, additional homolog groups (i.e. CH2 group) are considered to have close structural similarity and there is a presumed expectation that such compounds possess similar properties.
The KSR’s “obvious to try” rationale for supporting conclusion of obviousness requires the following three findings:
(1) a finding that at the relevant time, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem; (2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem; (3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
Here, Suma discloses the challenges of loading, stability and controlled release of peptides in their natural state from carriers, in that linked-peptides are stable under normal physiological conditions but can disassemble into their natural form under certain biological triggers (pg. 4009). Suma discloses a finite number of identified, predictable linkers containing carbamate alkylene disulfide group that are tunable and are stable in extracellular environment at higher GSH intracellular environment and allow the peptide to dissociate into their native state (pg. 4014, Fig. 4). Further, Kramer also discloses cleavable linkers that are also finite in number (HYN-SS, SS) and will produce a predictable solutions.
One of the KSR rationale that may be used to support a conclusion of obviousness is obvious to try. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have modified the liposomal nanoparticle with an oligonucleotide conjugated to an antigen via a linker of Radovic-Moreno in view of Kramer and Suma and arrive at the claimed invention with a reasonable expectation of success. Radovic-Moreno demonstrates that OVA antigen-conjugated liposomal nanostructure via externally-facing oligonucleotide “provokes unexpectedly more potent induction of immune stimulatory effects in vitro” (Fig. 10, pg. 29), and Kramer demonstrates that conjugation of CpG oligonucleotide to a OVA-antigen via a disulfide, cleavable linker results in a greater anti-tumor immune response in vivo, and Suma demonstrates that disulfide linkers with carbamate alkylene groups results in dissociation of an antigen in its native state, i.e. a linker having “traceless” properties. Thus, a skilled artisan would try and expect reasonable success by designing an OVA antigen-conjugated liposomal nanostructure via externally-facing oligonucleotide CpG of Radovic-Moreno with cleavable disulfide linkers of Kramer that is further modified with traceless carbamate alkylene groups of Suma to release an antigen in its native state for improved functional antigen. Thus, cl. 1, 18, 56-62 are obvious.
Regarding instant cl. 15, Radovic-Moreno discloses that nanostructure may also include an antigen, including cancer antigens (pg. 29, line 15, 23); Suma discloses a KLAK peptide that is pro-apoptotic when targeting cancer cell line (Fig. 3, pg. 4014).
Regarding instant cl. 16, Radovic-Moreno discloses cancer antigens can be encoded by viral genes (pg. 33, line 18); and discloses a variety of virus, including papilloma virus (pg. 32, line 5).
Regarding instant cl. 17, Radovic-Moreno discloses a nanostructure with a liposomal core (pg. 14, line 21).
Regarding instant cl. 19, Radovic-Moreno discloses the oligonucleotide shell anchored to the surface of liposomal core through the use of a linker, i.e. associative moiety, which can be cholesterol (pg. 18, line 22, pg. 19, line 5).
Regarding instant cl. 21, Radovic-Moreno discloses a oligonucleotide shell have 2-10 different nt. sequences (pg. 4, line 15-16).
Regarding instant cl. 22, Radovic-Moreno discloses oligonucleotides of chimeric RNA-DNA oligonucleotides (pg. 4, line 10).
Regarding instant cl. 28, Radovic-Moreno discloses extrusion of lipid DOPC mixture through 50 nm followed by 30 nm extrusion membranes (pg. 41, line 20).
Regarding instant cl. 29 , Radovic-Moreno discloses a oligonucleotide shell have 2-10 different nt. sequences (pg. 4, line 15-16).
Regarding instant cl. 31, Radovic-Moreno discloses nanostructures maybe administered in any appropriate pharmaceutical carrier (pg. 33, line 25).
Regarding instant cl. 34, Radovic-Moreno discloses nanostructures of the invention useful as a vaccine (pg. 34, line 19).
Regarding instant cl. 53, Radovic-Moreno discloses oligonucleotides is single-stranded (pg. 4, line 5).
Response to Arguments
Applicant's arguments filed 10/14/2025 (“the Remarks”) have been fully considered but they are not persuasive.
Since the instant 103 rejection does not use the Low reference, the Remarks will address arguments against Radovic-Moreno reference and the unexpected results.
The Remarks argue that Office has not established prima facie case of obviousness with following arguments:
Radovic-Moreno does not disclose benefits of using “traceless configuration” (pg. 8).
The specification provides for unexpected results of Fig. 12, 23C illustrating improved T-cell proliferation and increased cytokine expression with “traceless linkers” (pg. 9)
The argument is not persuasive.
Regarding argument 1), for the obvious rejection, the Suma reference discusses “traceless” properties of NDEC and NDBC linkers.
Regarding argument 2), the MPEP requires that the results are in commensurate with the recited claims. The NDEC linker (see figure below), which is used to demonstrate the results and as noted in the rejection, is a bit distinct than the claimed carbamate alkylene linkers. Thus the results based on NDEC are not commensurate with the claimed linker structures, unless if it is shown that the results of NDEC and the claimed structures would be the same. Further, the claims are also directed to the broad genus of antigens, while the results are based on the antigen of gp100; the use of different antigens, e.g. the structure of antigen, the whole antigen protein versus a peptide of antigen, may have different outcomes that would have affect the overall conclusion.
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NDEC: as currently understood based on the figure: gp100-NH-C(O)-O-C2alkylene-S-S-C-DNA.
Double Patenting
Rejection of claims 1, 15, 16, 17, 18, 19, 21, 22, 28, 29, 31, 34, 53, 56-62 is maintained, and new claims 58-62 are rejected as noted below.
Claims 1, 15, 16, 17, 18, 19, 21, 22, 28, 29, 31, 34, 53, 56-62 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19, 21, 23, 24, 25, 28, 31, 33, 34, 35, 38, 39 of copending Application No. 17/743,422 (referred as ‘422) in view of Suma et al. (3/2017, J. Am. Chem. Soc., 139, 4009-4018, referred as Suma, in IDS of 6/8/22).
This is a provisional nonstatutory double patenting rejection.
‘422 claim 1 teaches a SNA comprising a nanoparticle (NP), a shell of oligonucleotides (ON) attached to NP core, wherein one or more oligonucleotides is attached to the NP core through a hydrophobic anchor comprising C12 subunits; claim 4 teaches a SNA comprises an antigen that is attached to one or more oligonucleotides through a linker; claim 7 teaches the shell of ON comprises immunostimulatory ON; claim 8 and 9 teach TLR agonist; cl. 10, 11 teach TLR9, cl. 12 teach CpG nucleotide sequence, Cl. 13 teaches SEQ ID NO: 3 and Cl. 14 teaches SEQ ID NO: 4, both SEQ ID NOs are CpG nt. sequence (instant Table 1, the specification can be used for definitional purposes), Cl. 16 teaches a carbamate alkylene disulfide linker, Cl. 17 and 18 teach nanoparticle core is liposomal core and liposome, respectively, Cl. 19, 20 teach liposome comprises DOPC, Cl. 23, 24 teach the shell has DNA oligonucleotides (plural form), Cl. 25 teaches shell of ON comprises single-stranded DNA and double stranded DNA; Cl. 28 teaches shell comprises 75 ON; Cl. 31 teaches diameter of SNA is about 1 to about 500 nm.; Cl. 33 teaches diameter of SNA is less than 50 nm.; Cl. 35 teaches antigen is a tumor antigen; Cl. 38 teaches recites a pharmaceutically acceptable carrier; Cl. 39 teaches a vaccine.
Regarding instant cl. 57, it would be prima facie obvious based on claim 13, which recites SEQ ID NO: 13, to design a complementary sequence based on the double-stranded taught in claim 25.
‘422 does not disclose the recited linkers: NH-C(O)-O-C2-5alkylene-S-S-C2-7alkylene (cl. 1(i), 59), nor NH-C(O)-O-CH2-Ar-S-S-C2-7alkylene (cl. 1(ii), 61), nor NH-C(O)-O-C2-4alkylene-CH(X)-S-S-CH(Y)C2-6alkylene (cl. 60) nor Antigen-NH-C(O)-O-CH2-Ar-S-S-CHXC2-6alkylene-Oligonucleotide (cl. 62); specifically the “Ar” group, which is the recited meta- or para-substituted phenyl group.
Suma (3/2017, J. Am. Chem. Soc., 139, 4009-4018) discloses testing various types of proapoptotic peptide nanoparticles (PPNs) composed of pro-apoptotic KLAK-peptides cross-linked to PEG-moieties via various types of linkers (pg. 4009, 4012). Suma discloses that the cross-linking chemistry is based on linkers comprising disulfide and carbamate alkylene groups (pg. 4009-4010). Suma tested three linkers: NDBC (“B-PPN”, has a phenyl group), NDEC (“E-PPN”)and SPDP (“S-PPN”), (see Fig. 2 below, left panel; pg. 4010). Suma discloses the disassembly to be tunable based on the linkers used (pg. 4009, see right panel of a figure from abstract: Cleavage fragmentation (slow), Cleavage fragmentation (fast) and Cleavage and no fragmentation).
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Suma demonstrates that in culture cells, treatment with B-PPN or E-PPN significantly reduced cell viability and cytotoxicity of PPNs was higher than free peptides; and comparing B-PPN and E-PPN, B-PPN induced a greater reduction in cell viability (pg. 4013, see Fig. 2a, b, relevant to instant cl. 1(i), 58-62; both B-PPN and E-PPN comprise carbamate alkylene dithiolate linkers; B-PPN has a phenyl group (i.e. “Ar” (relevant to instant cl. 61, 62) and E-PPN has a C2 alkylene group (relevant to instant cl. 1(i), 58-59). Further, the E-PPN and B-PPN disassemble into native-state peptides, i.e. the linkers are traceless (pg. 4009).
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have modified SNA with double-stranded CpG oligonucleotide linked to antigens via carbamate linkers of ‘422 in view of Suma and arrive at the claimed invention with a reasonable expectation of success. Based on Suma’s demonstration that B-PPN and E-PPN have similar cytotoxicity activity, a skilled artisan would expect reasonable success substituting NDBC or NDEC linkers of Suma for carbamate alkylene thiolate linker of ‘422 for similar immune activity. Although, both NDEC and NDBC up to three CH2 short of the required alkylene length of instant claimed carbamate linkers, but as provided by MPEP, additional homolog groups (i.e. CH2 group) are considered close structural similarity that there is a presumed expectation that such compounds possess similar properties, thus claims 1, 15, 16, 17, 18, 19, 21, 22, 28, 29, 31, 34, 53, 56-62 are obvious.
Response to Arguments
Applicant's arguments filed 10/14/2025 (“the Remarks”) have been fully considered but they are not persuasive.
The Remarks note that since the ‘422 is a later filed application that it should drop due to “all other rejections are improper and/or rendered moot” (pg. 10). Since the 103 rejection is maintained, along with an additional 103 rejection based on Skakuj, the provisional nonstatutory double patenting rejection is maintained.
Conclusion
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/KEYUR A VYAS/ Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600