DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This Office action is in response to the communication filed 10-2-25.
Claims 79, 80, 82, 83, 86-98 are pending in the instant application.
Response to Arguments and Amendments
Withdrawn Objections/Rejections
Any objections or rejections not repeated in this Office action are hereby withdrawn.
New Rejections Necessitated by Amendments
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 79, 80, 82, 83, 86-98 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stephanopoulos et al (US 2024/0035014) in view of Lee et al (US 2017/0216457), Duvall et al (US 2018/0064749), Ahn et al (US 2016/0208245), Lee et al (WO 2012/125987), the combination further in view of Colletti et al (US 2017/0081425).
The claims are drawn to compositions comprising a hydrophobic moiety and/or a hydrophilic moiety, and a nucleotide attachment moiety, which attachment moiety is attached to an oligonucleotide which is self-assembled into a nanoparticle comprising at least four oligonucleotide strands of 3-200 nucleotides each in length, which nanoparticle is conjugated to one or more cargo molecules. Cargo molecules optionally comprise a thiol, amine, alkyne, azide, tetrazine, norbornene, dibenzocyclooctyne, and the 2’ position of sugars of the component nucleotides within the oligonucleotide chains optionally comprise a modification selected from the group 2‘-O-(2-methoxyethyl) (2MOE), 2’-methoxy (2’OMe), 2’-fluoro (2’F), 2-’O-acetalesters, 2-guanidinomethyl]-2-ethylbutyryloxymethy] (GMEBuOM), 2-amino-2-methylpropionyloxymethyl (AMPrOM), 2-aminomethyl-2-ethylbutyryloxymethyl (AMEBuOM), 2'-O-Pivaloyloxymethyl ( PivOM), 2’ amino locked nucleic acids (LNA) modified with amines or peptides mentioned above, 2'-O- [N,N-dimethylamino)ethoxy ethyl, 2'-N-[N,N-dimethylamino)ethoxy ethyl, 2'-N- imidazolacetyamide, 2’-O-[3-(guanidinium)propyl], 2’-N-[3-(guanidinium)propyl], 2’-O- [3-(guanidinium)ethyl], 2’-N-[3-(guanidinium ethyl], 2'-O-(N-(aminoethyl)carbamoyl)methyl, 2'-N-(NV-(aminoethyl)carbamoyl)methyl, 2’-O-[N-(2-((2- aminoethyl)amino)ethyl) acetamide, 2’-N-[N-(2-((2-aminoethyl)amino)ethy1) acetamide, 2’-N-2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctanamide, 2'-N-imidazolacetamide, 2’-O-imidazole methyl, 2'-N-guanidylbenzylamide, and 4'-C-guanidinincarbohydrazidomethyl, 2’-O-imidazolemethyl, 2’-N-imidazolemethylamine ethyl,
which nanoparticle is conjugated to one or more cargo molecules optionally comprising an mRNA molecule, a lnRNA molecule, a miRNA molecule, an siRNA molecule, a shRNA molecule, a ASO molecule, a peptide, a polypeptide, a protein, an antibody, a label, a reporter, a stabilizing agent, a targeting moiety, and a therapeutic agent, which nucleotide attachment moiety is conjugated to a nucleic acid in the oligonucleotide via a linkage to either a 2' position of a sugar or base in the nucleic acid, or at the 3’ or 5’ end of a component oligonucleotide, or which nucleotide attachment moiety is attached to a component oligonucleotide strand within the nanoparticle, and which nucleotide attachment moiety is attached to the cargo molecule, which nucleic acid nanoparticle comprises a nucleic acid having at least one linkage optionally comprising a 3-(2-nitrophenyl)-propyl phosphoramidite linkage, 3-phenylpropyl phosphoramidite linkage, alkyl phosphorothioate linkage, aminobutyl phosphoramidite linkage, aryl phosphorothioate linkage, dimethylamino phopsphoramidite linkage, guanidinobutylphosphoramidate linkage, or a phosphorothioate linkage,
which hydrophobic moiety optionally promotes escape of the cargo molecule from an endosome within a cell of a subject, which hydrophilic moiety optionally promotes escape of the cargo molecule from an endosome within a cell of a subject, or which hydrophilic moiety optionally comprises an amine optionally comprising spermine, ethylenediamine, methylethylenediamine, ethylethylenediamine, imidazole, spermine-imidazole-4-imine, N-ethyl-N'-G- dimethylaminopropy!)-guanidiny! ethylene imine, dimethylaminoethyl acrylate, amino vinyl ether, 4-imidazoleacetic acid, diethylaminopropylamide, sulfonamides (e.g. sulfadimethoxine sulfamethoxazole, sulfadiazine, sulfamethazine), amino ketals, N-2-hydroxylpropyltimehyl ammonium chloride, imidazole-4-imines, methyl-imidazoles, 2-(aminomethy])imidazole, 4-(aminomethyl)imidazole, 4(5)-(Hydroxymethy])imidazole, N-(2-aminoethy1)-3-((2-aminoethyl)(methyl)amino)propanamide, 2-(2- ethoxyethoxy )ethan-1-amine, bis(3-aminopropyl)amine, [N,N-dimethylamino)ethoxy Jethyl, N-(2-aminoethyl)-3-((2- aminoethyl)(ethyl)amino)propanamide, (N-(aminoethyl)carbamoyl)methyl, N-(2-((2- aminoethyl )amino)ethyl acetamide 3,3'-((2-aminoethy] )azanediyl)bis(N-(2-aminoethyl)propanamide), guanidyl benzylamide, 3 (guanidinium)propy]], dimethylethanolamine, 1-(2,2-dimethyl-1,3-dioxolan-4-yl)-N,N-dimethylmethanamine, 2-(2,2-dimethyl-1,3-dioxolan-4-yl)-N,N-dimethylethan-1-amine, N-(2-((2-(2-aminoethoxy )propan-2-yl)oxy)ethyl)acetamide, aminobutyl, aminoethyl, 1-(2-aminoethy1)-3-(3-(dimethylamino)propyl1)-2-ethyl guanidine, 1-(3-amino-3-oxopropyl)-2,4,6-trimethylpyridin-1-ium, 1-(1,3-bis(carboxyoxy)propan-2-yl)-2,4,6-trimethylpyridin-1l-ium, guanidinylethyl amine, ether hydroxyl triazole, imidazole, guanidyl and a B-aminoester,
which hydrophilic group is positively-charged at a pH of about 7.0, or which hydrophobic moiety optionally comprises cholesterol, cholesteryl-TEG, tocopherol, methyl, ethyl, butyl, hexyl, octyl, dodecyl, hexadecyl, octadecyl, and 2-methoxyethyl., or which hydrophobic component comprises a peptide optionally attached via a thiol-maleimide linkage, an amide linkage, a disulfide linkage, or a triazole linkage.
Stephanopoulos et al (US 2024/0035014) teach oligonucleotides self-assembled into nanoparticles, which nanoparticles comprise at least four oligonucleotide strands of 3-100 nucleotides (Figures 13A-E, ¶¶ 0052, 0076).
Stephanopoulos teaches cargo molecules comprising therapeutic nucleic acids, polypeptides, combinations thereof (¶¶ 0004, 0052-0056).
Stephanopoulos teaches conjugated cargo molecules and nucleotide attachment moieties comprising thiols and amines, including 5’ amino modifications (¶¶ 0076-0079).
Lee et al (US 2017/0216457) teach self-assembling nanoparticles comprising delivery of therapeutic cargo comprising mRNA (see esp. the abstract, page 1, ¶¶ 0041-0044, Example 5 on page 5).
Duvall et al (US 2018/0064749) teach siRNA-amines conjugated to hydrophobic groups (e.g. albumin binding groups including divalent lipid moieties for increasing in vivo stability). Duvall teaches cellular internalization of Cy5-labeled siRNA lipid conjugates in tumor cells. Duvall teaches a variety of crosslinkers for conjugating RNA molecules, as well as teaching negatively charged and hydrophobic amino acid peptides, cell penetrating peptides that promote cellular uptake of cargo molecules, including CPP “Tat” and poly(Arginine). Duvall teaches siRNA conjugates for facilitating cell type targeting and mediation of endosomal escape. Duvall teaches amine-modified single stranded DNA modified at the 5’ end and RNA modified at the 3’ end for producing nucleic acid conjugates (see esp. the abstract, Figure 1, text on pages 1, 2, 4-6, 8 and 9).
Ahn et al (US 2016/0208245) teach compositions comprising siRNA, DNA-cholesterol conjugates, folate-DNA conjugates, and self-assembling amphiphilic nanoparticles, additionally comprising ligand specific targeting agents, including but not limited to RGD peptides, cancer targeting aptamers ( see esp. the abstract, Figure 1, pages 1-2, 6-7, claims 1-13, 24).
Lee et al (WO 2012/125987) teach three dimensional, self-assembling higher ordered structures for nanoscale delivery and adapted for delivery of nucleic acids. Lee teaches covalent attachment of targeting ligand moieties, payload moieties attached to ligand moieties, siRNA, and targeted constructs for treating cancer. Lee teaches hydrophilic moieties comprising ethylene imines (see e.g., pages 1-8, Figures 1-21, pages 38, 39, 48-51).
Colletti et al (US 2017/0081425) teach nucleic acid compositions comprising RNA and oligonucleotide conjugates comprising phosphorothioate internucleotide linkages, 2’-O-Me sugar modifications, and the optional attachment of conjugated moieties on the 3’ and/or 5’ termini of the oligonucleotide moieties, including via a thiol linkage (see esp. the abstract, ¶¶ 1-114, 124, 189-191, 287).
Applicant’s Arguments
Applicant submits that Duvall is concerned with products and methods of RNA treatment and administration and specifically teaches the use of an RNA molecule directly conjugated to an albumin-binding group which acts to extend the circulation persistence of the RNA (see paragraphs [0010] and [0077] and claim 1). Duvall does not disclose or teach compositions comprising nanoparticles formed of at least four oligonucleotides of 3 to 200 nucleotides in length each that are conjugated to one or more cargo molecules as is required by amended claim 79.
Applicant also submits that Ahn discloses a nanoparticle formed by complimentary RNA/DNA base-pairing between an RNA transcript containing siRNA to be delivered, a DNA-cholesterol conjugate and a folate-DNA conjugate (see paragraph [0011]) … Ahn teaches the use of a polymerized RNA transcript in which siRNAs to be delivered are repeatedly linked by RCT and this improves low intracellular delivery efficiency (see paragraph [0025]).
Applicant submits that Lee teaches that the oligonucleotides forming the 3D nanoparticles disclosed therein can comprise a “second portion” on the exterior surface of the nanoparticle which can be a ligand hybridization element (see paragraph [0007]). The purpose of this ligand hybridization element is to allow for a ligand oligonucleotide to hybridize to a complementary sequence within the ligand hybridization element (see paragraph [0011]). Lee teaches that a payload moiety may be attached to the ligand oligonucleotide (see paragraph [0012]).
Applicant additionally submits that Coletti teaches compositions comprising an oligonucleotide (including RNA) linked to a targeting ligand wherein the oligonucleotide is the payload (see paragraph [0005]) for use in conjunction with peptide conjugates.
Applicant argues that these references do not teach oligonucleotides self-assembled into nanoparticles, which nanoparticles comprise at least four oligonucleotide strands of 3-100 nucleotides.
Response to Applicant’s Arguments
Contrary to Applicant’s arguments and assertions, the instant 103 rejection citing Stephanopoulos et al (US 2024/0035014) in view of Lee et al (US 2017/0216457), Duvall et al (US 2018/0064749), Ahn et al (US 2016/0208245), Lee et al (WO 2012/125987), the combination further in view of Colletti et al (US 2017/0081425) is proper.
Contrary to Applicant’s arguments, the combined teachings render the instant invention obvious. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In this case, Stephanopoulos et al (US 2024/0035014) teach oligonucleotides self-assembled into nanoparticles, which nanoparticles comprise at least four oligonucleotide strands of 3-100 nucleotides (Figures 13A-E, ¶¶ 0052, 0076).
Stephanopoulos teaches cargo molecules comprising therapeutic nucleic acids, polypeptides, combinations thereof (¶¶ 0004, 0052-0056).
Stephanopoulos teaches conjugated cargo molecules and nucleotide attachment moieties comprising thiols and amines, including 5’ amino modifications (¶¶ 0076-0079).
Lee et al (US 2017/0216457) teach self-assembling nanoparticles comprising delivery of therapeutic cargo comprising mRNA (see esp. the abstract, page 1, ¶¶ 0041-0044, Example 5 on page 5).
Duvall et al (US 2018/0064749) teach siRNA-amines conjugated to hydrophobic groups (e.g. albumin binding groups including divalent lipid moieties for increasing in vivo stability). Duvall teaches cellular internalization of Cy5-labeled siRNA lipid conjugates in tumor cells. Duvall teaches a variety of crosslinkers for conjugating RNA molecules, as well as teaching negatively charged and hydrophobic amino acid peptides, cell penetrating peptides that promote cellular uptake of cargo molecules, including CPP “Tat” and poly(Arginine). Duvall teaches siRNA conjugates for facilitating cell type targeting and mediation of endosomal escape. Duvall teaches amine-modified single stranded DNA modified at the 5’ end and RNA modified at the 3’ end for producing nucleic acid conjugates (see esp. the abstract, Figure 1, text on pages 1, 2, 4-6, 8 and 9).
Ahn et al (US 2016/0208245) teach compositions comprising siRNA, DNA-cholesterol conjugates, folate-DNA conjugates, and self-assembling amphiphilic nanoparticles, additionally comprising ligand specific targeting agents, including but not limited to RGD peptides, cancer targeting aptamers ( see esp. the abstract, Figure 1, pages 1-2, 6-7, claims 1-13, 24).
Lee et al (WO 2012/125987) teach three dimensional, self-assembling higher ordered structures for nanoscale delivery and adapted for delivery of nucleic acids. Lee teaches covalent attachment of targeting ligand moieties, payload moieties attached to ligand moieties, siRNA, and targeted constructs for treating cancer. Lee teaches hydrophilic moieties comprising ethylene imines (see e.g., pages 1-8, Figures 1-21, pages 38, 39, 48-51).
Duvall is concerned with products and methods of RNA treatment and administration and specifically teaches the use of an RNA molecule directly conjugated to an albumin-binding group which acts to extend the circulation persistence of the RNA (see paragraphs [0010] and [0077] and claim 1).
Lee teaches that the oligonucleotides forming the 3D nanoparticles disclosed therein can comprise a “second portion” on the exterior surface of the nanoparticle which can be a ligand hybridization element (see paragraph [0007]). The purpose of this ligand hybridization element is to allow for a ligand oligonucleotide to hybridize to a complementary sequence within the ligand hybridization element (see paragraph [0011]). Lee teaches that a payload moiety may be attached to the ligand oligonucleotide (see paragraph [0012]).
Coletti teaches compositions comprising an oligonucleotide (including RNA) linked to a targeting ligand wherein the oligonucleotide is the payload (see paragraph [0005]) for use in conjunction with peptide conjugates.
Contrary to Applicant’s assertions, the instant invention would have been obvious in light of the combined teachings of Stephanopoulos, Lee, Duvall, Ahn, Lee and Colletti for the aforementioned reasons.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
For these reasons, the instant invention would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Certain papers related to this application may be submitted to Art Unit 1637 by facsimile transmission. The faxing of such papers must conform with the notices published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 C.F.R. ' 1.6(d)). The official fax telephone number for the Group is 571-273-8300. NOTE: If Applicant does submit a paper by fax, the original signed copy should be retained by applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jane Zara whose telephone number is (571) 272-0765. The examiner’s office hours are generally Monday-Friday, 10:30am - 7pm. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jennifer Dunston, can be reached on (571)-272-2916. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (703) 308-0196.
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Jane Zara
12-2-25
/JANE J ZARA/Primary Examiner, Art Unit 1637