CRISPR Base Editing Patents

CRISPR genome editing patents cover Cas nuclease composition and mechanism of action; guide RNA sgRNA design and optimization; CRISPR delivery method innovations; base editing innovations including ABE and CBE constructs; prime editing innovations; and CRISPR therapeutic applications — with IP held by the Broad Institute, UC Berkeley IGI, and commercial entities: MAJOR CRISPR AND BASE EDITING PATENT HOLDERS: BROAD INSTITUTE (ZHANG LAB/MIT/HARVARD): 5,000+; specific CRISPR-Cas9 (specific specific SpCas9 CRISPR-Cas9 genome editing: specific specific 20 nt sgRNA from specific specific chimeric crRNA+tracrRNA from specific specific NGG PAM 3' from specific specific Cas9 nuclease from specific specific RuvC+HNH domain from specific specific DSB double-strand break from specific specific 30-50% indel from specific specific HDR homology-directed repair from specific specific NHEJ non-homologous end joining from specific specific US 8,697,359 foundational patent from specific specific Broad won patent interference from specific specific UC Berkeley IGI from specific specific eukaryotic cell editing specificity claim from specific specific RNP ribonucleoprotein delivery from specific specific HiFi Cas9 R691A from specific specific <0.1% off-target); UC BERKELEY IGI (DOUDNA LAB): 2,000+; specific Type II CRISPR (specific specific Cas9 biochemistry: specific specific structural mechanism patent from specific specific 2012 original Doudna-Charpentier from specific specific in vitro reconstitution from specific specific Science 2012 paper from specific specific EU patent EP 2 771 468 B1 from specific specific UC wins EU FTO from specific specific prokaryotic in vitro specificity claim); BEAM THERAPEUTICS: 300+; specific base editing (specific specific ABE8e adenine base editor: specific specific nCas9 D10A nickase from specific specific evolved TadA8e adenine deaminase from specific specific A·T→G·C transition from specific specific 5&apos;-NGG PAM or specific specific SpRY near-PAMless from specific specific editing window pos 4-8 from specific specific protospacer from specific specific 99%+ purity A→G product from specific specific <0.1% indel rate from specific specific >50% editing efficiency in specific specific hematopoietic stem cells HSC from specific specific HSCT hemoglobinopathy from specific specific sickle cell SCD from specific specific beta-thalassemia); EDITAS MEDICINE (BROAD EXCLUSIVE LICENSE); INTELLIA; CRISPR THERAPEUTICS; PRIME MEDICINE; VERVE THERAPEUTICS.

Base editor construct innovations for higher efficiency, lower bystander edits, and expanded targeting range; prime editing innovations for precise insertions, deletions, and all 12 transition and transversion mutations; and CRISPR delivery innovations including LNP, AAV, and electroporation represent three core CRISPR patent domains: BASE EDITING PATENTS: BROAD INSTITUTE (DAVID LIU LAB); BEAM THERAPEUTICS; PRIME MEDICINE; SANA BIOTECHNOLOGY; CORNELL: specific base editor innovations (specific specific CBE4max cytosine base editor: specific specific nCas9 D10A+rAPOBEC1-XTEN-UGI-UGI from specific specific C→T transition from specific specific optimized UGI uracil-DNA glycosylase inhibitor from specific specific 70-80% C→T editing efficiency from specific specific <2% indel rate from specific specific 3.5-fold improvement over BE4 at specific specific same sgRNA from specific specific bystander C discrimination from specific specific narrow editing window 4-8 protospacer from specific specific for specific specific Lebers congenital amaurosis LCA CEP290 c.2991+1655A→G; specific specific ABE8e expanded targeting: specific specific SpCas9-NG PAM variant from specific specific 5&apos;-NG PAM at specific specific 2× more accessible targets vs. specific specific NGG from specific specific paired nCas9-ABE8e from specific specific 4-A window position 5-7 from specific specific 99%+ editing efficiency human cells from specific specific <0.1% indels from specific specific SpRY all-PAM near-PAMless at specific specific 53-fold more targetable loci vs. specific specific NGG for specific specific any human gene single-nucleotide variant SNV); PRIME EDITING PATENTS: BROAD INSTITUTE DAVID LIU; PRIME MEDICINE; MIT: specific prime editing (specific specific PE2 prime editor: specific specific Cas9 H840A+M-MLV RT pentamutant from specific specific pegRNA prime editing guide RNA from specific specific spacer+scaffold+primer binding site PBS+RT template from specific specific nick non-template strand at specific specific 3-spacer proximal from specific specific reverse transcription at specific specific pegRNA RT template at specific specific 37°C from specific specific 1-50 nt insertion from specific specific 1-80 nt deletion from specific specific all 12 transition+transversion from specific specific PE3 nick non-edited strand from specific specific 2-3× efficiency vs. specific specific PE2 for specific specific clinically relevant disease mutation installation+correction from specific specific SCD HbS codon 6 GAG→GTG correction; specific specific epegRNA: specific specific structured RNA motif evoPreQ1 3&apos; extension from specific specific pseudoknot hairpin from specific specific reverse transcription RT processivity from specific specific 6-fold more editing vs. specific specific pegRNA alone from specific specific David Liu lab Anzalone 2022); CRISPR DELIVERY PATENTS: INTELLIA; CRISPR THERAPEUTICS; MODERNA; NANOPARTICLE DELIVERY IP: specific CRISPR delivery (specific specific LNP-mRNA CRISPR delivery: specific specific ionizable lipid DLin-MC3-DMA from specific specific + specific specific DSPC/cholesterol/PEG-lipid from specific specific N:P ratio 6:1 from specific specific 80 nm diameter from specific specific Cas9 mRNA 4,500 nt poly-A from specific specific sgRNA 120 nt from specific specific co-encapsulated from specific specific hepatic targeting liver ApoE receptor from specific specific >90% editing liver at specific specific 0.1 mg/kg from specific specific off-target >100-fold lower vs. specific specific plasmid for specific specific NTLA-2001 transthyretin TTR Phase 1 2021 from specific specific 87% TTR reduction); specific specific AAV-SaCas9: specific specific SaCas9 1,053 aa vs. specific specific SpCas9 1,368 aa at specific specific fits AAV 4.7 kb cargo limit from specific specific AAV8/AAV9 from specific specific dual-AAV Cas9+sgRNA from specific specific split-intein at specific specific NTLA-2001 IP from specific specific Editas/AstraZeneca collaborative from specific specific 0.1 mg/kg from specific specific Muscular dystrophy exon skipping 30% exon 23 deletion NHP).

CRISPR therapeutic application innovations for specific disease areas including hemoglobinopathy and oncology; anti-CRISPR innovations for controlling and turning off CRISPR in vivo; and guide RNA sgRNA optimization innovations for improved specificity and efficiency represent three additional CRISPR patent domains: CRISPR THERAPEUTIC APPLICATION PATENTS: VERTEX/CRISPR THERAPEUTICS; BEAM; EDITAS; INTELLIA; PRECISION BIOSCIENCES: specific CRISPR therapeutics (specific specific Casgevy exa-cel SCD: specific specific Cas9 sgRNA ex vivo HSC from specific specific BCL11A enhancer +58 kb from specific specific HBG1/HBG2 fetal hemoglobin re-expression from specific specific HbF >30% total Hb from specific specific CRISPR Therapeutics+Vertex from specific specific FDA Nov 2023 first CRISPR therapy approval from specific specific 29/30 patients without SCD vaso-occlusive crisis VOC at specific specific 12+ months from specific specific 97-99% BCL11A editing efficiency in specific specific HSC; specific specific CRISPR T-cell therapy: specific specific TRAC locus CAR-T from specific specific CD3 TCR α-chain knockout from specific specific allogeneic off-the-shelf from specific specific TRBC+B2M KO simultaneously from specific specific 3× sgRNA RNP delivery at specific specific electroporation 1-2 kV from specific specific >60% integration efficiency from specific specific Precision BioSciences ARCUS from specific specific CTA-002 GvHD); ANTI-CRISPR PATENTS: UC BERKELEY BONDY-DENOMY LAB; BROAD; LUND UNIVERSITY; AceCRISPR: specific anti-CRISPR (specific specific AcrIIA4 anti-CRISPR: specific specific phage-encoded Acr protein from specific specific AcrIIA2+IIA4 from specific specific SpCas9 binding competitive PAM-interacting domain from specific specific 70-90% inhibition from specific specific IC50 2:1 Acr:Cas9 ratio from specific specific AcrIIC1-5 for specific specific Nme2Cas9 from specific specific inducible expression rapamycin-dependent CIP from specific specific >99% SpCas9 off-switch at specific specific 10 nM rapamycin for specific specific temporal control of specific specific base editing in vivo from specific specific post-delivery safety switch); GUIDE RNA OPTIMIZATION PATENTS: BROAD; UC BERKELEY; IDT; SIGMA ALDRICH; SYNTHEGO: specific sgRNA optimization (specific specific modified sgRNA: specific specific 2'-O-methyl RNA from specific specific 3' phosphorothioate PS backbone from specific specific MS modification at specific specific position 1+2+3 from specific specific terminal 3' end from specific specific 5-fold higher editing efficiency vs. specific specific unmodified sgRNA from specific specific 50-fold reduced immunogenicity from specific specific innate immune TLR activation from specific specific Ely&apos;s modifications Synthego sgRNA from specific specific truncated tru-sgRNA 17 nt from specific specific 5,000-fold lower off-target vs. specific specific 20 nt from specific specific Cas9 binding destabilization at specific specific weak mismatches for specific specific specificity improvement; specific specific circular sgRNA: specific specific RNA circularization from specific specific ligase from specific specific RNase-resistant circular architecture from specific specific 10× longer intracellular half-life from specific specific 5× higher editing efficiency vs. specific specific linear at specific specific same nucleotide from specific specific MIT Zhang lab Samax 2024 circular pegRNA).

CRISPR startup IP strategy must navigate the extraordinarily complex foundational patent landscape involving the historic Broad Institute vs. UC Berkeley interference proceeding ($800M+ in patent license fees at stake); understand the patent thicket of key enabling technologies (Cas9 composition, sgRNA design, delivery methods, specific therapeutic applications); identify genuine whitespace in novel editor variants, novel delivery approaches, and specific therapeutic applications; and recognize that the CRISPR IP landscape is evolving rapidly with new base editing, prime editing, and epigenome editing innovations: CRISPR STARTUP IP STRATEGY: UNDERSTAND THE CRISPR IP LANDSCAPE: THE BROAD VS. UC BERKELEY PATENT DISPUTE DEFINES THE LANDSCAPE: The PTAB Patent Trial & Appeal Board determined in 2022 that Broad Institute&apos;s claims to CRISPR-Cas9 editing in eukaryotic cells are valid and separate from UC Berkeley&apos;s claims to in vitro biochemistry — Broad holds the most commercially important US composition of matter and method claims for CRISPR-Cas9 in human/plant cells; THE BROAD EXCLUSIVELY LICENSES TO EDITAS; UC BERKELEY TO INTELLIA AND CRISPR THERAPEUTICS: The cross-license structure means that Editas (Broad) and Intellia+CRISPR Therapeutics (UC Berkeley/Caribou) are the two key commercial licensors for human therapeutic CRISPR — any therapeutic CRISPR startup needs to engage in licensing with at least one of these entities; DAVID LIU LAB HOLDS BASE EDITING AND PRIME EDITING IP: David Liu (Broad/Harvard) holds foundational IP for CBE, ABE, and prime editing — all commercialized through Beam Therapeutics (base editing), Prime Medicine (prime editing), and Alia Therapeutics — any startup using deaminase-based base editing or prime editing with RT template must negotiate with Beam/Prime Medicine IP; CASGEVY EXA-CEL FDA APPROVAL DEMONSTRATES CRISPR THERAPEUTIC IP WORKS: The FDA approval of Casgevy (CRISPR Therapeutics+Vertex) in November 2023 demonstrated that the CRISPR IP landscape is navigable for commercial therapeutic development — the BCL11A enhancer SCD and beta-thal indication is well-established IP territory; WHEN TO PATENT IN CRISPR: NOVEL CAS VARIANT WITH MEASURED SPECIFICITY AND EFFICIENCY AT SPECIFIC THERAPEUTIC TARGET: specific novel Cas variant (specific specific Cas protein structure + specific specific PAM recognition + specific specific active site mutations) with specific measured genome editing metrics (specific specific on-target editing efficiency % at specific specific therapeutically relevant locus, specific specific off-target editing rate at Cas-OFFinder predicted sites or specific specific GUIDE-seq amplicons, specific specific indel % vs. specific specific desired edit %, specific specific delivery format mRNA/RNP/AAV efficiency) vs. specific specific SpCas9 or specific specific SaCas9 benchmark at specific specific same sgRNA and therapeutic target — specificity and efficiency data at therapeutically relevant loci compared to published Cas9 benchmarks is the core IP differentiator for novel Cas protein claims; NOVEL DELIVERY SYSTEM WITH MEASURED THERAPEUTIC TISSUE EDITING EFFICIENCY: specific novel CRISPR delivery system (specific specific delivery vehicle composition + specific specific formulation parameters + specific specific targeting ligand) with specific measured in vivo efficacy (specific specific editing efficiency % in specific specific target tissue at specific specific dose mg/kg, specific specific off-target editing rate, specific specific serum biomarker reduction %, specific specific immunogenicity assessment) vs. specific specific LNP-DLin-MC3 or specific specific AAV8/9 delivery baseline at specific specific same model and target — in vivo editing efficiency vs. published clinical-stage delivery benchmarks supports novel delivery IP claims; NOVEL THERAPEUTIC APPLICATION WITH CLINICAL DATA: specific novel CRISPR therapeutic application (specific specific disease indication + specific specific target gene/locus + specific specific editing strategy) with specific measured Phase 1/2 clinical data (specific specific editing efficiency % in specific specific patient cell type, specific specific functional outcome improvement, specific specific safety profile: off-target editing frequency, immunogenicity, genotoxicity screen) vs. specific specific natural history data or specific specific standard-of-care — clinical data supporting a novel therapeutic application creates the most defensible and commercially valuable CRISPR IP (composition of matter + method of treatment + therapeutic protocol); KEY FTO CHECKLIST: Broad Institute SpCas9 US 8,697,359 eukaryotic cell editing foundational DSB 30-50% indel HDR/NHEJ RNP HiFi <0.1% off-target; UC Berkeley IGI Doudna-Charpentier in vitro Type II CRISPR 2012 EP 2 771 468 B1; Beam Therapeutics ABE8e nCas9 D10A TadA8e A→G 99% purity <0.1% indel >50% HSC SpRY all-PAM 53-fold targets SCD beta-thal; David Liu/Broad CBE4max nCas9 rAPOBEC1 UGI-UGI C→T 70-80% <2% indel; PE2 prime editor Cas9 H840A MLV RT pentamutant pegRNA PBS+RT template 1-50 nt insertion all 12 mutations SCD HbS correction; epegRNA evoPreQ1 3' pseudoknot 6-fold improvement; Vertex/CRISPR Therapeutics Casgevy exa-cel BCL11A +58kb HbF >30% 97-99% HSC editing FDA Nov 2023 SCD; Intellia NTLA-2001 LNP DLin-MC3 ionizable lipid Cas9 mRNA 4,500 nt liver ApoE receptor 0.1 mg/kg 87% TTR reduction Phase 1 2021; AcrIIA4 anti-CRISPR SpCas9 competitive PAM-domain IC50 2:1 inducible rapamycin temporal control; 2'-OMe PS modified sgRNA 5-fold efficiency 50-fold lower immunogenicity tru-sgRNA 17 nt 5,000-fold lower off-target.