v0.5.1: disable apply_patch in agents prone to append-mode failures
Root cause: apply_patch finds anchor lines in read-cached file state, but file may have been modified between read and patch, causing stalls. Changes: - dr-verifier: disable apply_patch AND edit; force read-then-write protocol for evidence file appends - dr-analyst: document write-preferred protocol for sources.jsonl appends - dr-polisher: disable apply_patch; keep edit for small string replacements - dr-editor-in-chief / dr-translator: disable apply_patch Recovery procedure documented in dr-verifier for write failures.
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kai
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{"id":"src_E01","tier":2,"score":7.5,"type":"news","url":"https://investors.alnylam.com/press-release","title":"Alnylam RNAi Product Approvals Timeline 2018–2025 (Onpattro/Givlaari/Oxlumo/Leqvio/Amvuttra/Rivfloza/Qfitlia)","year":2025,"venue":"Alnylam Pharmaceuticals Press Releases","accessed_at":"2026-04-21","key_claim":"Seven GalNAc-siRNA drugs approved FDA 2018–2025; Qfitlia approved March 2025 completing P5x25 strategy","used_in":["ch01"],"authority":1.5,"recency":2.0,"primacy":1.5,"verifiability":1.5,"coi":0.5,"conflict_of_interest":"Company press release — authoritative for approval dates but authored by Alnylam","blacklist_checked":true,"retraction_checked":false,"notes":"Primary FDA approval chronology corroborated across multiple independent sources including biochempeg.com table and PMC clinical review"}
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{"id":"src_E02","tier":2,"score":7.6,"type":"news","url":"https://ir.arrowheadpharma.com/news-releases/news-release-details/arrowhead-pharmaceuticals-initiates-phase-12a-study-aro-dimer-pa","title":"Arrowhead Pharmaceuticals Initiates Phase 1/2a Study of ARO-DIMER-PA – the First Dual Functional RNAi Therapeutic for Mixed Hyperlipidemia","year":2025,"venue":"Arrowhead Pharmaceuticals Press Release","accessed_at":"2026-04-21","key_claim":"ARO-DIMER-PA (PCSK9+APOC3) is first clinical-stage dual-functional RNAi molecule, Phase 1/2a initiated 2025","used_in":["ch01"],"authority":1.5,"recency":2.0,"primacy":1.5,"verifiability":1.5,"coi":0.5,"conflict_of_interest":"Company-authored press release; clinical phase initiation fact is independently verifiable via ClinicalTrials.gov","blacklist_checked":true,"retraction_checked":false,"notes":"TRiM platform dual-target molecule; NHP preclinical data cited internally"}
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{"id":"src_E03","tier":3,"score":6.5,"type":"news","url":"https://biocytogen.com/blogs/dual-target-nucleic-acid-therapeutics-humanized-models","title":"Accelerating Dual-Target Small Nucleic Acid Therapeutics with Humanized Models","year":2025,"venue":"Biocytogen Blog","accessed_at":"2026-04-21","key_claim":"UK Biobank data: combined APOC3+PCSK9 protective alleles confer 10% lower CHD risk vs single allele (citing Wang et al. 2025)","used_in":["ch01"],"authority":1.0,"recency":2.0,"primacy":0.5,"verifiability":0.5,"coi":1.0,"conflict_of_interest":"Commercial vendor blog; Wang et al. 2025 primary citation not directly accessed","blacklist_checked":true,"retraction_checked":false,"notes":"The 10% CHD risk reduction figure requires primary source verification against Wang et al. 2025 UK Biobank publication"}
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{"id":"src_E04","tier":2,"score":7.8,"type":"journal","url":"https://www.cell.com/molecular-therapy-family/nucleic-acids/fulltext/S2162-2531(24)00324-X","title":"Development, opportunities, and challenges of siRNA nucleic acid drugs","year":2025,"venue":"Molecular Therapy Nucleic Acids","accessed_at":"2026-04-21","key_claim":"Six siRNA drugs commercially approved by 2025; clinical trial table includes complement C5 program cemdisiran in Phase 3","used_in":["ch01"],"authority":2.0,"recency":2.0,"primacy":1.0,"verifiability":1.5,"coi":1.0,"conflict_of_interest":"None disclosed","blacklist_checked":true,"retraction_checked":true,"notes":"Open access Cell/Elsevier review; good pipeline table for confirmation of Phase status"}
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{"id":"src_E05","tier":2,"score":7.4,"type":"report","url":"https://tides.wuxiapptec.com/wp-content/uploads/2024/07/Fast-Track-to-Phase-I-Two-siRNA-IND-CMC-Packages_final-approved.pdf","title":"Fast-Track to Phase I: Two siRNA IND CMC Packages Completed in 14 Months","year":2024,"venue":"TIDES Conference / WuXi AppTec","accessed_at":"2026-04-21","key_claim":"Standard GalNAc-siRNA GMP optimization: initial yield 13%/crude purity 18% improved to 62%/75% after process development; 500g GMP batch in 10 months","used_in":["ch01"],"authority":1.5,"recency":2.0,"primacy":1.5,"verifiability":1.5,"coi":0.5,"conflict_of_interest":"CDMO-authored case study; WuXi AppTec has commercial interest in favorable presentation","blacklist_checked":true,"retraction_checked":false,"notes":"Technical detail level suggests genuine process disclosure not purely promotional; specific numbers used in Ch01 for baseline yield quantification"}
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{"id":"src_E06","tier":1,"score":8.8,"type":"journal","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12899625/","doi":"10.3390/molecules31060897","title":"Refined Design and Liquid-Phase Assembly of GalNAc-siRNA Conjugates: Comparative Efficiency Validation in PCSK9 Targeting","year":2026,"venue":"Molecules (MDPI)","accessed_at":"2026-04-21","key_claim":"Commercial GalNAc-preloaded CPG supports have loading below 100 µmol/g hindering industrial-scale synthesis; liquid-phase synthesis enables gram-to-kg scale potential","used_in":["ch01"],"authority":2.0,"recency":2.0,"primacy":2.0,"verifiability":2.0,"coi":1.0,"conflict_of_interest":"None disclosed","blacklist_checked":true,"retraction_checked":true,"notes":"Same paper indexed as src_A03/src_B04/src_C01 in initial scan — used here specifically for CPG loading limitation quote; peer-reviewed primary synthesis paper"}
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{"id":"src_E07","tier":3,"score":5.5,"type":"news","url":"https://www.bocsci.com/research-area/formulating-sirna-for-liver-targeted-delivery-galnac-conjugation-tips.html","title":"GalNAc siRNA Formulation for Liver Targeting — Technical Overview","year":2025,"venue":"BOC Sciences Technical Notes","accessed_at":"2026-04-21","key_claim":"GalNAc cluster as phosphoramidite monomer extends coupling cycle time from 2 min to 6 min due to diffusion limitations in 500 Å CPG pores","used_in":["ch01"],"authority":1.0,"recency":2.0,"primacy":0.5,"verifiability":0.5,"coi":0.5,"conflict_of_interest":"Commercial vendor; cycle-time claim may derive from unpublished internal data","blacklist_checked":true,"retraction_checked":false,"notes":"Cycle-time figure flagged as requiring primary source verification; used only in Ch01 as a directional indicator with appropriate confidence level"}
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{"id":"src_E08","tier":3,"score":6.0,"type":"database","url":"https://synapse.patsnap.com/organization/e8cb014d0dbbc49f59602b29e212c16c","title":"BeBetter Med — Drug pipelines and Clinical Trials (Synapse/Patsnap)","year":2026,"venue":"Patsnap Synapse Database","accessed_at":"2026-04-21","key_claim":"BEBT-701 (AGT+PCSK9) NCT07368608 Phase 1/2 trial registered; start date January 26 2026; sponsor BeBetter Med","used_in":["ch01"],"authority":1.0,"recency":2.0,"primacy":1.0,"verifiability":1.5,"coi":1.0,"conflict_of_interest":"Database aggregator, no inherent conflict","blacklist_checked":true,"retraction_checked":false,"notes":"NCT number and start date confirmed from ClinicalTrials.gov registry via Synapse aggregation"}
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{"id":"src_E09","tier":1,"score":9.0,"type":"journal","url":"https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)00507-0/fulltext","doi":"10.1016/S0140-6736(25)00507-0","title":"Durability and efficacy of solbinsiran, a GalNAc-conjugated siRNA targeting ANGPTL3, in adults with mixed dyslipidaemia (PROLONG-ANG3)","year":2025,"venue":"The Lancet","accessed_at":"2026-04-21","key_claim":"Solbinsiran Phase 2 PROLONG-ANG3: 205 patients, variable apoB reductions (significant only at 400 mg); 100 mg and 800 mg arms missed primary endpoint — illustrating variable single-target outcomes","used_in":["ch01"],"authority":3.0,"recency":2.0,"primacy":2.0,"verifiability":2.0,"coi":0.0,"conflict_of_interest":"Eli Lilly-sponsored trial; declared industry conflicts among investigators","blacklist_checked":true,"retraction_checked":true,"notes":"Primary counter-evidence for Section CE01; Lancet publication score elevated despite COI because the COI is declared and trial was randomized controlled"}
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{"id":"src_E10","tier":3,"score":6.0,"type":"news","url":"https://www.bioxconomy.com/modalities/dual-targeting-sirnas-could-treat-complex-genetic-diseases","title":"Dual-targeting siRNAs could treat complex genetic diseases","year":2024,"venue":"Bioxconomy","accessed_at":"2026-04-21","key_claim":"Dual-target siRNAs present doubled off-target risk surface; 'careful safety evaluation will be essential in future translational studies' (citing Sugimoto et al.)","used_in":["ch01"],"authority":1.0,"recency":2.0,"primacy":0.5,"verifiability":0.5,"coi":1.0,"conflict_of_interest":"Independent science journalism; Sugimoto primary citation not directly accessed","blacklist_checked":true,"retraction_checked":false,"notes":"Counter-evidence source CE02; primary Sugimoto publication should be located for stronger citation in Ch01 future revision"}
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{"id":"src_E23","tier":2,"score":7.8,"type":"report","url":"https://capella.alnylam.com/wp-content/uploads/2025/02/Alnylam-RD-Day-2025.pdf","title":"Alnylam R&D Day 2025 — GEMINI platform preclinical data (ANGPTL3+AGT dual siRNA single entity)","year":2025,"venue":"Alnylam Pharmaceuticals R&D Day","accessed_at":"2026-04-21","key_claim":"GEMINI combines two siRNAs in a single chemical entity; GEMINI-CVR targets ANGPTL3+AGT with biannual dosing goal; preclinical data show superior dual knockdown vs mixture","used_in":["ch03"],"authority":1.5,"recency":2.0,"primacy":1.5,"verifiability":1.5,"coi":0.5,"conflict_of_interest":"Company R&D Day; technical content primary; corroborated by 10-K SEC filing","blacklist_checked":true,"retraction_checked":false,"notes":"Alnylam 2024 10-K (alny-20241231) independently corroborates GEMINI platform description and pre-IND status"}
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{"id":"src_E24","tier":2,"score":7.2,"type":"database","url":"https://www.ribolia.com/en/pipeline/pipeline/core-pipeline","title":"Suzhou Ribo Life Science — Core Pipeline (RBD4059 Phase 2, RBD5044 Phase 2, RBD7022 Phase 2)","year":2026,"venue":"Ribo IR / HKEX 06938","accessed_at":"2026-04-21","key_claim":"7 clinical-stage single-target assets; dual-target in active R&D under RiboGalSTAR™; no dual-target IND as of April 2026","used_in":["ch03"],"authority":1.5,"recency":2.0,"primacy":1.5,"verifiability":1.0,"coi":0.5,"conflict_of_interest":"Company IR page; corroborated by ESC 2025 presentations and pharmaphorum independent coverage","blacklist_checked":true,"retraction_checked":false,"notes":"Ribo IPO raised HKD 1.59B on HKEX Jan 2026; pipeline page is real-time updated"}
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{"id":"src_E25","tier":2,"score":7.5,"type":"news","url":"https://www.ribolia.com/en/media-center/our-products-news/50","title":"Ribo ESC 2025 — RBD5044 Phase I: 84% APOC3 knockdown sustained at 6-month follow-up; RBD7022 Phase I: 75% PCSK9 max reduction at 6 months","year":2025,"venue":"Ribo Press Release / ESC 2025","accessed_at":"2026-04-21","key_claim":"RBD5044 single injection: 84% APOC3 knockdown sustained through 6-month follow-up; supports Q6M dosing; well-tolerated","used_in":["ch03"],"authority":1.5,"recency":2.0,"primacy":1.5,"verifiability":1.5,"coi":0.5,"conflict_of_interest":"Company press release; clinical data presented at peer-reviewed conference (ESC 2025)","blacklist_checked":true,"retraction_checked":false,"notes":"ESC 2025 presentation is independent conference review; multiple Ribo assets presented same day"}
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{"id":"src_E26","tier":3,"score":6.2,"type":"news","url":"https://www.phirda.com/artilce_41242.html","title":"2026最热：小核酸龙头来了 — Ribo IPO strategy and dual-target R&D roadmap","year":2026,"venue":"China Medical Innovation Association (phirda.com)","accessed_at":"2026-04-21","key_claim":"Ribo explicitly prioritizes dual-target and multi-target technology breakthroughs; RSC 2.0 modification system; RiboGalSTAR™ liver delivery","used_in":["ch03"],"authority":1.0,"recency":2.0,"primacy":0.5,"verifiability":0.5,"coi":0.5,"conflict_of_interest":"Association publication; corroborates HKEX prospectus language; dual-target R&D priority confirmed","blacklist_checked":true,"retraction_checked":false,"notes":"Used for strategic context only; Ribo HKEX prospectus is the primary source for dual-target R&D priority claim"}
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{"id":"src_E27","tier":2,"score":7.4,"type":"news","url":"https://pharmaphorum.com/news/rna-specialist-ribo-files-205m-ipo-hong-kong","title":"RNA specialist Ribo files $205m IPO in Hong Kong — 7 clinical assets, dual-target in R&D","year":2026,"venue":"pharmaphorum","accessed_at":"2026-04-21","key_claim":"Ribo HKD 1.59B IPO; 7 clinical-stage assets; Boehringer Ingelheim MASH + Qilu dyslipidaemia partnerships >$2B combined; RiboGalSTAR™ dual-target extension in development","used_in":["ch03"],"authority":1.5,"recency":2.0,"primacy":0.5,"verifiability":1.5,"coi":1.0,"conflict_of_interest":"Independent trade press (pharmaphorum); no conflict; corroborates HKEX prospectus data","blacklist_checked":true,"retraction_checked":false,"notes":"Pharmaphorum is Tier 2 trade media; independent confirmation of Ribo pipeline and partnership data"}
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{"id":"src_E28","tier":2,"score":7.5,"type":"news","url":"https://www.argobiopharma.com/news/111.html","title":"Argo Biopharma: BW-00163 (AGT siRNA) advances to Phase 2; Novartis milestone payment; $4B+ total deal value","year":2025,"venue":"Argo Biopharma Press Release","accessed_at":"2026-04-21","key_claim":"BW-00163 progressed to Phase 2 via Novartis June 2025; $185M upfront + $4B+ total potential from Jan 2024 deal for two cardiovascular assets","used_in":["ch03"],"authority":1.5,"recency":2.0,"primacy":1.5,"verifiability":1.5,"coi":0.5,"conflict_of_interest":"Company press release; deal terms independently referenced in VCBeat and Novartis regulatory filings","blacklist_checked":true,"retraction_checked":false,"notes":"NCT06857955 (BW-00163 Phase 2 Novartis-sponsored) independently registered on ClinicalTrials.gov"}
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{"id":"src_E29","tier":2,"score":7.6,"type":"news","url":"https://www.prnewswire.com/news-releases/argo-biopharma-doses-first-patients-in-phase-ii-clinical-trials-of-sirna-therapy-bw-40202-302747128.html","title":"Argo Biopharma doses first patients in Phase II trials of BW-40202 (CFB siRNA, PNH + IgAN)","year":2026,"venue":"PR Newswire / Argo Biopharma","accessed_at":"2026-04-21","key_claim":"First patient dosed April 20, 2026 in Phase II BW-40202 trials for PNH and IgAN; BW-40202 is single-target CFB siRNA; RADS™ platform","used_in":["ch03"],"authority":1.5,"recency":2.0,"primacy":1.5,"verifiability":1.5,"coi":0.5,"conflict_of_interest":"Company press release on PR Newswire; independently corroborated by CTR20252839 registry","blacklist_checked":true,"retraction_checked":false,"notes":"Very recent (April 20, 2026); confirmed in both NMPA ChiCTR registry and Australian IND registry"}
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{"id":"src_E30","tier":2,"score":7.2,"type":"database","url":"https://sirnaomics.com/en/science-pipeline/pipeline/","title":"Sirnaomics Pipeline — muRNA dual-target programs STP271G (PCSK9+ANGPTL3), STP237G (AGT+APOC3), STP247G (CFB+C5)","year":2026,"venue":"Sirnaomics (HKEX 2257)","accessed_at":"2026-04-21","key_claim":"Sirnaomics has 3+ preclinical muRNA dual-target programs; PDoV-GalNAc scaffold also preclinical; muRNA design confirmed as single-molecule by RSC Med Chem 2025","used_in":["ch03"],"authority":1.5,"recency":2.0,"primacy":1.5,"verifiability":1.0,"coi":0.5,"conflict_of_interest":"Company pipeline page; muRNA architecture independently described in RSC Medicinal Chemistry review 2025","blacklist_checked":true,"retraction_checked":false,"notes":"PDoV-GalNAc and GalAhead™ muRNA are distinct Sirnaomics scaffolds; both preclinical for dual-target programs"}
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{"id":"src_E31","tier":2,"score":7.0,"type":"news","url":"https://www.stcn.com/article/detail/3343990.html","title":"迈威生物 (688062) 2MW7141 dual-target siRNA licensed to Kalexo Bio; ≤$1B deal value","year":2025,"venue":"Securities Times (STCN) / Shanghai STAR Market regulatory disclosure","accessed_at":"2026-04-21","key_claim":"2MW7141 is preclinical-stage dual-target siRNA for lipid abnormalities; ≤$1B deal with Kalexo (Aditum Bio); target identity undisclosed; first-in-class non-LNP delivery claimed","used_in":["ch03"],"authority":1.5,"recency":2.0,"primacy":1.5,"verifiability":1.0,"coi":0.5,"conflict_of_interest":"STCN aggregates Shanghai STAR Market regulatory disclosures; 688062 is publicly listed company; deal terms are formal disclosure","blacklist_checked":true,"retraction_checked":false,"notes":"STCN (Securities Times) is official SHEX disclosure channel; deal value constitutes mandatory regulatory disclosure for listed company"}
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{"id":"src_E32","tier":2,"score":7.3,"type":"news","url":"https://www.caixinglobal.com/2026-02-27/chinas-biotech-push-into-small-nucleic-acid-drugs-draws-global-pharma-102417490.html","title":"China's Biotech Push Into Small Nucleic Acid Drugs Draws Global Pharma (Caixin Global Feb 2026)","year":2026,"venue":"Caixin Global","accessed_at":"2026-04-21","key_claim":"Over 100 Chinese small nucleic acid drug pipelines by Jan 2026 (Insight data); global siRNA market $2.7B (2019) to $5.7B (2024); >$36B in 2025 sector transactions","used_in":["ch03"],"authority":1.5,"recency":2.0,"primacy":0.5,"verifiability":1.5,"coi":1.0,"conflict_of_interest":"Caixin is independent financial journalism; data attributed to Huaxi Securities and Insight database","blacklist_checked":true,"retraction_checked":false,"notes":"Caixin is premium financial media with editorial standards; the 100+ pipeline figure should be treated as directional (definitionally broad)"}
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{"id":"src_E11","tier":1,"score":7.2,"type":"journal","url":"https://www.sciencedirect.com/science/article/abs/pii/S0168365914004118","doi":"10.1016/j.jconrel.2014.07.049","title":"Disulfide-Containing Parenteral Delivery Systems and Their Redox-Biological Fate","year":2014,"venue":"Journal of Controlled Release","accessed_at":"2026-04-21","key_claim":"Intracellular GSH 1–10 mM; extracellular plasma GSH ~2–20 µM; ~500-fold gradient drives selective intracellular disulfide cleavage for siRNA delivery","used_in":["ch02"],"authority":2.0,"recency":0.6,"primacy":2.0,"verifiability":1.5,"coi":1.0,"conflict_of_interest":"None disclosed; academic review","blacklist_checked":true,"retraction_checked":true,"notes":"Foundational redox biology review; mechanism unchanged since publication; score adjusted for age (-0.6 recency penalty for 12-year-old paper in stable-mechanism category)"}
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{"id":"src_E12","tier":2,"score":7.5,"type":"journal","url":"https://www.chromatographyonline.com/view/analysis-of-sirna-with-denaturing-and-non-denaturing-ion-pair-reversed-phase-liquid-chromatography-methods","title":"Analysis of siRNA with Denaturing and Non-Denaturing Ion-Pair Reversed-Phase Liquid Chromatography Methods","year":2023,"venue":"LCGC International","accessed_at":"2026-04-21","key_claim":"Denaturing IP-RPLC separates hetero-duplex, homo-duplex, and single-strand populations in dual-siRNA constructs; method validation requirements described","used_in":["ch02"],"authority":1.5,"recency":2.0,"primacy":1.5,"verifiability":1.5,"coi":1.0,"conflict_of_interest":"None disclosed; analytical methods article","blacklist_checked":true,"retraction_checked":false,"notes":"Professional analytical methods journal; specific siRNA duplex separation method validation described; supports hetero-duplex QC claim for covalent tandem paradigm"}
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{"id":"src_E13","tier":1,"score":8.6,"type":"journal","url":"https://pubs.rsc.org/en/content/articlehtml/2023/cs/d2cs00788f","doi":"10.1039/D2CS00788F","title":"Targeted delivery of oligonucleotides using multivalent protein-carbohydrate interactions","year":2023,"venue":"Chemical Society Reviews (RSC)","accessed_at":"2026-04-21","key_claim":"Alnylam triantennary GalNAc Kd = 2.3 nM for ASGPR; 10^6-fold affinity gain from mono to triantennary; tetraantennary only modest further improvement; cluster effect mechanism","used_in":["ch02"],"authority":2.5,"recency":2.0,"primacy":1.5,"verifiability":2.0,"coi":1.0,"conflict_of_interest":"None disclosed; independent academic review","blacklist_checked":true,"retraction_checked":true,"notes":"Chem Soc Rev high IF; comprehensive review of multivalent carbohydrate-ASGPR binding; Kd = 2.3 nM value confirmed from Nair et al. JACS 2014 primary data cited within"}
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{"id":"src_E14","tier":1,"score":7.5,"type":"regulatory","url":"https://www.ich.org/page/quality-guidelines","title":"ICH Q6A — Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and Drug Products (Chemical Substances)","year":1999,"venue":"ICH / FDA / EMA","accessed_at":"2026-04-21","key_claim":"Specifications framework for drug substance identity and purity; mixture-API composition ratio control requirements; <5% CV inference for fixed-composition mixture products","used_in":["ch02"],"authority":2.0,"recency":0.5,"primacy":2.0,"verifiability":2.0,"coi":1.0,"conflict_of_interest":"None; regulatory guidance","blacklist_checked":true,"retraction_checked":false,"notes":"Still-authoritative ICH guidance; specific <5% CV figure for siRNA cocktail composition is inferred not explicitly stated — flagged as unverified in evidence table C15; recommend FDA OPQ consultation"}
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{"id":"src_E15","tier":1,"score":8.3,"type":"journal","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC5762979/","doi":"10.1016/j.omtn.2017.11.010","title":"Evaluation of GalNAc-siRNA Conjugate Activity in Pre-clinical Animal Models with Reduced Asialoglycoprotein Receptor Expression","year":2017,"venue":"Molecular Therapy Nucleic Acids","accessed_at":"2026-04-21","key_claim":"Triantennary GalNAc-ASGPR Kd ~2 nM; ASGPR receptor saturation documented at doses >5 mg/kg; in silico model parameters: Kd=2nM, kon=1e5 M-1s-1, ASGPR ~600 nM intrahepatic","used_in":["ch02"],"authority":2.0,"recency":1.0,"primacy":2.0,"verifiability":2.0,"coi":1.0,"conflict_of_interest":"Alnylam-affiliated authors; declared; data directly relevant and specific","blacklist_checked":true,"retraction_checked":true,"notes":"Key quantitative ASGPR saturation data; Kd value corroborates src_E13; saturation threshold at >5 mg/kg provides basis for cocktail receptor saturation counter-argument; COI declared and methodology sound"}
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{"id":"src_E40","tier":1,"score":8.0,"type":"journal","url":"https://pubs.acs.org/doi/10.1021/acs.oprd.4c00188","doi":"10.1021/acs.oprd.4c00188","title":"Acetonitrile Regeneration from Oligonucleotide Production Waste","year":2024,"venue":"Organic Process Research & Development (ACS)","accessed_at":"2026-04-21","key_claim":"Approximately 85% of total acetonitrile usage in SPOS is consumed during synthesis wash steps","used_in":["ch04"],"authority":2.0,"recency":2.0,"primacy":2.0,"verifiability":2.0,"coi":1.0,"conflict_of_interest":"None disclosed","blacklist_checked":true,"retraction_checked":false,"notes":"ACS OPR&D primary paper on solvent use in oligo manufacturing; 85% stat is key for PMI analysis"}
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{"id":"src_E41","tier":2,"score":6.8,"type":"report","url":"https://synergbiopharma.com/wp-content/uploads/2025/10/SynerG_SPOS-and-LPOS_whitepaper.pdf","title":"Solid-Phase Oligonucleotide Synthesis (SPOS) and Liquid-Phase Oligonucleotide Synthesis (LPOS): A Comparative Review","year":2025,"venue":"SynerG BioPharma White Paper","accessed_at":"2026-04-21","key_claim":"PMI for 20-mer therapeutic oligos: 3,035–7,023 (avg 4,299); MeCN consumption up to 1,000 kg/kg API; AJIPHASE 21-mer siRNA: 60% yield, >90% purity","used_in":["ch04"],"authority":1.5,"recency":2.0,"primacy":1.0,"verifiability":1.5,"coi":0.5,"conflict_of_interest":"CDMO-affiliated white paper; PMI data cites published sources; AJIPHASE claim cites Ajinomoto","blacklist_checked":true,"retraction_checked":false,"notes":"Useful aggregator of SPOS/LPOS comparative data; primary sources should be traced where possible"}
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{"id":"src_E42","tier":1,"score":8.5,"type":"journal","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11071452/","title":"Biochemical and structural insights into a 5' to 3' RNA ligase — T4 RNA Ligase 1 substrate requirements","year":2024,"venue":"PMC / Nucleic Acids Research","accessed_at":"2026-04-21","key_claim":"T4 RNA Ligase 1 requires 5'-phosphate, 3'-hydroxyl, and free 2'-hydroxyl; substrate incompatible with 2'-OMe at ligation junction in wild-type form","used_in":["ch04"],"authority":2.0,"recency":2.0,"primacy":2.0,"verifiability":2.0,"coi":1.0,"conflict_of_interest":"None disclosed","blacklist_checked":true,"retraction_checked":false,"notes":"Primary mechanistic constraint paper for T4 Rnl1; key for explaining why engineered ligases are required for 2'-modified siRNA ligation"}
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{"id":"src_E43","tier":2,"score":7.8,"type":"news","url":"https://ir.codexis.com/news-events/press-releases/detail/442/codexis-signs-agreement-to-manufacture-50-g-sirna-using-its-eco-synthesis-manufacturing-platform","title":"Codexis signs agreement to manufacture 50 g siRNA using its ECO Synthesis® Manufacturing Platform","year":2026,"venue":"Codexis IR Press Release","accessed_at":"2026-04-21","key_claim":"Codexis agreed in March 2026 to manufacture 50 g siRNA for a cardiovascular indication preclinical program via ECO Synthesis; confirms commercial traction","used_in":["ch04"],"authority":1.5,"recency":2.0,"primacy":1.5,"verifiability":2.0,"coi":0.5,"conflict_of_interest":"Company press release; fact of agreement independently verifiable from IR filing","blacklist_checked":true,"retraction_checked":false,"notes":"March 4, 2026 announcement; confirms ECO Synthesis is at commercial engagement stage"}
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{"id":"src_E44","tier":2,"score":7.5,"type":"news","url":"https://www.globenewswire.com/news-release/2023/07/24/2709622/0/en/GreenLight-Announces-Completion-of-Merger-with-Fall-Line-Endurance-Fund.html","title":"GreenLight Announces Completion of Merger with Fall Line Endurance Fund — $45.5M go-private transaction, July 24, 2023","year":2023,"venue":"GlobeNewswire / Goodwin Law","accessed_at":"2026-04-21","key_claim":"GreenLight Biosciences Holdings taken private July 24, 2023 at $45.5M; surviving entity pivoted exclusively to agriculture RNA (Calantha, Norroa); therapeutic siRNA program discontinued","used_in":["ch04"],"authority":1.5,"recency":1.5,"primacy":1.5,"verifiability":2.0,"coi":1.0,"conflict_of_interest":"None — factual M&A announcement","blacklist_checked":true,"retraction_checked":false,"notes":"CRITICAL CORRECTION: GreenLight did NOT go bankrupt; it was acquired and pivoted to agriculture. The $1/g IVT cost claim applies to agricultural unmodified dsRNA only, not therapeutic siRNA"}
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{"id":"src_E45","tier":2,"score":7.0,"type":"report","url":"https://d1io3yog0oux5.cloudfront.net/_f07ef482839a89d64e69eb116fc3ecf6/codexis/db/1165/11842/pdf/CDXS+TIDES+EU+Presentation+November+2023.pdf","title":"Revolutionizing Nucleic Acid Synthesis with Engineered Enzymes — Codexis TIDES EU 2023 Presentation (TdT engineering)","year":2023,"venue":"Codexis / TIDES Europe Conference","accessed_at":"2026-04-21","key_claim":"Iterative TdT evolution showing progressive improvement in 2'-OMe and 2'-F modified NQP incorporation efficiency across multiple evolution rounds","used_in":["ch04"],"authority":1.5,"recency":1.5,"primacy":1.5,"verifiability":1.5,"coi":0.5,"conflict_of_interest":"Company presentation; data appears genuine process development disclosure","blacklist_checked":true,"retraction_checked":false,"notes":"2023 TIDES EU presentation; shows TdT engineering in progress for modified RNA; current status (2025-2026) per DeciBio Q&A suggests still not at GMP-ready stage for full alternating 2'-OMe/2'-F 21-mers"}
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