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 .
Claim Status
Claims 6-14, 18-21, 23-26, 33-36, 40, 43, 45-51, 58-61, 65-68, 71-74 are cancelled. Claim 22, 44 are amended.
Claims 1-5, 15-17, 22, 27-32, 37-39, 41-42, 44, 52-57, 62-64, 69-70 are pending examination on the merits.
Priority
This application is a national stage application, of International Patent Application No. PCT/US21/33760, filed 05/21/2021, which claims priority from U.S. Provisional Application 63/029225, filed 05/22/2020 is acknowledged.
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.
Claims 15-17, 37-39, 62-64 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 phrase “forms part of a cell” is unclear and renders the meets and bounds of the claim indefinite. It is ambiguous whether the claim requires (i) that the complex be internalized within a cell, (ii) the complex is stably incorporated into a cellular structure, (iii) the cell endogenously contains or expresses such a complex.
The specification provides no definition, structural criteria, or experimental description to clarify what it means for gene editing agent bound to a phosphorothioate complex to “form part of a cell”. As a result, one of ordinary skill in the art would be not reasonably appraised of the scope of the claim, and different interpretations could lead to substantially different claim boundaries.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 15-17, 37-39, 62-64 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The phrase “form part of a cell” could encompass multiple interpretations, such as incorporation into the cell membrane, integration into cell organelles, stable association with intracellular components, or endogenous production within the cell.
The specification does not reasonably indicate to one of ordinary skill in the art that the inventors had possession of a complex that “form part of a cell” under any of these interpretations.
Claim Rejections - 35 USC § 102
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 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.
Claims 1-2, 15-17, 69-70 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Donohoue et al. (“Donohoue”, US 2016/0362667 A1, cited as reference 2 on IDS filed 07/10/2024).
Regarding claim 1, Donohoue teaches compositions and methods relating to Class 2 CRISPR-Cas (it reads on first gene editing agent) associated polynucleotides lacking a spacer element (casPNs) and distinct spacer element sequence polynucleotides (sesPN s) comprising a target nucleic acid binding sequence (it reads on second gene editing agent) (e.g., paragraph 0011). Donohoue teaches nucleic acids comprising modified backbone residues or linkages, that (i) are synthetic, naturally occurring, and non-naturally occurring, and (ii) have similar binding properties as a reference polynucleotide (e.g., DNA or RNA). Examples of such analogs include, but are not limited to, phosphorothioates (e.g., paragraph 0064). Donohoue teaches Peptide-nucleic acids (PNAs) are synthetic homologs of nucleic acids wherein the polynucleotide phosphate- sugar backbone is replaced by a flexible pseudopeptide polymer. Nucleobases are linked to the polymer. PNAs have the capacity to hybridize with high affinity and specificity to complementary sequences of RNA and DNA (e.g., paragraph 0065). Donohoue teaches that phosphorothioate nucleic acids, the phosphorothioate (PS) bond substitutes a sulfur atom for a nonbridging oxygen in the polynucleotide phosphate backbone. This modification makes the internucleotide linkage resistant to nuclease degradation (it reads on chemical linker) (e.g., paragraph 0066; Fig. 10). Donohoue teaches that a casPN is capable of associating with a Class 2 CRISPRCas protein to form a Cas protein/casPN nucleoprotein complex, wherein the associating forms a nucleic acid sequence binding channel in the Cas protein/casPN complex capable of binding a nucleic acid sequence. However, a Cas protein/casPN nucleoprotein complex alone does not provide site-specific binding to a target nucleic acid sequence. [it reads on first editing agent] (e.g., paragraph 0129). (e.g., paragraph 0128). Donohoue teaches casPN refers to a single-strand polynucleotide comprising a tracr element and/or specific secondary structures [it reads on gRNA]. In one embodiment, a casPN comprises a tracr element [it reads on a second editing agent]. When the casPN comprising the tracr element complexes with a Cas protein, the Cas protein more preferentially binds DNA sequences containing PAM sequences associated with the Cas protein than DNA sequences without PAM sequences (e.g., paragraph 0130). Donohoue spacer element of the sgRNA hybridized to the complementary target DNA sequence in the 3' to 5' DNA strand (e.g., paragraph 0033; Fig. 4B).
Regarding claim 2, Donohoue teaches Class 2 CRISPR-Cas nucleoprotein complex wherein (i) the Cas protein comprises an engineered Cas protein comprising a Cys substitution of a non-Cys amino acid residue or an inserted Cys amino acid, (ii) the sesPN comprises a thiol cross-linking moiety, and (iii) the engineered Cas protein substituted Cys amino acid residue or inserted Cys amino acid is covalently bound to the sesPN thiol crosslinking moiety (e.g., paragraph 0018).
Regarding claim 15-17, for purpose of prosecution the broadest reasonable interpretation (BRI) of the phrase “forms part of a cell” will be understood as meaning “introduced into a cell”. Donohoue teaches methods of introducing polynucleotides into host cells, viral or bacteriophage infection, transfection, conjugation, electroporation, calcium phosphate precipitation, polyethyleneimine-mediated transfection, DEAE-dextran mediated transfection, protoplast fusion, lipofection, liposome-mediated transfection, particle gun technology, direct microinjection, and nanoparticle mediated
delivery (e.g., paragraph 0194). Donohoue teaches that the "host cell" generally refers to a biological cell. A cell can be the basic structural, functional and/or biological unit of a living organism. A cell can originate from any organism having one or more cells. Examples of host cells, a cell from a mammal (e.g., a pig, a cow, a goat, a sheep, a rodent, a rat, a mouse, a non-human primate, a human, etc.). Furthermore, a cell can be a stem cell or progenitor cell (e.g., paragraph 0091).
Regarding claim 69, Donohoue teaches pharmaceutical compositions comprising a sesPN, a casPN, and a Cas protein, or one or more polynucleotides encoding a sesPN, a casPN, and a Cas protein. Pharmaceutical compositions may further comprise pharmaceutically acceptable vehicles (e.g., paragraph 0228).
Regarding claim 70, Donohoue teaches compositions and methods relating to Class 2 CRISPR-Cas associated polynucleotides lacking a spacer element (casPNs) and distinct spacer element sequence polynucleotides ( sesPN s) comprising a target nucleic acid binding sequence (it reads on second gene editing agent) (e.g., paragraph 0011). Donohoue teaches improved cell delivery of sesPN into cells expressing casPN and Cas protein (versus delivery of crRNA into cells expressing tracrRNA and Cas protein) due to the smaller size of the sesPN (e.g., paragraph 0234).
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.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Donohoue et al. (“Donohoue”, US 2016/0362667 A1, cited as reference 2 on IDS filed 07/10/2024) as applied to claims 1-2, 15-17, 69-70 above, and further in view of Kuhn et al. (“Kuhn”, Bioconjugate Chem. 2020, cited as reference 12 on IDS filed 07/10/2024).
Donohoue does not teach the phosphorothioate nucleic acid bound to the C-terminus of the gene editing agent as required by claim 3. However, this is cured by Kuhn.
Kuhn teaches Lipid-containing oligoaminoamides (lipo-OAAs) were identified as the most efficient carriers for intracellular Cas9/sgRNA delivery and gene disruption. The lipo-OAA-containing hydroxy-stearic acid (OHSteA) was superior to the analogues with saturated or unsaturated fatty acids without hydroxylation; it formed smaller and more defined nanoparticles with Cas9/sgRNA and improved the cellular uptake and endosomal release, which altogether resulted in an increased nuclear association and the highest gene knock out levels (e.g., abstract). Kuhn teaches that cysteines (C) and hydrophobic motifs, like the tyrosine (Y) tripeptide, have been shown to improve nanoparticle stability (e.g., paragraph 2nd, column left, page 730). Kuhn teaches recombinant Cas9 was produced by bacterial expression of a plasmid pET28a/Cas9-Cys containing the human codon-optimized Cas9 nuclease gene with a N-terminal His-tag and a C-terminal cysteine (e.g., paragraph 2nd, column right, page 736). Kuhn teaches ATTO647N-Labeling of Cas9 Protein (at C-terminal Cysteine) (e.g., paragraph 1st, column left, page 737).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to modify the complex comprising the complex Class 2 CRISPR-Cas covalently bound to phosphorothioate taught by Donohoue with a cysteine residue at the C-terminal of Cas9 taught by Kuhn, for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of obtaining a C-terminal cysteine modified CRISPR Cas to form a covalent bounding with the phosphorothioate oligonucleotide.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to do so in order to develop a C-terminal cysteine modified CRISPR Cas to form a covalent bounding with the phosphorothioate oligonucleotide resistant to nuclease degradation.
Claims 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over Donohoue et al. (“Donohoue”, US 2016/0362667 A1, cited as reference 2 on IDS filed 07/10/2024) as applied to claims 1-2, 15-17, 69-70 above, and further in view of Babcock et al. (“Babcock”, WO 2009/143345 A2, cited as reference 4 on IDS filed 07/10/2024 ).
Donohoue does not teach the chemical linker is a pH sensitive as
required by instant claim 4. Donohoue does not teach wherein the
chemical linker is a thioester linker as required by instant claim 5.
However, this is cured by Babcock.
Babcock teaches a method of using a complex or a molecule comprising a targeting moiety to deliver a second molecule effectively
to HCV or to a cell being infected or having the potential to be infected by HCV, resulting in the prevention, immunization, inhibition or cure of HCV infection, or other beneficial effects related to HCV infection (e.g., abstract). Babcock teaches any agent (e.g., a complex or conjugate) comprising a targeting moiety (e.g., a therapeutic targeting moiety) and a nucleic acid molecule, wherein the agent delivers the nucleic acid molecule to a target cell of interest (e.g., a tumor cell, immune cell, or a cell infected
with a virus other than HCV) (e.g., paragraph 3rd, page 2). Babcock teaches one or more nucleic acid molecules (e.g., about 2, about 5, about 10, about 15, about 20, about 25, or about 30 nucleic acid molecules) may be conjugated to the protein. The nucleic acid and protein may be covalently linked, e.g., via an intervening linker. In one preferred embodiment, the protein of the conjugate comprises a sulfhydryl moiety. The nucleic acid of the conjugate comprises a carbonyl moiety at the 3' or 5' terminus. In preferred embodiments, the carbonyl moiety is present in a modified terminal ribonucleotide. In other preferred embodiments, the nucleic acid molecules are linked to modified lysine residues within the protein (e.g., paragraph 4th, page 2). Babcock teaches the protein and the nucleic acid are linked by a heterobifunctional crosslinker to form the conjugate. In certain embodiments, the heterobifunctional crosslinker links the sulfhydryl and carbonyl moieties to form the conjugate. In one embodiment, the crosslinker is bonded (e.g., via a hydrazide moiety) to the carbonyl moiety of the nucleic acid (e.g., a terminal ribonucleotide comprising a carbonyl group, e.g., an aldehyde-modified ribonucleotide) via a hydrazone bond. In
another embodiment, the crosslinker is bonded to an amino moiety of the nucleic acid (e.g., a terminal nucleotide comprising an amino group, e.g., a terminal nucleotide comprising a primary amine (e.g., an amino alkyl phosphoester) at the 2' or 3' position). In another embodiment, the crosslinker (e.g., the maleimide moiety of a crosslinker) is covalently bonded to the sulfhydryl moiety of the protein (e.g., a modified lysine residue comprising a sulfhydryl moiety) via a thioester bond (e.g., paragraph 2nd, page 3). Babcock teaches cleavable reagents are typically built into the cross-bridge or reactive ends of a reagent using disulfides, glycol groups, diazo bonds, esters, sulfone groups, or acetal linkages. In one preferred embodiment, the cleavage element is built in as a pH-liable
hydrazone bond between the hydrazide end of the heterobifunctional linker and the aldehyde group on an alkylated RNA interference agent of this invention. In another preferred embodiment, the said hydrazone bond in the linker is stable in serum at pH 7.4 but hydrolyzes at pH 5.0 in the endosomes, leading to the release of the siRNA conjugated to the antibody (e.g., paragraph 1st, page 37).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to modify the complex comprising the Class 2 CRISPR-Cas covalently bound to phosphorothioate through a chemical linker taught by Donohoue with a pH-sensitive chemical linker taught by Babcock, for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of obtaining a C-terminal cysteine modified CRISPR Cas to form a covalent bounding with the phosphorothioate oligonucleotide through a chemical linker that is stable at physiological pH.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to do so in order to develop a C-terminal cysteine modified CRISPR Cas to form a covalent bounding with the phosphorothioate oligonucleotide through a chemical linker sensitive at variations of pH, and hydrolyzes at pH 5.0 in the endosomes, leading to the release of the CRISPR Cas for gene editing in a cell.
Claim 22, 27-28, 37-39, 41, 44, 52-53, 55, 62-64 are rejected under 35 U.S.C. 103 as being unpatentable over Donohoue et al. (“Donohoue”, US 2016/0362667 A1, cited as reference 2 on IDS filed 07/10/2024) as applied to claims 1-2, 15-17, 69-70 above, and further in view of Herrmann et al. (“Herrmann”, WO 2017/024238 A1, cited as reference 3 on IDS filed 04/28/2025).
Donohoue does not teach the a double-stranded phosphorothioate oligonucleotide as required by instant claims 22, 27-28, 41, 44, 52-53, 55. However, this is cured by Herrmann.
Herrmann teaches cell penetrating conjugates. In one aspect, the cell
penetrating conjugate includes a phosphorothioate nucleic acid connecting a first non-cell penetrating protein to a second protein. The phosphorothioate nucleic acid enhances the intracellular delivery of the both proteins (e.g. paragraph 0005). Herrmann teaches a method of forming a cell penetrating conjugate is provided. The method includes hybridizing a first phosphorothioate nucleic acid attached to a first noncell penetrating protein to a second phosphorothioate nucleic acid attached to a second protein, thereby forming a cell penetrating conjugate (e.g., paragraph 0006). Herrmann teaches the phosphorothioate nucleic acid is a single-stranded nucleic acid. In embodiments, the phosphorothioate nucleic acid is a double-stranded nucleic acid. Where the phosphorothioate nucleic acid is a double-stranded nucleic acid, the phosphorothioate nucleic acid includes a first phosphorothioate nucleic acid hybridized to a second phosphorothioate nucleic acid, the first phosphorothioate nucleic acid attached to the first non-cell penetrating protein and the second phosphorothioate nucleic acid attached to the second non-cell penetrating protein (e.g., paragraph 0129). Herrmann teaches the phosphorothioate nucleic acid is independently attached to a lysine, arginine, cysteine, or histidine of the first non-cell penetrating protein. In embodiments, the phosphorothioate nucleic acid is independently attached to a lysine, arginine, cysteine, or histidine of the second non-cell penetrating protein. In embodiments, the phosphorothioate nucleic acid is attached to a cysteine of the first non-cell penetrating protein. In embodiments, the phosphorothioate nucleic acid is attached to a cysteine of the second non-cell penetrating protein. (e.g., paragraph 0101).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to modify the teachings of Herrmann -a first phosphorothioate nucleic acid attached to a first noncell penetrating protein to a second phosphorothioate nucleic acid attached to a second protein covalently bound through cysteine residues- and replace the proteins with CRISPR Cas9 and gRNA taught by Donohoue, for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of obtaining a first phosphorothioate nucleic acid attached to a CRISPR Cas9 (or a first gene editing agent) and a second phosphorothioate nucleic acid attached to a gRNA (or other gene editing agent) where the phosphorothioate nucleic acid is a double-stranded nucleic acid.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to do so in order to develop a phosphorothioate nucleic acid complex for intracellular delivery of gene editing agents.
Claims 29-30, 54 are rejected under 35 U.S.C. 103 as being unpatentable over Donohoue et al. (“Donohoue”, US 2016/0362667 A1, cited as reference 2 on IDS filed 07/10/2024) and Herrmann et al. (“Herrmann”, WO 2017 /024238 A1, cited as reference 3 on IDS filed 04/28/2025) as applied to claims 1-2, 15-17, 22, 27-28, 37-39, 41, 44, 52-53, 55, 62-64, 69-70 above, and further in view of Kuhn et al. (“Kuhn”, Bioconjugate Chem. 2020, cited as reference 12 on IDS filed 07/10/2024).
Donohoue and Herrmann do not teach the phosphorothioate nucleic acid bound to the C-terminus of the gene editing agent as required by claims 29-30, 54. However, this is cured by Kuhn.
The teaching of Kuhn are discussed above.
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to modify the first phosphorothioate nucleic acid attached to a CRISPR Cas9 (or a first gene editing agent) and a second phosphorothioate nucleic acid attached to a gRNA (or second gene editing agent) where the phosphorothioate nucleic acid is a double-stranded nucleic acid taught by Donohoue and Herrmann with a cysteine residue at the C-terminal of gene editing agent taught by Kuhn, for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of obtaining a C-terminal cysteine modified CRISPR Cas (gene editing agent) to form a covalent bounding with the phosphorothioate oligonucleotide.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to do so in order to develop a C-terminal cysteine modified CRISPR Cas (or a gene editing agent) to form a covalent bounding with the phosphorothioate oligonucleotide resistant to nuclease degradation.
Claims 31-32, 56-57 are rejected under 35 U.S.C. 103 as being unpatentable over Donohoue et al. (“Donohoue”, US 2016/0362667 A1, cited as reference 2 on IDS filed 07/10/2024) and Herrmann et al. (“Herrmann”, WO 2017 /024238 A1, cited as reference 3 on IDS filed 04/28/2025) as applied to claims 1-2, 15-17, 22, 27-28, 37-39, 41, 44, 52-53, 55, 62-64, 69-70 above, and further in view of Babcock et al. (“Babcock”, WO 2009/143345 A2, cited as reference 4 on IDS filed 07/10/2024 ).
Donohoue and Herrmann do not teach the chemical linker is a pH sensitive as required by instant claims 31, 56. Donohoue does not teach wherein the chemical linker is a thioester linker as required by instant claims 32, 57.
However, this is cured by Babcock.
The teaching of Babcock are discussed above.
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to modify the first phosphorothioate nucleic acid attached to a CRISPR Cas9 (or a first gene editing agent) and a second phosphorothioate nucleic acid attached to a gRNA (or second gene editing agent) where the phosphorothioate nucleic acid is a double-stranded nucleic acid taught by Donohoue and Herrmann with a pH-sensitive chemical linker taught by Babcock, for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of obtaining a C-terminal cysteine modified CRISPR Cas (gene editing agent) to form a covalent bounding with the phosphorothioate oligonucleotide through a chemical linker that is stable at physiological pH.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to do so in order to develop a C-terminal cysteine modified CRISPR Cas (or a gene editing agent) to form a covalent bounding with the phosphorothioate oligonucleotide through a chemical linker sensitive at variations of pH, and hydrolyzes at pH 5.0 in the endosomes, leading to the release of the CRISPR Cas (or a gene editing agent) for gene editing in a cell.
Claims 42 are rejected under 35 U.S.C. 103 as being unpatentable over Donohoue et al. (“Donohoue”, US 2016/0362667 A1, cited as reference 2 on IDS filed 07/10/2024) and Herrmann et al. (“Herrmann”, WO 2017 /024238 A1, cited as reference 3 on IDS filed 04/28/2025) as applied to claims 1-2, 15-17, 22, 27-28, 37-39, 41, 44, 52-53, 55, 62-64, 69-70 above, and further in view of D’Amico et al. (“D’Amico”, Genes & Development, 2020, cited as reference 10 on IDS filed 07/10/2024).
Donohoue and Herrmann do not teach targeting STAT3 as required by instant claim 42. However, this is cured by D’Amico.
D’Amico teaches impact of STAT3 activity in KRAS-driven lung and
pancreatic cancer. Loss of STAT3 preferentially associates with the acquisition of mesenchymal-like phenotypes and more aggressive tumor behavior (e.g., abstract). D’Amico teaches STAT3 loss of function, by using the CRISPR/Cas9 system to generate stable knockouts for STAT3 (e.g., paragraph 1st, column right, page 1177; Fig. 2). D’Amico teaches that loss of STAT3 accelerates KRAS-induced lung cell tumorigenesis (e.g., paragraph 1st, right column, page 1179; Fig. 4).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to target STAT3 taught by D’Amico with complex -first phosphorothioate nucleic acid attached to a CRISPR Cas9 and a second phosphorothioate nucleic acid attached to a gRNA where the phosphorothioate nucleic acid is a double-stranded nucleic acid taught by Donohoue and Herrmann, for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of obtaining a method comprising CRISPR Cas system (CRISPR Cas and sgRNA bound independently to phosphorothioate) complexes that are capable of site-directed STAT3.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to do so in order to develop a method comprising CRISPR Cas complexes that are capable of site-directed binding to target nucleic complementary to the target nucleic acid binding sequence of the sgRNA.
Conclusion
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/JULIO WASHINGTON GOMEZ RODRIGUEZ/Examiner, Art Unit 1637
/J. E. ANGELL, Ph.D./Primary Examiner, Art Unit 1637