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 .
Detailed Action
This action is in response to the papers filed October 8, 2025.
Election/Restrictions
Applicant’s reply filed 10/08/2025 to the Requirement for Restriction/Election mailed 08/28/2025 is acknowledged.
Applicant elected without traverse:
Group 1, drawn to a composition comprising a nanoparticle;
survival motor neuron 2 (SMN2), as the gene targeted by the antisense oligonucleotide;
Cas endonuclease targeted to the SMN-2 gene, as the gene editing reagent and target gene thereof.
The nonelected antisense oligonucleotides targeting the survival motor neuron 1 (SMN1) gene and the DMD gene are hereby rejoined.
In view of the above rejoinders, applicant is advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claims 26, 71, 97-101 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/28/2025.
Claim Amendments
Applicant’s amendment to the claims filed 10/08/2025 is acknowledged.
Claims 31-70, 72-83, 85-96 have been cancelled.
Claims 1-30, 71, 84, 97-101 are pending.
Claims 26, 71, 97-101 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claims 1-25, 27-30, and 84 are under examination.
Priority
The instant application 17/913,540 was filed on 09/22/2022. This application is a national stage of international application PCT/US2021/027319 filed 04/14/2021, claiming priority based on U.S. Provisional Application No. 63/010,250 filed 04/15/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/28/2023 has been considered.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, or by applicant in an information disclosure statement (IDS), they have not been considered.
Claim Objections
Claim 20 is objected to because of the following informalities:
Claim 20 contains a misspelling “phosphorothioate.” The correct spelling is “phosphorothioate.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 6 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 6 recites that the antisense oligonucleotide is complementary to an mRNA from “genes for other developmental disorders.” The recitation is found to be indefinite. In particular, it is unclear what “other” developmental disorders means because the claims do not previously recite any developmental disorder. Accordingly, it is unclear which developmental disorders are excluded by the limitation “other developmental disorders.” For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 18 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.
The limitations “the targeting complexes” and “the endosomal escape peptides” lack antecedent basis in claim 18. For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 20 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 20, line 6, contains the trademark/trade name Locked Nucleic Acid® (U.S. Serial No. 76,298,895). Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a class of modified RNA nucleotides called "bridged nucleic acids" (or also referred to as "inaccessible RNA") and, accordingly, the identification/description is indefinite. See, e.g., Fatima et al. (2025) “Synthetic Oligodeoxyribonucleotides and Human Health” Journal of Scientific and Technical Research, 15(1):09-26, on page 17, last paragraph: “A locked nucleic acid (LNA) also known as bridged nucleic acid (BNA) is often referred to as inaccessible RNA. This is a modified RNA nucleotide in which the ribose moiety is modified with an extra bridge connecting the 2’ oxygen and 4’ carbon.”
Claims 21-25, 27-30 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.
The limitation “the gene-editing reagent” in claim 21 lacks antecedent basis. Likewise, the limitation “the nucleic acid encoding the gene-editing reagents” in claim 22 lacks antecedent basis.
For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Dependent claims 22-25, 27-30 are included in the basis of the rejection because they do not correct the deficiencies of the claim upon which they depend.
Claims 22-25, 27-30 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.
Claim 22 recites that “the gene-editing reagents, or the nucleic acid encoding the gene-editing reagents, are packaged in a nanoparticle for delivery” and “wherein an inner region of the nanoparticle comprises a polymer, metal, or liposome, and an outer region of the nanoparticle comprises a scaffold of scaffold nucleic acid.” However, claim 1, upon which claim 22 depends, already recites a composition comprising “a nanoparticle; and an antisense oligonucleotide carried by the nanoparticle.” Accordingly, claim 22 is indefinite because it is unclear if the limitation “the nanoparticle” refers to (1) the nanoparticle comprising the antisense oligonucleotide, as claimed in claim 1, or (2) the nanoparticle comprising the gene-editing reagents, as claimed in claim 22. For the same reasons, the limitations referring to “the nanoparticle” in claims 23-24, 27-28 are indefinite.
Therefore, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Dependent claims 23-25, 27-30 are included in the basis of the rejection because they do not correct the deficiencies of the claim upon which they depend.
Claims 22-25, 27-30 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.
Claim 22 recites the limitation “a scaffold of scaffold nucleic acid.” The limitation is indefinite because one of ordinary skill in the art would not have been reasonably appraised of the scope and meaning of “a scaffold of scaffold nucleic acid,” and neither the claims nor specification of the present application provide a definition. In particular, while it may have been clear to one of ordinary skill in the art the scope and meaning of “a scaffold of nucleic acid” or “a scaffold nucleic acid,” it would have been unclear what a “a scaffold of scaffold nucleic acid” refers to.
For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Dependent claims 23-25, 27-30 are included in the basis of the rejection because they do not correct the deficiencies of the claim upon which they depend.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-4, and 6 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Falzarano et al. (2014) "Nanoparticle delivery of antisense oligonucleotides and their application in the exon skipping strategy for Duchenne muscular dystrophy" Nucleic acid therapeutics, 24(1), 87-100, of record.
Falzarano discloses antisense oligonucleotides (AONs) for exon skipping, by targeting pre-mRNA, in treating genetic disorders, such as Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). Abstract.
The AON is a splice-switching oligonucleotide (SSO) which, for example, induces exon inclusion in SMA or corrects the reading frame to allow production of functional proteins in DMD. Pg. 87-88; fig. 1.
To improve the bioavailability of these therapeutic AONs, nanoparticles (NPs) are used as delivery vehicles. Abstract; pg. 89-90; fig. 3.
Therefore, Falzarano is found to teach or fairly suggest a composition for treating a genetic condition comprising a nanoparticle and an AON carried by the nanoparticle (claim 1); wherein the AON is complementary to and hybridizes to mRNA (claim 2); wherein the mRNA is transcribed from a SMA gene, i.e., a survival motor neuron (SMN) gene (claim 3); wherein the AON is a SSO (claim 4); wherein the SSO is complementary to and hybridizes to an mRNA of the DMD gene (claim 6).
Dependent claim 2 further recites the AON is complementary to and hybridizes to an mRNA “when delivered to a fetal cell.” Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. The broadest reasonable interpretation of a product claim having structure that performs a function, which only needs to occur if a condition precedent is met, requires structure for performing the function should the condition occur. MPEP 2111.04. In this case, the limitation “when delivered to a fetal cell” describes an intended use or functional property of the claimed composition. As set forth above, Falzarano teaches an AON carried by a nanoparticle that is complementary to and hybridizes to an mRNA, and, therefore, said AON would function in the same way when delivered to a fetal cell, as claimed. Accordingly, the intended use or functional limitation is not found to necessarily imply a structural difference which patentably distinguishes the claimed composition from that of the prior art.
For these reasons, Falzarano anticipates the composition of claims 1-4, and 6.
Claims 1-8, 10, 15, 20, and 84 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2019/169203 A9 to Kang et al.
Kang discloses a composition comprising a spherical nucleic acid (SNA) comprising a core and an antisense oligonucleotide (AON) of 8-50 nucleotides targeted to the SMN2 pre-mRNA, wherein the AON is attached to the core and forms an oligonucleotide shell. Pg. 1, ll. 34-39. The SNA is a nanoparticle. Pg. 2, ll. 1-14; pg. 7, ll. 13-21. The AON is a splice-switching oligonucleotide (SSO). Pg. 6, ll. 30-38; pg. 17-18.
Therefore, Kang is found to teach or fairly suggest a composition for treating a genetic condition comprising a nanoparticle and an AON carried by the nanoparticle (claim 1); wherein the AON is complementary to and hybridizes to mRNA (claim 2); wherein the mRNA is transcribed from a survival motor neuron (SMN) gene (claim 3); wherein the AON is a SSO (claim 4); wherein the SSO is complementary to and hybridizes to an mRNA of the SMN2 gene (claim 6).
For these reasons, Kang anticipates the composition of claims 1-4, and 6.
Regarding claim 5, Kang teaches a “cell-targeting moiety” comprising a conjugate group or portion of a conjugate group that results in improved uptake to a particular cell type and/or distribution to a particular tissue relative to an oligomeric compound lacking the cell-targeting moiety. Pg. 30, ll. 29-31.
Regarding claim 7, Kang teaches the nanoparticle comprise a core, such as a metal core (pg. 6, ll. 19-27), liposomal core (pg. 19, ll. 11-20; pg. 47, ll. 19-39), and a polymer core (pg. 47, ll. 34-36). The “core” is found to read on the recited “inner region.” Kang further teaches that oligonucleotides are attached to the core and form an oligonucleotide shell. Pg. 1, ll. 34-39; pg. 47, ll. 21-28. The “oligonucleotide shell” is found to read on the recited “outer region comprising a scaffold of nucleic acid.”
Regarding claim 8, the AON is linked to the nucleic acid of the scaffold. Pg. 1, ll. 34-39; pg. 19, ll. 21-28; pg. 47, ll. 21-28; pg. 49, ll. 15-29.
Regarding claim 10, Kang teaches a “cell-targeting moiety” comprising a conjugate group or portion of a conjugate group that results in improved uptake to a particular cell type and/or distribution to a particular tissue relative to an oligomeric compound lacking the cell-targeting moiety. Pg. 30, ll. 29-31.
Regarding claim 15, Kang discloses that the core is hollow, such as a liposomal core encapsulating an aqueous core. Pg. 19, ll. 11-20; pg. 47, ll. 29-39.
Regarding claim 20, Kang discloses the AON is 8-50 nucleosides in length (pg. 13, ll. 18-22), 10-40 nucleosides in length (pg. 11, ll. 24-33), or 10-35 nucleosides in length (pg. 27). Kang further discloses that the AON contains nucleotide modifications, such as a phosphorothioate (PS) backbone modification or 2'O methyl modification. Pg. 2, ll. 25-37.
Claim 84 recites a composition comprising a nanoparticle, a payload carried by the nanoparticle, and one or more targeting complexes linked to the nanoparticle. As outlined above, Kang anticipates such a nanoparticle.
Claim 84 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2020/014270 A1 to Desai et al.
Desai discloses polymeric particles that are functionalized by attaching biomolecules of interest for presentation on the surface of the particles. The polymeric particles may further encapsulate biomolecules for release in vivo. Biomolecules include therapeutic nucleic acids, peptides and proteins. See, e.g., par. 5, 48.
The particles are nanoparticles comprising an inner region comprising polymeric core, such as a PLGA core, and an outer region comprising a scaffold of DNA. See, e.g., par. 49-52, 189; fig. 1.
The particles further comprise a plurality of targeting complexes, such as an antibody, linked thereto. See, e.g., par. 61-73, 82-83, 189; fig. 1.
Accordingly, Desai anticipates claim 84.
Claims 1-2, 5, 7, 10, 14-16, and 84 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2008/0166414 A1 to Hanes et al.
Hanes discloses polymeric particles suitable for transporting bioactive agents across mucosal barriers. See, e.g., Abstract. The polymeric particle comprises a polymer core, a bioactive agent, and a surface-altering agent, such as a nucleic acid coating. See, e.g., par. 4-5. The polymeric particles are nanoparticles. See, e.g., par. 15. The bioactive agent may be an antisense oligonucleotide. See, e.g., par. 99-100.
Accordingly, Hanes anticipates the composition of claim 1.
Regarding dependent claim 2, Hanes teaches the antisense oligonucleotide is complementary to, and hybridizes to, a messenger RNA (mRNA). See, e.g., par. 99-100.
Regarding dependent claim 5, Hanes teaches the nanoparticle further comprises a plurality of targeting complexes. See, e.g., par. 3-4, 108.
Regarding depend claim 7, Hanes teaches the polymeric particle comprises a polymer core, a bioactive agent, and a surface-altering agent, such as a nucleic acid coating. See, e.g., par. 4-5.
Regarding dependent claim 10, Hanes teaches a plurality of targeting complexes linked to the nucleic acid of the scaffold. See, e.g., par. 3-4, 108.
Regarding dependent claim 14, Hanes teaches the polymer is PLGA. See, e.g., par. 75.
Regarding dependent claim 15, Hanes teaches the polymeric particles comprise a bioactive agent, which is a payload. See, e.g., par. 4-5.
Regarding dependent claim 16, Hanes teaches the bioactive agent or payload may be an antisense oligonucleotide. See, e.g., par. 99-100.
Claim 84 recites a composition comprising a nanoparticle, a payload carried by the nanoparticle, and one or more targeting complexes linked to the nanoparticle. As outlined above, Hanes anticipates such a nanoparticle.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-11, 14-16, 19-20, and 84 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/014270 A1 to Desai et al.; in view of Falzarano et al. (2014) "Nanoparticle delivery of antisense oligonucleotides and their application in the exon skipping strategy for Duchenne muscular dystrophy" Nucleic acid therapeutics, 24(1), 87-100; and WO 2019/169203 A9 to Kang et al.
Desai discloses polymeric particles that are functionalized by attaching biomolecules of interest for presentation on the surface of the particles. The polymeric particles may further encapsulate biomolecules for release in vivo. Biomolecules include therapeutic nucleic acids, peptides and proteins. See, e.g., par. 5, 48.
The particles are nanoparticles comprising an inner region comprising polymeric core, such as a PLGA core, and an outer region comprising a scaffold of DNA. See, e.g., par. 49-52, 189; fig. 1.
Desai does not teach that the nanoparticle carries an antisense oligonucleotide, as claimed in claim 1.
However, Falzarano is relevant prior art for disclosing antisense oligonucleotides (AONs) for exon skipping, by targeting pre-mRNA, in treating genetic disorders, such as Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). Abstract. The AON is a splice-switching oligonucleotide (SSO) which, for example, induces exon inclusion in SMA or corrects the reading frame to allow production of functional proteins in DMD. Pg. 87-88; fig. 1. To improve the bioavailability of these therapeutic AONs, nanoparticles (NPs) are used as delivery vehicles. Abstract; pg. 89-90; fig. 3.
In addition, Kang is relevant prior art for disclosing a composition comprising a spherical nucleic acid (SNA) comprising a core and an antisense oligonucleotide (AON) of 8-50 nucleotides targeted to the SMN2 pre-mRNA, wherein the AON is attached to the core and forms an oligonucleotide shell. Pg. 1, ll. 34-39. The SNA is a nanoparticle. Pg. 2, ll. 1-14; pg. 7, ll. 13-21. The AON is a splice-switching oligonucleotide (SSO). Pg. 6, ll. 30-38; pg. 17-18.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the composition of Desai to further comprise an antisense oligonucleotide (AON) carried by the nanoparticle, as found in Falzarano and Kang, with a reasonable expectation of success because nanoparticles are effective carriers of therapeutic AONs and improve the bioavailability thereof.
For these reasons, claim 1 would have been prima facie obvious over the prior art.
Regarding dependent claim 2, the limitation wherein the antisense oligonucleotide is complementary to, and hybridizes to, a messenger RNA (mRNA) is taught by Falzarano (Abstract; pg. 87-88; fig. 1) and Kang (pg. 1, ll. 34-39; pg. 6, ll. 30-38; pg. 17-18).
The claims further recite the functional properties and intended use of the claimed composition when delivered to a fetal cell. Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. The broadest reasonable interpretation of a product claim having structure that performs a function, which only needs to occur if a condition precedent is met, requires structure for performing the function should the condition occur. MPEP 2111.04. In this case, the limitations describe an intended use or functional property of the claimed composition. Since the composition of the cited references is capable of performing the functional/use limitations, said limitations are not found to necessarily imply a structural difference which patentably distinguishes the claimed composition from the prior art.
Regarding dependent claim 3, Kang teaches the mRNA is transcribed from a survival motor neuron gene. Pg. 1, ll. 34-39.
Regarding dependent claim 4, the limitation wherein the AON is a splice-switching oligonucleotide (SSO) is taught by Falzarano (Abstract; pg. 87-88; fig. 1) and Kang (pg. 1, ll. 34-39; pg. 6, ll. 30-38; pg. 17-18).
Regarding dependent claim 5, Desai teaches the nanoparticle further comprises a plurality of targeting complexes, such as an antibody. See, e.g., par. 61-73, 82-83, 189; fig. 1.
Regarding dependent claim 6, Falzarano teaches that the AON is a SSO that is complementary to and hybridizes to the mRNA from the DMD gene (pg. 87-88; fig. 1). Kang teaches that the AON is a SSO that is complementary to and hybridizes to the mRNA from the survival motor neuron 2 (SMN2) gene (Abstract).
Regarding dependent claim 7, Desai teaches the particles are nanoparticles comprising an inner region comprising polymeric core, such as a PLGA core, and an outer region comprising a scaffold of DNA. See, e.g., par. 49-52, 189; fig. 1.
Regarding dependent claim 8, Desai discloses polymeric particles that are functionalized by attaching biomolecules of interest for presentation on the surface of the particles. See, e.g., par. 5, 48. The biomolecules are linked to the DNA scaffold. See, e.g., par. 49-52, 189; fig. 1. As discussed above, Falzarano and Kang teach that therapeutic agent carried by nanoparticle, or “biomolecule,” is an AON.
Regarding dependent claim 9, Falzarano teaches polymeric nanoparticles may be functionalized with a cell-penetrating peptide (CPP) for their ability to transport access the plasma and endosomal membranes. Pg. 91.
Regarding dependent claim 10, Desai teaches the nanoparticle further comprises a plurality of targeting complexes, such as antibodies, linked to the nucleic acid of the scaffold. See, e.g., par. 61-73, 82-83 189; fig. 1.
Regarding dependent claim 11, the claim recites the targeting complexes comprise antibodies that bind to cell-surface markers on fetal cells or cells after birth. Desai teaches that the targeting complexes target surface markers of a particular tissue or cell type. See, e.g., par. 61-73, 82-83. Since the fetal cells or cells after birth would also express the surface markers of a particular tissue or cell type, Desai is found to meet the limitations of dependent claim 11.
Regarding dependent claim 14, Desai teaches that the polymer is PLGA. See, e.g., par. 52, 189; fig. 1.
Regarding dependent claim 15, Desai teaches the inner region of the nanoparticle surrounds a core that contains a payload. See, e.g., par. 5, 48.
Regarding dependent claim 16, Desai teaches the payload comprises therapeutic nucleic acids, peptides and proteins. See, e.g., par. 5, 48.
Regarding claim 19, as outlined above, the structural features of the claimed composition are taught or fairly suggested by the cited references. The functional property and/or intended use limitations of claim 19 are not found to necessarily imply a structural difference that patentably distinguishes the claimed invention from the prior art.
Regarding dependent claim 20, Kang discloses the AON is 8-50 nucleosides in length (pg. 13, ll. 18-22), 10-40 nucleosides in length (pg. 11, ll. 24-33), or 10-35 nucleosides in length (pg. 27). Kang further discloses that the AON contains nucleotide modifications, such as a phosphorothioate (PS) backbone modification or 2'O methyl modification. Pg. 2, ll. 25-37.
Claim 84 recites a composition comprising a nanoparticle, a payload carried by the nanoparticle, and one or more targeting complexes linked to the nanoparticle. As outlined above, the cited references teach or fairly suggest such a nanoparticle.
Claims 21-25, 27-30 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/014270 A1 to Desai et al.; Falzarano et al. (2014) "Nanoparticle delivery of antisense oligonucleotides and their application in the exon skipping strategy for Duchenne muscular dystrophy" Nucleic acid therapeutics, 24(1), 87-100; and WO 2019/169203 A9 to Kang et al., as applied to claims 1-11, 14-16, 19-20, and 84 above; in further view of WO 2020/069331 A1 to Cheng et al.
Claim 21 recites a gene-editing reagent is targeted to a gene for which a variant promotes an alternative splicing of mRNA that causes a disease, such that when the composition is delivered to a fetus in utero, the gene editing reagent corrects or ameliorates the effect of the variant to thereby inhibit the alternative splicing.
Prior to the effective filing date of the instantly claimed invention, Cheng is relevant prior art for teaching gene-editing reagents for modulating alternative splicing, e.g., by inducing exon inclusion and/or exon exclusion events. The gene-editing reagent is a catalytically inactive programmable nuclease, such as dCasRx, fused to an RNA-binding protein that, when guided to the target of interest by the gRNA, regulates alternative splicing in the cell. Abstract. In particular, the gRNA targets survival of motor neuron 2 (SMN2) gene. Pg. 17.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the composition of Desai to further provide a gene-editing reagent targeted to a gene for which a variant promotes an alternative splicing of mRNA that causes a disease, such that the gene editing reagent corrects or ameliorates the effect of the variant to thereby inhibit the alternative splicing when delivered to a cell, as found in Cheng, with a reasonable expectation of success in order to treat a subject in need thereof, e.g., subjects having spinal muscular atrophy (SMA) caused by alternative splicing of the SMN2 gene.
Regarding dependent claim 22, Desai teaches thee particles are nanoparticles comprising an inner region comprising polymeric core, such as a PLGA core, and an outer region comprising a scaffold of DNA. See, e.g., par. 49-52, 189; fig. 1. Biomolecules include therapeutic nucleic acids, peptides and proteins. See, e.g., par. 5, 48. As set forth above, the cited references teach or fairly suggest the “biomolecule” is the gene-editing reagent.
Regarding dependent claim 23, Desai teaches the nanoparticle further comprises a plurality of targeting complexes, such as antibodies, linked to the nucleic acid of the scaffold. See, e.g., par. 61-73, 82-83 189; fig. 1.
Regarding dependent claim 24, Falzarano teaches polymeric nanoparticles may be functionalized with a cell-penetrating peptide (CPP) for their ability to transport access the plasma and endosomal membranes. Pg. 91.
Regarding dependent claim 25, Desai teaches that the polymer is PLGA. See, e.g., par. 52, 189; fig. 1.
Regarding dependent claim 27, Cheng teaches the gene-editing reagents include nucleic acids encoding the gene-editing reagents and a Cas endonuclease. Abstract; pg. 2, 14-15, 21.
Regarding dependent claim 28, Cheng teaches the gene editing reagents include a Cas endonuclease complexed with a guide RNA as a ribonucleoprotein (RNP). Pg. 2, 4, 18.
Regarding dependent claim 29, Cheng teaches the guide RNA (gRNA) targets the Cas endonuclease to a gene to inhibit formation of a splicing isoform of a transcript of the gene. Abstract; pg. 17.
Regarding dependent claim 30, Cheng teaches the guide RNA targets the Cas endonuclease to a survival motor neuron gene to inhibit alternative splicing of the SMN gene to inhibit spinal muscle atrophy in a cell. Abstract; pg. 17; fig. 1.
Claims 12-13, 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/014270 A1 to Desai et al.; Falzarano et al. (2014) "Nanoparticle delivery of antisense oligonucleotides and their application in the exon skipping strategy for Duchenne muscular dystrophy" Nucleic acid therapeutics, 24(1), 87-100; and WO 2019/169203 A9 to Kang et al., as applied to claims 1-11, 14-16, 19-20, and 84 above; in further view of US 2008/0166414 A1 to Hanes et al.
Dependent claim 12 recites the antisense oligonucleotide is linked to the nucleic acid of the scaffold by disulfide bonds.
Hanes is relevant prior art for disclosing polymeric particles suitable for transporting bioactive agents across mucosal barriers. See, e.g., Abstract. The polymeric particle comprises a polymer core, a bioactive agent, and a surface-altering agent, such as a nucleic acid coating. See, e.g., par. 4-5. The polymeric particles are nanoparticles. See, e.g., par. 15. The bioactive agent may be an antisense oligonucleotide. See, e.g., par. 99-100.
Hanes further discloses means of conjugating moieties, such as therapeutic agents, to the polymeric particles, e.g., via disulfide bonds. The disulfide bond is cleavable under cellular conditions and may permit the therapeutic agent to separate from the particle after delivery to the target. See, e.g., par. 117-120.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to further modify the nanoparticle, as taught by Desai, Falzarano and Kang combined, such that the antisense oligonucleotide is linked to the nucleic acid of the scaffold by disulfide bonds, in view of Hanes, with a reasonable expectation of success because disulfide bonds are cleavable under cellular conditions and permit the therapeutic agent to separate from the particle after delivery to the target.
Regarding dependent claim 13, Desai teaches the nanoparticle further comprises a plurality of targeting complexes, such as an antibody. See, e.g., par. 61-73, 82-83, 189; fig. 1. Falzarano teaches polymeric nanoparticles may be functionalized with a cell-penetrating peptide (CPP) for their ability to transport access the plasma and endosomal membranes. Pg. 91.
Regarding dependent claim 17, Kang the AON targets to the SMN2 pre-mRNA. Pg. 1, ll. 34-39. The SNA is a nanoparticle. Pg. 2, ll. 1-14; pg. 7, ll. 13-21. The AON is a splice-switching oligonucleotide (SSO). Pg. 6, ll. 30-38; pg. 17-18.
Regarding dependent claim 18, as outlined above, the structural features of the claimed composition are taught or fairly suggested by the cited references. The functional property and/or intended use limitations of claim 18 are not found to necessarily imply a structural difference that patentably distinguishes the claimed invention from the prior art.
Conclusion
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/JAMES JOSEPH GRABER/Examiner, Art Unit 1631