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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10/06/2025 has been entered.
Election/Restrictions
Claims 1-3, 5, 12, 14, 15, 17, 19, 21, 24, 29, 32, 33, 36, 40, 42-43, 44, 46, 49, 51, 55, 59, 63-66 are pending.
Claims 1-3, 5, 12, 14, 15, 17, 19, 21, 24, 29, 32, 33, 43, 44, 46, 49, 63-66 of elected Group I and the species of Formula 2 with R1 group being
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from claim 29 and
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from claim 1 and SEQ ID NO: 2 (a Wuhan strain, cl. 5) is examined here.
Claims 36, 40, 42, 51, 55, 59 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Priority
The application claims benefit of multiple provisional applications, including 63/458102, filed on 04/08/2023, 63/549343 filed on 02/02/2024, 63/575093, filed on 04/05/2024, and 63/588932 filed on 10/09/2023.
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. 63/458102, 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. The ‘102 does not disclose the broad genus of second lipid nanoparticle specifically required in instant claim 46 and its dependent claims: the second lipid nanoparticle with structure recited in the claim. It does not appear that ‘102 discloses “a second nanoparticle” nor a “second lipid nanoparticle comprising a second bi-functional compound.”
The priority document ‘093, with the filing date of 04/05/2024, discloses the broad language of instant claim 46.
Thus, claims 1-3, 5, 12, 14, and 49 will enjoy the benefit of the filing date of ‘102, i.e. of 04/08/2023; while claims 46, 15, 17, 19, 21, 24, 29, 32, 33, 43, and 44, 63-66 will enjoy the benefit of instant application’s filing date of 04/05/2024.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/06/2025 was filed before the mailing date of this Office Action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Rejection of claim 5 is withdrawn, there’s a space between or and the.
Claim 63 is objected to because of the following informalities: Claim 63 has trademark superscripts, i.e. “TM”, for certain products: (SM-102TM and ALC-0315TM). Search in USPTO’s database of registered trademarks (tess2.uspto.gov) did not provide hits on these marks as receiving a trademark (both with and without the dash were searched), and appears to be a shortened product name and not a brand name. Appropriate correction is required: removing the “TM” superscript will cure the objection.
Claim 64 has a mis-abbreviated compound. Claim 64 recites “(DPOE)”, it should be “(DOPE)”.
Claim Rejections - 35 USC § 112
Rejection of claims 5, 12, and 14 is withdrawn, the claims are amended.
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.
Claims 1 and its dependents 2-3, 5, 12, 14, 15, 17, 19, 21, 24, 29, 32, 33, 43, 44, 46, 49, 63-66 are 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.
Claims 1 and 65 are rejected for reciting “a derivative thereof” of cholesterol, the term “derivate” is a relative term which fails to apprise one of ordinary skill in the art of its scope, i.e. the metes and bound of a cholesterol derivative; the basis for excluding a lipid that is not a cholesterol derivate is uncertain nor does the specification provide sufficient guidance. All the dependent claims are rejecting for failing to overcome the 112(b) rejection.
In interest of compact prosecution, the claims will be interpreted without the “a derivative thereof” term and removal of “a derivative thereof” will cure the rejection.
Claim 65 is rejected for reciting the following “trifluoroacetate salt (Dios-Arg, 2H-Cho-Arg, or Cho- Arg)”, the parentheticals make it unclear if trifluoroacetate is a species of cholesterol or that it is the salt form of each of the cholesterol moieties listed in the parenthesis.
In the interest of compact prosecution, it will be interpreted as a “trifluoroacetate salt of Dios-Arg, 2H-Cho-Arg, or Cho-Arg”.
The term “about” in claims 5, 12, 14 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The limits of “about” are not defined in the specification, thus there is uncertainty in determining the scope of the claim.
In the interest of compact prosecution, the claim will be interpreted without the language of “about”, e.g. for cl. 5: “an amino acid sequence having at least 99%, 98% . . . or 80% identity to SEQ ID NO: 2”
Claim Rejections - 35 USC § 103
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.
Claims 1, 3, 5, 12, 14, 15, 17, 19, 21, 24, 29, 32, 33, 43, 44, 46, 49, 64-66 are rejected under 35 U.S.C. 103 as being unpatentable over Nel et al. (WO2023069551, pub. 04/27/2023, filing date 10/19/2022) and Wang et al. (2014, Vaccine, 32, 5475-5483) and Goswami et al. (2021, Pharmaceutics, 13, pg. 1-14), and as evidenced by Reyes et al. (9/2023, Biomolecules, 13, doi.org/10.3390/biom13091421) and Gong et al. (2021, Signal Transduction and Targeted Therapy, 6, pg. 1- 24) for claim 1 and as evidenced by Pappalardo et al. (2021, Mol. Pharmaceutics, 18, 2540-2555 for cl. 33.
Regarding instant claims 1, 19, 21, 24, 29, 32, 43, 49, 64-66, Nel discloses an immunogenic nanoparticle (NP) that is capable of raising an immune response directed to SARS-CoV-2 and encapsulates a nucleic acid(s) encoding a multi-epitope vaccine that can be used in combination with covid-19 vaccines, such as spike protein mRNA vaccine(s), to invoke a strong CD8+ or CD4+ T-cell response (cl. 1, abstract). Nel discloses the Omicron Ba.I variant with various mutations, see Fig. 2 (below) providing a schematic diagram of a spike protein with mutation sites.
Nel’s Fig. 2
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As evidenced by Gong, the Omicron variant of Nel would have a reduced glycan profile due to mutations that are unable to be glycosylated at various mutated O-linked or N-linked sites. Gong discloses SARS-CoV-2 is decorated by a large number of highly glycosylated proteins, including spike protein, and the protein’s glycosylation (both N-linked and O-linked) extensively affects host recognition, penetration, binding, recycling, and pathogenesis (pg. 1). N-glycosylation refers to glycans attached to asparagine (Asn, N) residue; while O-glycosylation usually occurs on serine (Ser, S), threonine (Thr, T) and tyrosine (Tyr, Y) residues (pg. 1). Gong’s Table 1 (pg. 6) discloses reported O-glycosites on spike protein, i.e. on the T or S sites of the protein, that are noted by dashed arrows above in Fig. 2 of Nel to point out the mutation at the T or S site. Another mutation is N501Y, which as evidenced by Reyes, a post-filing reference that discloses “[t]he N-site modifications that could affect the N-glycosylation of the variants, due to its mutation in the amino acid asparagine “N,” including alpha (N501Y) (pg. 6, solid arrow in fig. above).
Regarding the nanoparticle, Fig. 17 (an excerpt of Fig. 17 is below) discloses a cationic lipid nanoparticle (LNP) comprising a DSPE-PEG2000-Mannose, a phosphatidyl lipid conjugated with a mannose moiety, which is a targeting moiety used for targeting various cell types (par. 394, relevant to instant cl. 1, 19, 21, 46). Mannose is a substituted glycosyl group for R1 (relevant to instant claims 1, 19, 46), a heterocycloalkyl comprising an O group (relevant to instant cl. 24) and is either a mannoside or a mono-mannoside (relevant to instant claims 19 and 21, respectively). Further, Nel discloses immunogenic nanoparticle comprising DLin-MC3-DMA, DSPC, cholesterol and PEG-2000-C-DMG (par. 238-240, relevant to ionizable lipid, phosphatidylcholine, a cholesterol, and a PEG-lipid, respectively, of cl. 1 and cl. 64, 65, and 66). So although Nel discloses the use of 4 of the 5 for an embodiment, it discloses the 5 recited lipid components to formulate a LNP and discloses skilled artisan optimizing helper lipid components (par. 494-497). Nel discloses use of active ingredient (the LNP) with excipient (par. 559, rel. to cl. 1).
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Nel discloses a high encapsulation efficiency (>97%) of mRNAs using LNPs comprising DSPE-PEG2000-Mannose (par. 394) and that the mannose structure ligands coating the LNPs improve nucleic acid uptake in lymph node dendritic cells (DC) (par. 540) and demonstrate that mannose covered LNPs containing GFP mRNA had “increased uptake of fluorescent protein” [sic? – authors may mean increased expression] in antigen presenting cell than LNPs lacking mannose (par. 541, Fig. 19).
Nel does not disclose the instant linker structure of claims 1 and 43, which comprises the Formula 3 (of cl. 32) and the phenol modified mannoside (of cl. 29 and 32).
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Wang discloses producing a lymphatic-targeted vaccine delivery liposome, a DOTAP-PEG-Mannose liposome (LP-Man) encapsulating an OVA antigen and demonstrating LP-Man being effectively accumulated in lymph nodes and spleen, but also enhanced uptake by resident antigen-presenting cells and its vaccine elicited sustained antibody production and robust recall responses three months after priming (abstract). Wang discloses formulation of DSPE-Man, see below (Supplemental material, pg. 1, see below (A)):
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Instant elected structure of cl. 1, 43, inverted for comparison:
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The only difference between Wang’s DSPE-PEG2000-Man and instant structure is circled in the inverted instant structure of cl. 1 and 43. Wang’s DSPE-PEG2000-Man has a PEG moiety in between an amide and phenyl groups (represented by “e” in fig. A, as noted above the PEG2000 has 32 polyethylene glycol repeats), while the instant structure of claims 1 and 43 has an amide group linked together by a 2 carbon alkyl chain in between the phenyl and amide groups. Comparing the DSPE-PEG2000-Man with instant structure of claim 29: Wang’s DSPE-PEG2000-Man structure lacks an ethylene group between the nitrogen and phenyl moiety along with a lack of carbonyl.
It is understood by one skill in the art that linker/attachment groups can be replaced with linkers/attachment groups of choice.
For example, Goswami discloses attaching a mannose group to a cholesterol moiety that is incorporated into a lipid nanoparticle, and provides for different formulation process (pg. 4, Scheme 1b, see below).
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Similarly, one can also modify the DSPE, a helper lipid component of a lipid nanoparticle, instead of the cholesterol or in addition to cholesterol-mannose moiety as provided in Goswami. The Goswami scheme provides for a reaction resulting in amides with alkyl attachment group to the terminal amine group of the cholesterol. Similarly, one can react succinic anhydride with terminal amino head of DSPE then with the D-mannopyranosylphenyl isothiocyanate to derive a similar product as instant elected structures of claims 1, 29, 32 and 43.
Further 2144.09(II) provides for obviousness when the structures are “homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties” and 2144.08(II)(A)(4)(c) that for consideration of rejection based on similar subgenus or species group, its properties and uses should also be considered. Here, the structure of linker groups and components of lipid molecules of a lipid nanoparticle that are used to target lymph node cells are similar, or at least not patentably distinct.
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 substituted the PEG2000 linker/attachment groups of Nel in view of Wang and Goswami and arrive at the claimed invention with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to substitute the PEG2000 linker/attachment group of Nel with a linker group linking the DSPE with the mannose-phenyl of Wang and Goswami to provide a similar LNP moiety that is directed to lymph nodes for a longer vaccination period. Thus claims 1, 19, 21, 24, 29, 32, 43, 46, 64-66 are obvious.
Regarding instant cl. 46, Nel discloses the use of therapeutic cocktails, i.e. pharmaceutical composition, comprising different nanoparticles with different targeting moieties that can bind to different targets (par. 593), thus contemplates the use of multiple LNPs targeting different targets. Fig. 20 discloses a similar LNP as Fig. 17 above with a TLR agonist component, thus the first lipid nanoparticle and second lipid nanoparticle are different in membrane components. Thus, here the first and second lipid nanoparticles comprise similar material as noted above for instant cl. 1, but the second nanoparticle also comprises the TLR agonist component.
Regarding instant cl. 3, Nel discloses an immunogenic nanoparticle (NP) comprising one or more lipids encapsulating nucleic acid encoding covid-19 peptide antigens comprising one or more CD8+ T-cell epitopes (par. 10-13). Nel discloses that the NP can comprise one or more of the covid-19 peptides of SEQ ID NO: 34-48, and one of the SEQ ID NOs is SEQ ID NO: 35, which is KGIYQTSNFRVQPTESIVRF (par. 15).
Further, since these are peptides, i.e. shorter length amino acid sequences, of covid-19 protein (SARS-CoV), they would necessarily have reduced glycan profile compared to a full-length spike protein (relevant to instant cl. 3).
Regarding instant cl. 5, the claim recites “the spike protein comprises an amino acid sequence set forth in” elected SEQ ID NO: 2. Here, under BRI, the claim is interpreted as a spike protein that comprises any amino acid sequence of any length that matches a portion of SEQ ID NO: 2.
Nel discloses that the NP can comprise one or more of the covid-19 peptides of SEQ ID NO: 34-48, and one of the SEQ ID NOs is SEQ ID NO: 35, which is KGIYQTSNFRVQPTESIVRF (par. 15). SEQ ID NO: 35 has 20 amino acids that is identical to position 310 to 329 of instant SEQ ID NO: 2, see alignment below (Qy is Nel SEQ ID NO: 5; Db is instant SEQ ID NO: 2).
Qy 1 KGIYQTSNFRVQPTESIVRF 20
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Db 310 KGIYQTSNFRVQPTESIVRF 329
Regarding instant cl. 12, the claim is directed to a group of amino acid sequences. One is SEQ ID NO: 44 (LDSKVGGNYN).
Nel discloses an embodiment of immunogenic nanoparticle wherein the nucleic acid encodes an amino acid peptide with SEQ ID NO: 140 (KLDSKVGGNYNY, par. 134), which has the full sequence of instant SEQ ID NO: 44.
Regarding instant cl. 14, Nell discloses various embodiments of immunogenic nanoparticles comprising nucleic acid encoding immunogenic peptides. One immunogenic peptide is SEQ ID NO: 149 (par. 143), which comprises instant SEQ ID NO: SEQ ID NO: 61 (GPKKSTNLVKNKC, see top alignment below). Another is SEQ ID NO: 151 (par. 145), which comprises instant SEQ ID NO: 62 (TEVPVAIHADQ, see bottom alignment below).
Portion of Nel SEQ ID NO: 149: 3 GPKKSTNLVKNKC 15
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Instant SEQ ID NO: 61 1 GPKKSTNLVKNKC 13
Portion of Nel SEQ ID NO: 151: 18 TEVPVAIHADQ 28
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Instant SEQ ID NO: 62 1 TEVPVAIHADQ 11
Regarding instant cl. 15, Nel discloses a mannose group (R2, also a substituted or non-substituted glycosyl group) linked by an attachment group (recited also as RA) to the phospholipid DSPE moiety. Nel discloses a PEG moiety as an attachment group (a substituted alkyl group) of the DSPE and the mannose moiety (the specification defines glycosyl group comprising mono-mannoside, par. 39).
Regarding instant cl. 17, 33, Nel discloses a mannose attached to PEG2000-DSPE (par. 394, Fig. 17 above); as evidenced by Pappalardo et al. (2021, Mol. Pharmaceutics, 18, 2540-2555) a PEG2000, comprises 44 (OCH2CH2) subunits, see Fig. 1B, thus a species reading within the range of 2-72 recited in instant cl. 17.
DSPE comprises C18 saturated hydrocarbon chains (relevant to instant cl. 33).
Regarding instant cl. 44, Nel is silent on glycolipid C34, thus it is inferred that it is not a lipid component. Further the LNP composition of the embodiment disclosed in Table 41 does not have glycolipid C34 nor alpha-galactosylceramide (par. 543).
Regarding instant cl. 49, Nel discloses LNP further comprises an adjuvant, and discloses that a commercially available pan-HLA DR-binding epitope (PADRE) sequence (SEQ ID NO: 180) can be used as an adjuvant in immunotherapeutic vaccine development (par. 459).
Claims 2, 3 are rejected under 35 U.S.C. 103 as being unpatentable over Nel et al. (WO2023069551, pub. 04/27/2023, filing date 10/19/2022) and further in view of Wang et al. (2014, Vaccine, 32, 5475-5483) and Goswami et al. (2021, Pharmaceutics, 13, pg. 1-14), and as evidenced by Reyes et al. (9/2023, Biomolecules, 13, doi.org/10.3390/biom13091421) and Gong et al. (2021, Signal Transduction and Targeted Therapy, 6, pg. 1- 24) as applied to claims 1, 3, 5, 12, 14, 15, 17, 19, 21, 24, 29, 32, 33, 43, 44, 46, 49, 64-66 above, and further in view of Huang et al. (2021; Huang shares co-inventor with instant applications, but is outside the 102(b)(1) exception grace period, thus qualifies as a 102(a)(1), referred as Huang, in IDS of 07/24/24, cite 24).
As noted above, Nel discloses a LNP comprising a mannosylated-DSPE encapsulating nucleic acids encoding SARS-CoV peptides of the spike protein or even mRNA of spike protein to produce vaccine to invoke a strong CD8+ T-cell response, and the vaccine is based on the rational combination of well-conserved T-cell epitopes identified in COVID-19 and viral variants (abstract, par. 8).
Nel does not disclose substitution of asparagine (N) to glutamine (Q) at N-linked glycosylation sequons (N-X-S/T), wherein X is any a.a. residue except proline.
Huang discloses a SARS-CoV-2 spike protein, a key immunogen that is frequently mutated with conserved epitopes shielded by glycans, with N-glycans trimmed to the monoglycosylated state (Smg) (abstract). The spike protein with trimmed N-glycans elicited a stronger immune response and demonstrated, in transgenic mice, that removal of glycan shields better exposes the conserved sequences for an effective and a broad-spectrum vaccine development (abstract). Huang tested mutating/deleting various spike protein glycosylation sites: N to Q mutations along with deletion of N site (N331Q, N343Q of the RBD region resulted in reduction of infectivity in vitro; relevant to instant cl. 2; deletion of N122 glycosylation in NTD region resulted in low protein expression and reduced infectivity; relevant to instant cl. 3), and N801Q and N1194Q universally abolished virus infectivity in all five cell lines tested, pg. 2).
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. 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 spike protein or its peptides of Nel in view of Huang and arrive at the claimed invention with a reasonable expectation of success. As Huang discloses either mutating/deleting the N-glycosylation sites of a S protein of SARS-CoV resulted in reduced infectivity due to introducing a more exposed antigen, a skilled artisan would have been motivated to modify the spike protein or its antigenic-epitope peptides of Nel by either mutating/deleting the N-glycosylation site(s) of a S protein of SARS-CoV as taught by Huang to generate a more exposed antigen to be used for improved neutralizing antibody production. Thus, claims 2 and 3 are obvious.
Claim 63 is rejected under 35 U.S.C. 103 as being unpatentable over Nel et al. (WO2023069551, pub. 04/27/2023, filing date 10/19/2022) and further in view of Wang et al. (2014, Vaccine, 32, 5475-5483) and Goswami et al. (2021, Pharmaceutics, 13, pg. 1-14), and as evidenced by Reyes et al. (9/2023, Biomolecules, 13, doi.org/10.3390/biom13091421) and Gong et al. (2021, Signal Transduction and Targeted Therapy, 6, pg. 1- 24) as applied to claims 1, 3, 5, 12, 14, 15, 17, 19, 21, 24, 29, 32, 33, 43, 44, 46, 49, 64-66 above, and further in view of Mashima and Takada (2022, Curr Issues Mol Biol., 44, 5013-5027).
Rejection of claims 11, 3, 5, 12, 14, 15, 17, 19, 21, 24, 29, 32, 33, 43, 44, 46, 49, 64-66 is noted above.
Nel, Wang, Goswami, Reyes, Gong do not disclose the ionizable lipids of instant cl. 63.
Mashima discloses lipid components of LNPs that are FDA-approved, the LNPs contain several types of cationic ionizable lipids: SM-102, ALC-0315 and DLin-MC3-DMA (Table 1).
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 the ionizable cationic lipid of Nel in view of Mashima and arrive at the claimed invention with a reasonable expectation of success. Based on the knowledge that FDA-approved LNP comprises SM-102 and ALC-0315 cationic ionizable lipids, a skilled artisan can reasonably expect success by substituting ionizable cationic lipid (DLin-MC3-DMA) of Nel with either SM-102 or ALC-0315 of Mashima to deliver vaccine. Thus, claim 63 is obvious.
Response to Arguments
Applicant's arguments filed 10/06/2025 (“the Remarks”) have been fully considered but they are not persuasive.
The Remarks contend the following:
1) The Remarks contend that claim 1 amendment has 5 different lipids components (L1-L5).
2) Wang teaches liposome and not LNP and that despite teaching DPSE-PEG lipid conjugated with mannose head as instant claims, the “major component DOTAP, used in Wang is known not [to be] suitable for an LNP as it is a permanently cationic lipid” (pg. 19);
3) Apparently, “present claims represent a different concept of how to incorporate a targeted delivery functionality into an LNP” and this is a “key limitation” missing in the other references (pg. 19-20): here the claimed invention uses 5 components, the 5th being the recited bi-functional compound, comprising the mannose moiety, since “modifying a targeted delivery functional moiety onto an existing lipid component is undesirable, especially on a DSPC. This is because DSPC is a net neutral compound” (pg. 19).
The argument is not persuasive.
Regarding contention 1), Nel teaches each of the 5 lipid components and modifying the lipid components of a LNP to optimize its function depending on physiological factors.
Regarding contention 2) as the Applicant’s points out “DOTAP is not suitable for an LNP,” and recognizing this is a well-known problem in the LNP formulation, Nel and others (see Mashima) use or suggest using a different cationic lipid (such as DLin-MC3-DMA) for their LNP.
Regarding 3): Although it is correct that prior art of record does not disclose 5 lipid components in a single LNP, the use of DSPE, DSPC and cholesterol as a helper-lipid is known (see Sun et al. [1/2023, Pharmaceutical Research, 40: 27-47] Fig. 3 noting phosphotidylethanolamines and phosphatidylcholines, as helper lipids). DSPE is a phosphotidylethanolamine. Thus a skilled artisan can divide the helper-lipid component, including DSPC, DSPE, and cholesterol, in appropriate concentration to achieve similar function of an overall cumulative helper lipid component(s) noted in prior art. Nel discloses DSPE, DSPC, cholesterol, ionizable cationic lipid, and combines DSPE and PEG-lipid into a singular lipid component, i.e. DSPE-PEG-mannose (see fig. above); a skilled artisan can optimize the concentration of lipid components known in the prior art. Further, the Remarks fail to provide objective evidence of how the differences in the product provides an improved function over that of the product of prior art. Currently, the claimed invention is obvious over the prior art cited since there is not a patentable distinction between the minute differences of the instant claimed invention and that of the cited prior art or is obvious over the cited prior art.
Thus the rejection is maintained.
Double Patenting
It should be noted that the Remarks of 10/06/2025 do not address the double patenting rejection and therefore all the rejections are maintained.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Application No. 18/629707 (Has an NOA issued)
Claims 1, 2, 3, 12, 14, 17, 19, 21, 24, 32, 33, 43, 44 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, 6, 8, 11, 16, 19, 20, 30-31 of copending Application No. 18/629707 in view of Huang et al. (posted 8/26/2021; bioRxiv, www.biorxiv.org/content/10.1101/2021.05.25.445523v2; Huang shares co-inventor with instant applications, but is outside the 102(b)(1) exception grace period, thus qualifies as a 102(a)(1), referred to as Huang).
This is a provisional nonstatutory double patenting rejection.
‘707 claims 1, 30 are drawn to a compound for forming a lipid nanoparticle comprising the compound of instant bi-functional compound claimed structure of cl. 1, and (withdrawn) claim 39 refers to such a nanoparticle comprising a payload, wherein the payload is a nucleic acid, a polypeptide, a protein. Further, to define the content of LNP of cl. 1, a table noting exemplary LNPs comprise, ionizable lipid, phosphatidylcholine, cholesterol, PEG-lipid, and bifunctional compound lipid (instant compound 22, same as elected structure of cl. 1, 43; par. 73, Table pg. 20-22).
‘707 does not disclose a payload encoding a spike protein of SARS-CoV wherein the spike protein has a reduced and/or deleted glycan profile.
Huang discloses a SARS-CoV-2 spike protein, a key immunogen that is frequently mutated with conserved epitopes shielded by glycans, with N-glycans trimmed to the monoglycosylated state (Smg) that elicits stronger immune response and demonstrates, in transgenic mice, that removal of glycan shields improves the exposure of the conserved sequences for an effective and simple approach to broad-spectrum vaccine development (abstract, relevant to instant cl. 1). Huang tested various lentivirus-based pseudovirus variants, including variants that had N to Q glycosite mutations, i.e. reduced glycan profiled, along with deletion of N site, i.e. a deleted glycan profile (N331Q, N343Q of the RBD region resulted in reduction of infectivity in vitro [pg. 2, line 17; relevant to instant cl. 2]; deletion of N122 glycosylation in NTD region resulted in low protein expression and reduced infectivity [pg. 2, line 19-20; relevant to instant cl. 3], and N801Q and N1194Q universally abolished virus infectivity in all five cell lines tested, pg. 2, lines 22-23).
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 LNP of ‘707 in view of Huang and arrive at the claimed invention with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine LNP comprising a payload of ‘707 by encapsulating it with a lentiviral encoding a SARS-CoV-2 spike protein comprising mutated/deleted N-glycosites and O-glycosites or reduced glycans of Huang for improved production of neutralizing antibody that recognizes more variants.
Claim 1 of ‘707 corresponds with instant claim 15.
Claim 4 of ‘707 corresponds with instant cl. 17.
Claim 6 of ‘707 corresponds with instant cl. 19.
Claim 8 of ‘707 corresponds with instant cl. 21.
Claim 11 of ‘707 corresponds with instant cl. 24.
Claim 16 of ‘707 corresponds with instant cl. 29.
Claim 19 of ‘707 corresponds with instant cl. 32.
Claim 20 of ‘707 corresponds with instant cl. 33.
Claim 30 of ‘707 corresponds with instant cl. 1, 43.
Claim 31 of ‘707 corresponds with instant cl. 44.
Claims 1, 5, 12, 14, 46, 49 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim claims 1, 2, 4, 6, 8, 11, 16, 19, 20, 30-31 of copending Application No. 18/629707 in view of Nel et al. (WO2023069551, pub. 04/27/2023, filing date 10/19/2022, referred as Nel).
‘707 does not disclose an amino acid sequence set forth in SEQ ID NO: 2 (cl. 5) or an amino acid sequence selected from a group consisting of SEQ ID NOs recited in claims 12 and 14.
Regarding instant cl. 1, Nel discloses an immunogenic nanoparticles (NP) that is capable of raising an immune response directed SARS-CoV-2 and further may comprise mRNA multi-epitope vaccines that can be used in combination with covid-19 vaccines, such as the spike protein mRNA vaccine(s) to invoke a strong CD8+ or CD4+ T-cell response (abstract). Nel discloses the Omicron Ba.I variant with mutations that aid in the virus evading the immune system, see Fig. 2 (below) a schematic diagram of spike protein with mutation sites, one is N501Y, which as evidenced by Reyes et al. (9/2023, “[t]he N-site modifications that could affect the N-glycosylation of the variants, due to its mutation in the amino acid asparagine “N,” are alpha (N501Y)” (pg. 6); for background, Reyes discloses that the spike protein is heavily glycosylated, which protects the virus active site from human defense system (abstract) and aids in host-cell entry (pg. 2)). Further, as evidenced by Gong et al. (2021, Signal Transduction and Targeted Therapy, 6, pg. 1- 24), Table 1 (pg. 6) discloses reported O-glycosites and O-glycopeptides in S protein, the T or S sites are noted by dashed arrows below in Fig. 2 of Nel. Thus, the Omicron variant would have a reduced glycan profile due to mutations of the various O-linked or N-linked sites.
Nel’s Fig. 2
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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 LNP compound comprising Formula 2 of ‘707 in view of Nel and arrive at the claimed invention with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to modify the LNP compound comprising Formula 2 of ‘707 by encapsulating the mRNA encoding covid spike protein of Nel to generate a vaccine against covid-19.
Regarding instant cl. 5, the claim recites “the spike protein comprises an amino acid sequence set forth in” elected SEQ ID NO: 2. Here, under BRI, the claim is interpreted as comprises any amino acid sequence of any length that matches a portion of SEQ ID NO: 2.
Nel discloses that the NP can comprise one or more of the covid-19 peptides of SEQ ID NO: 34-48, and one of the SEQ ID NOs is SEQ ID NO: 35, which is KGIYQTSNFRVQPTESIVRF (par. 15). SEQ ID NO: 35 has 20 amino acids that is identical to position 310 to 329 of instant SEQ ID NO: 2, see alignment below (Qy is Nel SEQ ID NO: 5; Db is instant SEQ ID NO: 2).
Qy 1 KGIYQTSNFRVQPTESIVRF 20
||||||||||||||||||||
Db 310 KGIYQTSNFRVQPTESIVRF 329
Regarding instant cl. 12, the claim is directed to a group of amino acid sequences. One is SEQ ID NO: 44 (LDSKVGGNYN).
Nel discloses an embodiment of immunogenic nanoparticle wherein the nucleic acid encodes an amino acid peptide with SEQ ID NO: 140 (KLDSKVGGNYNY, par. 134), which has the full sequence of instant SEQ ID NO: 44.
Regarding instant cl. 14, Nell discloses various embodiments of immunogenic nanoparticle comprising nucleic acid encoding immunogenic peptides. One immunogenic peptide is SEQ ID NO: 149 (par. 143), which comprises instant SEQ ID NO: SEQ ID NO: 61 (GPKKSTNLVKNKC, see top alignment below). Another is SEQ ID NO: 151 (par. 145), which comprises instant SEQ ID NO: 62 (TEVPVAIHADQ, see bottom alignment below).
Portion of Nel SEQ ID NO: 149: 3 GPKKSTNLVKNKC 15
|||||||||||||
Instant SEQ ID NO: 61 1 GPKKSTNLVKNKC 13
Portion of Nel SEQ ID NO: 151: 18 TEVPVAIHADQ 28
|||||||||||
Instant SEQ ID NO: 62 1 TEVPVAIHADQ 11
One of ordinary skill in the art would have been motivated to modify the LNP of ‘707 with the payload of spike protein peptides taught by Nel to generate vaccine against covid-19 infection with reasonable success.
Regarding cl. 46 and 49, Nel discloses the use of therapeutic cocktails comprising different nanoparticles with different targeting moieties that can bind to different targets (par. 593), thus contemplates the use of multiple LNPs targeting different targets and/or with different payloads, such as a S protein of SARS-CoV2, for vaccination purposes (par. 595). One of skill in the art would have been motivated to combine LNP of ‘707 with an adjuvant and/or LNP with a S protein and a mRNA for vaccine production as taught by Nel for an improved immunogenic response.
This is a provisional nonstatutory double patenting rejection.
Allowable Subject Matter
No claim is allowed.
Alignment of Instant SEQ ID NO: 2 (Qy) with ‘573 of SEQ ID NO: 2 (Db)
Title: US-18-629-722-2
Perfect score: 6727
Sequence: 1 MFVFLVLLPLVSSQCVNLTT..........CKFDEDDSEPVLKGVKLHYT 1273
Scoring table: BLOSUM62
Gapop 10.0 , Gapext 0.5
Searched: 1 seqs, 1193 residues
Total number of hits satisfying chosen parameters: 1
Minimum DB seq length: 0
Maximum DB seq length: inf
Post-processing: Minimum Match 0%
Maximum Match 100%
Listing first 1 summaries
Database : AASEQ2_02122025_190326.pep:*
SUMMARIES
%
Result Query
No. Score Match Length DB ID Description
----------------------------------------------------------------------------
1 6189 92.0 1193 1 AASEQ2_02122025_190326
ALIGNMENTS
RESULT 1
AASEQ2_02122025_190326
Query Match 92.0%; Score 6189; DB 1; Length 1193;
Best Local Similarity 98.9%;
Matches 1182; Conservative 1; Mismatches 10; Indels 2; Gaps 1;
Qy 14 QCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGT 73
||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QCVNLRTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGT 60
Qy 74 NGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEF 133
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEF 120
Qy 134 QFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFV 193
|||||||| ||||||||||||| |||||||||||||||||||||||||||||||||||
Db 121 QFCNDPFLDVYYHKNNKSWMES--GVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFV 178
Qy 194 FKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGD 253
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 179 FKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGD 238
Qy 254 SSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIY 313
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 239 SSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIY 298
Qy 314 QTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSAS 373
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 299 QTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSAS 358
Qy 374 FSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCV 433
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 359 FSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCV 418
Qy 434 IAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQ 493
|||||||||||||||||| ||||||||||||||||||||||||| |||||||||||||||
Db 419 IAWNSNNLDSKVGGNYNYRYRLFRKSNLKPFERDISTEIYQAGSKPCNGVEGFNCYFPLQ 478
Qy 494 SYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLT 553
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 479 SYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLT 538
Qy 554 ESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQ 613
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 539 ESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQ 598
Qy 614 DVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICAS 673
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 599 GVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICAS 658
Qy 674 YQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTK 733
||||||| | ||||||||||||||||||||||||||||||||||||||||||||||||
Db 659 YQTQTNSRGSAGSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTK 718
Qy 734 TSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPP 793
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 719 TSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPP 778
Qy 794 IKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQ 853
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 779 IKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQ 838
Qy 854 KFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQ 913
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 839 KFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQ 898
Qy 914 NVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAI 973
||||||||||||||||||||||||||||||||||||:|||||||||||||||||||||||
Db 899 NVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQNVVNQNAQALNTLVKQLSSNFGAI 958
Qy 974 SSVLNDILSRLDPPEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECV 1033
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 959 SSVLNDILSRLDPPEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECV 1018
Qy 1034 LGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREG 1093
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1019 LGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREG 1078
Qy 1094 VFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELD 1153
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1079 VFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELD 1138
Qy 1154 KYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQ 1208
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1139 KYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQ 1193
Conclusion
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/KEYUR A VYAS/Examiner, Art Unit 1637 /Soren Harward/Primary Examiner, TC 1600