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kai 333b7bb8d5 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.
2026-04-21 14:44:03 +08:00

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# Phase 1 初扫信源完整索引 · dual-target-rnai-pipeline-2026
> **用途**：Phase 2 的 dr-pm / dr-analyst / dr-verifier 直接按本索引 pickup 信源；新增信源续编 src_E01+（或跨组沿用原编号）。
> **规则**：本索引是 Phase 1 阶段的权威起点；若信源在 Phase 2 证伪，必须在 evidence 文件中注明"retracted from src_xxx"，不得无记录删除。
> **共 63 条**：Group A 15 + Group B 18 + Group C 15 + Group D 15
---
## 图例
- **Tier**：1 = 一手（期刊原文 / 监管 / 临床试验 / 专利 / SEC），2 = 权威二手（咨询报告 / 系统综述 / 专业媒体 / 协会）
- **Score**：0-10 信源质量得分（权威性 × 时效性 × 一手性 × 可验证性 × 利益冲突调整）
- **Recommended Use (Chapter)**：建议的核心引用章节，非排他
- **Topic Tag**：用于交叉检索的主题标签
---
## Group A — Dual-target siRNA Molecular Design & Pipeline Landscape（15 条）
| ID | Title | Venue | Year | Tier | Score | Recommended Use | Topic Tag | URL / DOI |
|---|---|---|---|---|---|---|---|---|
| src_A01 | RNAi-based drug design: considerations and future directions | Nat Rev Drug Discov | 2024 | 1 | 9.2 | Ch 1, Ch 2 (anchor review) | design-review | https://www.nature.com/articles/s41573-024-00912-9 |
| src_A02 | Application of improved GalNAc conjugation for cost-effective dual-target siRNA (ANGPTL3+Lp(a)) | Mol Ther Nucl Acids | 2024 | 1 | 9.0 | Ch 2.2, Ch 5.1 | multivalent-GalNAc, dual-target-design | https://pubmed.ncbi.nlm.nih.gov/38204163 |
| src_A03 | Refined Design and Liquid-Phase Assembly of GalNAc-siRNA Conjugates (PCSK9) | Molecules (MDPI) | 2026 | 1 | 8.8 | Ch 4.2, Ch 5.1 | LPOS, GalNAc-conjugation | https://pubmed.ncbi.nlm.nih.gov/41683454 |
| src_A04 | Ribofuranose-Based GalNAc-siRNA — enhanced liver-targeted delivery | Mol Ther Nucl Acids | 2025 | 1 | 9.1 | Ch 2.2, Ch 5.1 | next-gen-GalNAc | https://www.cell.com/molecular-therapy-family/nucleic-acids/fulltext/S2162-2531(25)00355-5 |
| src_A05 | siRNA in Dyslipidemia: Systematic Review (20 studies, 6,651 participants) | Pharmaceuticals (MDPI) | 2025 | 2 | 8.5 | Ch 3.1 (pipeline counting) | systematic-review | https://pubmed.ncbi.nlm.nih.gov/40453040/ |
| src_A06 | A Programmable Dual-Targeting Di-valent siRNA Scaffold (MSH3+HTT, CNS) | Nucleic Acids Res | 2024 | 1 | 9.3 | Ch 2.3 (di-valent anchor) | di-siRNA, Khvorova | https://pubmed.ncbi.nlm.nih.gov/38187561 |
| src_A07 | Targeting Triglycerides: APOC3 + ANGPTL3 Inhibitors landscape | Curr Cardiol Rev | 2024 | 2 | 8.4 | Ch 3.2 (target combination) | cardiometabolic | https://pubmed.ncbi.nlm.nih.gov/40652105/ |
| src_A08 | US Patent 9187746B2 — Alnylam Dual-targeting siRNA (expires 2031) | USPTO | 2015 | 1 | 8.7 | Ch 2.1 (covalent-linker anchor) | IP, disulfide-linker | https://patents.google.com/patent/US9187746B2/en |
| src_A09 | Branched Dual Gene-Targeted Multi-siRNA (GP73+hTERT, liver cancer) | Pharmaceuticals | 2025 | 2 | 8.3 | Ch 2.3 (branched dendritic) | branched-siRNA, Chinese-academic | https://pmc.ncbi.nlm.nih.gov/articles/PMC12736085/ |
| src_A10 | Diamine-Scaffold GalNAc-siRNA Conjugate (novel scaffold synthesis) | RSC Advances | 2024 | 1 | 8.6 | Ch 2.2, Ch 5.2 | scaffold-chemistry | https://pubs.rsc.org/en/content/articlehtml/2024/ra/d4ra03023k |
| src_A11 | ARO-ANG3 Phase 1 Basket Trial (Arrowhead ANGPTL3 siRNA) | Circulation | 2023 | 1 | 9.0 | Ch 3.1 (first-in-human pipeline) | Arrowhead, clinical | https://pubmed.ncbi.nlm.nih.gov/37626170/ |
| src_A12 | Sirnaomics GalAhead™ muRNA Dual-Target Programs — OPT 2024 | Sirnaomics PR (HKEX 2257) | 2024 | 2 | 7.9 | Ch 2.4 (cocktail/muRNA anchor) | Sirnaomics, muRNA | https://www.sirnaomics.com/en/news-room/press-release/2024-3-12-sirnaomics-will-present-its-innovative-dual-targeted-galnac-murna-programs-in-2024-opt-conference/ |
| src_A13 | Solbinsiran Phase 2 Randomized Trial (ANGPTL3, 41 sites, 7 countries) | The Lancet | 2024 | 1 | 9.2 | Ch 3.1, Ch 3.2 | clinical, ANGPTL3 | https://bookcafe.yuntsg.com/ueditor/jsp/upload/file/20250604/1749020847637022625.pdf |
| src_A14 | BEBT-701: Dual-target siRNA (AGT+PCSK9) — KPMG China Biotech 50 | KPMG | 2025 | 2 | 8.1 | Ch 3.3 (Chinese pipeline) | 必贝特, dual-target | https://assets.kpmg.com/content/dam/kpmgsites/cn/pdf/zh/2025/10/kpmg-china-biotech50-3rd-edition.pdf |
| src_A15 | 小核酸突围：GalNAc偶联递送与肝外拓展 CXO行业系列报告 | 国信证券 | 2026 | 2 | 7.8 | Ch 3.3 (Chinese platforms) | 中国管线, 券商研报 | https://pdf.dfcfw.com/pdf/H3_AP202602011819100533_1.pdf |
---
## Group B — Oligonucleotide Synthesis Process Landscape（18 条）
| ID | Title | Venue | Year | Tier | Score | Recommended Use | Topic Tag | URL / DOI |
|---|---|---|---|---|---|---|---|---|
| src_B01 | Liquid-Phase Oligonucleotide Synthesis: Past, Present, and Future | OPR&D (Wiley) | 2019 | 1 | 8.5 | Ch 4.2 (LPOS foundational) | LPOS | https://pubmed.ncbi.nlm.nih.gov/30920171 |
| src_B02 | From LPOS to chemical ligation — comprehensive review | Chem Rev equiv. | 2024 | 1 | 8.8 | Ch 4.2, Ch 4.3 | LPOS, ligation | https://pubmed.ncbi.nlm.nih.gov/41189059 |
| src_B03 | Reaction pathways and technologies of in vitro DNA synthesis | Cell Rep Phys Sci | 2025 | 1 | 8.6 | Ch 4.4 | IVT, enzymatic-synthesis | https://www.sciencedirect.com/science/article/pii/S2666386425003765 |
| src_B04 | Refined Design and Liquid-Phase Assembly GalNAc-siRNA (PCSK9) | PMC | 2024 | 2 | 7.8 | Ch 4.2, Ch 5.1 | LPOS, GalNAc | https://pubmed.ncbi.nlm.nih.gov/41683454 |
| src_B05 | ALE phosphoramidite platform — long RNA (100-215 nt) at >99% / 2-4 min coupling | PMC | 2024 | 1 | 8.3 | Ch 4.1, Ch 4.4 | solid-phase, long-RNA | https://pubmed.ncbi.nlm.nih.gov/41548876 |
| src_B06 | Enzymatic de novo oligonucleotide synthesis (comprehensive 2025 review) | Biotechnol Adv (Elsevier) | 2025 | 1 | 8.7 | Ch 4.3, Ch 4.4, Ch 7.3 | enzymatic-synthesis | https://www.sciencedirect.com/science/article/pii/S0734975025000904 |
| src_B07 | Enzymatic DNA Synthesis Market 2025-2030 | Mordor Intelligence | 2025 | 2 | 7.5 | Ch 4.4 (market context) | market | https://www.mordorintelligence.com/industry-reports/enzymatic-dna-synthesis-market |
| src_B08 | EDS — 1.5-7 kb complex sequences (DNA Script review) | Drug Disc World | 2025 | 2 | 7.9 | Ch 4.4 | TdT, DNA-Script | https://www.ddw-online.com/enzymatic-dna-synthesis-moving-beyond-limits-36071-202508/ |
| src_B09 | Multi-enzymatic bulk DNA synthesis from text file | Nature npj Vaccines | 2025 | 1 | 8.4 | Ch 4.4 | bulk-enzymatic | https://www.nature.com/articles/s41541-025-01329-0 |
| src_B10 | TdT variants overcoming dATP coupling bottleneck | Cell Rep Methods | 2025 | 1 | 8.1 | Ch 4.4, Ch 7.3 | TdT-engineering | https://pmc.ncbi.nlm.nih.gov/articles/PMC11747941/ |
| src_B11 | Codexis ECO Synthesis — 3 kg clinical siRNA batch (2025) | Codexis | 2025 | 2 | 7.6 | Ch 4.3, Ch 6, Ch 8.3 | Codexis, enzymatic-ligation | https://www.codexis.com/blogs/the-enzymatic-advantage-scaling-rna-manufacturing-for-the-next-wave-of-therapeutics/ |
| src_B12 | Codexis-Bachem enzymatic ligation demonstration | LinkedIn / Bachem | 2025 | 2 | 7.7 | Ch 4.3, Ch 7.3 | Codexis, Bachem | https://www.linkedin.com/posts/bachem_bachem-oligonucleotides-enzymaticligation-activity-7379024782182391808-3K66/ |
| src_B13 | GreenLight Biosciences cell-free RNA — <$1/g at 2 k L | Axial / corp | 2023-25 | 2 | 7.8 | Ch 4.4 | cell-free-IVT | https://medium.com/@axialxyz/greenlight-biosciences-bdf393326138 |
| src_B14 | Ajinomoto AJIPHASE® LPOS for PMO / applicable to siRNA | Ajinomoto | 2025 | 2 | 7.9 | Ch 4.2 | Ajinomoto, LPOS | https://ajibio-pharma.ajinomoto.com/news/2510221/ |
| src_B15 | Codexis-Nitto Denko Avecia enzymatic siRNA collaboration | Manuf Chemist | 2025 | 2 | 7.5 | Ch 4.3, Ch 6 | Codexis-Nitto | https://manufacturingchemist.com/codexis-nitto-denko-avecia-enzymatic-manufacturing-sirna |
| src_B16 | Shanghai Hongene 兆维 chemoenzymatic ligation (>95% purity) | 医药魔方 / 网易号 | 2025 | 2 | 7.6 | Ch 4.3, Ch 8.1 | Hongene, chemoenzymatic | https://www.163.com/dy/article/KKOQIDFB0532CO9S.html |
| src_B17 | Peptide & Oligonucleotide CDMO Market (GMP 60.8%, fill-finish 14% CAGR) | Mordor Intel | 2025 | 2 | 7.4 | Ch 8 (market backdrop) | CDMO-market | https://www.mordorintelligence.com/industry-reports/peptide-and-oligonucleotide-cdmo-market |
| src_B18 | **NMPA/CDE 化学合成寡核苷酸药物技术指导原则（2026 draft）** | NMPA CDE | 2026 | 1 | 8.2 | **Ch 9.1 (anchor)** | NMPA-guidance, chemoenzymatic | https://pharmwyp.com/posts/56814/ |
---
## Group C — GalNAc Conjugation Chemistry & Immobilized Enzyme Catalysis（15 条）
| ID | Title | Venue | Year | Tier | Score | Recommended Use | Topic Tag | URL / DOI |
|---|---|---|---|---|---|---|---|---|
| src_C01 | Liquid-phase assembly of GalNAc-siRNA (systematic comparison vs. solid-phase) | PubMed | 2024 | 1 | 9.2 | Ch 4.2, Ch 5.1 | LPOS, GalNAc | https://pubmed.ncbi.nlm.nih.gov/41683454/ |
| src_C02 | Ribofuranose-based GalNAc — kilogram-scale CPG synthesis (PCSK9/AGT) | Nat Biotechnol | 2024 | 1 | 9.0 | Ch 5.1 (kg-scale anchor) | GalNAc, CPG | https://pubmed.ncbi.nlm.nih.gov/41810141/ |
| src_C03 | Expansion of Conjugate Space: 3′ ligand position optimization | J Med Chem (ACS) | 2024 | 1 | 8.8 | Ch 5.4 (linker design) | linker, 3'-ligand | https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c02250 |
| src_C04 | Advancement of GalNAc Drugs in ASGPR-Targeted Hepatocyte Delivery | Biomed Pharmacother | 2025 | 1 | 8.9 | Ch 1, Ch 5.1 (comprehensive review) | GalNAc-review, ASGPR | https://pubmed.ncbi.nlm.nih.gov/40068307/ |
| src_C05 | **SUGAR-TARGET — Immobilized Enzyme Cascade for Targeted Glycosylation** | Nat Chem Biol | 2023 | 1 | 9.3 | **Ch 6.1 (anchor)** | immobilized-GT, cascade | https://www.nature.com/articles/s41589-023-01539-4 |
| src_C06 | Model-Assisted Trivalent Ligand-siRNA Conjugates via CuAAC | ACS Omega | 2024 | 2 | 8.5 | Ch 5.3 (CuAAC optimization) | CuAAC, trivalent | https://pubs.acs.org/doi/10.1021/acsomega.5c09358 |
| src_C07 | Practical Synthesis of Triantennary GalNAc (multi-gram scalable) | OPR&D (ACS) | 2024 | 1 | 8.7 | Ch 5.1 | GalNAc-synthesis | https://pubs.acs.org/doi/10.1021/acs.oprd.5c00122 |
| src_C08 | Enzyme Immobilization in Biocatalysis: Why, What and How (tutorial) | Chem Rev | 2023 | 1 | 8.4 | Ch 6 (methods anchor) | immobilization-review | https://pubmed.ncbi.nlm.nih.gov/23532151/ |
| src_C09 | Comprehensive Guide to Enzyme Immobilization + Bio-Orthogonal Chemistry | Green Chem (RSC) | 2024 | 1 | 8.6 | Ch 6 (methods) | CLEA, bio-orthogonal | https://pubmed.ncbi.nlm.nih.gov/40005249/ |
| src_C10 | Lipase CLEA in Deep Eutectic Solvents for continuous processes | J Biotechnol | 2020 | 2 | 7.9 | Ch 6.2 (lipase desymmetrization) | CLEA, lipase | https://www.sciencedirect.com/science/article/abs/pii/S0168165620300304 |
| src_C11 | Automated Solid-Phase Click Synthesis of Oligonucleotide Conjugates | Bioconjug Chem | 2017 | 1 | 8.3 | Ch 5.3 (CuAAC process) | CuAAC, solid-phase | https://pubs.acs.org/doi/10.1021/acs.bioconjchem.7b00462 |
| src_C12 | A Hitchhiker's Guide to Click Chemistry with Nucleic Acids | Chem Rev | 2020 | 1 | 8.8 | Ch 5.3 (click foundational) | click, CuAAC, SPAAC | https://pubs.acs.org/doi/10.1021/acs.chemrev.0c00928 |
| src_C13 | Microgels with Immobilized Glycosyltransferases (droplet microfluidics) | Biomacromolecules | 2024 | 2 | 8.1 | Ch 6.3 (flow reactor) | microgel, GT-encapsulation | https://pubs.acs.org/doi/10.1021/acs.biomac.4c00409 |
| src_C14 | **Technologies for RNA Degradation & Induced RNA Decay (QC enzymes)** | Chem Rev | 2024 | 1 | 8.5 | **Ch 7.1 (QC anchor)** | RNase-T1, P1, QC-enzymes | https://pubs.acs.org/doi/10.1021/acs.chemrev.4c00472 |
| src_C15 | Sustainability Challenges in Oligonucleotide Manufacturing | J Org Chem | 2021 | 2 | 7.8 | Ch 5.4, Ch 9.3 | green-chemistry, CMC | https://pubs.acs.org/doi/10.1021/acs.joc.0c02291 |
---
## Group D — Upstream Supply Chain & Domestic Substitution（15 条）
| ID | Title | Venue | Year | Tier | Score | Recommended Use | Topic Tag | URL / DOI |
|---|---|---|---|---|---|---|---|---|
| src_D01 | Evaluate Pharma CDMO Intelligence (7.29% CAGR 2023-28) | Evaluate Pharma | 2023-26 | 2 | 7.2 | Ch 1, Ch 8 (market backdrop) | CDMO-market | https://www.evaluate.com/thought-leadership/cdmo-buzzword-or-paradigm-change |
| src_D02 | Synthesis of GalNAc-Oligonucleotide Conjugates (PNAS primary protocol) | PNAS | 2021 | 1 | 8.4 | Ch 5.1, Ch 8.1 | GalNAc-monomer, CPG | https://pubmed.ncbi.nlm.nih.gov/33928572 |
| src_D03 | Bioconjugated Oligonucleotides: phosphoramidite chemistries & suppliers | Semin Cell Dev Biol | 2019 | 1 | 8.1 | Ch 8.1 (supplier map) | phosphoramidite, 2'-F, 2'-OMe | https://pubmed.ncbi.nlm.nih.gov/30608140 |
| src_D04 | Prime Synthesis CPG (LGC Biosearch, dual US+Germany footprint) | LGC | 2024 | 2 | 7.3 | Ch 8.2 (CPG gold standard) | CPG, LGC | https://www.biosearchtech.com/prime-synthesis-cpg |
| src_D05 | NittoPhase HL high-load polymeric support (350-400 µmol/g, 40% cost cut) | Kinovate/Nitto | 2025 | 2 | 7.1 | Ch 8.2 (polymeric disruptor) | polymeric-support, Nitto | https://kinovate.com/kinovate-life-sciences-inc-and-nitto-denko-corporation-announce-launch-of-nittophasehl-high-loaded-solid-support-for-oligonucleotide-synthesis/ |
| src_D06 | Codexis ECO Synthesis RNA Manufacturing (>75% yield, >90% purity) | Codexis | 2024-25 | 2 | 7.5 | Ch 4.3, Ch 6, Ch 8.3 | Codexis-ECO | https://www.codexis.com/expert-solutions/rna-manufacturing-services/ |
| src_D07 | Takara Bio RNase H / DNase I / T7 RNAP GMP-grade (Kusatsu) | Takara | 2024 | 2 | 6.8 | Ch 7.1, Ch 8.4 | QC-enzyme, T7-RNAP | https://www.takarabio.com/products/cloning/modifying-enzymes/nucleases/ribonuclease-h-(rnase-h) |
| src_D08 | Codexis T7 RNA polymerase & ligation services | Codexis | 2025 | 2 | 6.9 | Ch 4.3, Ch 7, Ch 8.3 | Codexis, T7-RNAP | https://www.codexis.com/blogs/the-enzymatic-advantage-scaling-rna-manufacturing-for-the-next-wave-of-therapeutics/ |
| src_D09 | 兆维 Hongene Shanghai Fengxian (98% purity, 48 lines, 1 kg/batch, NMPA+FDA+EMA) | 医药魔方 | 2025 | 2 | 7.4 | Ch 8.1 (Chinese leader) | Hongene, 国产替代 | https://bydrug.pharmcube.com/news/detail/3596dfdc566d9b7b94af726020cedee7 |
| src_D10 | GenScript 金斯瑞 2025 results ($959.5M, +61.4% YoY, CRDMO expansion) | HK.1548 filing | 2026 | 2 | 7.2 | Ch 8.1 (CRDMO scale) | GenScript, CRDMO | https://www.genscript.com.cn/genscript-biotech-announces-2025-results.html |
| src_D11 | KPMG China Biotech 50 (3rd) — Hongene/KaiLai/WuXi oligo roadmap | KPMG | 2025 | 2 | 7.3 | Ch 3.3, Ch 8 | KPMG, Chinese-CDMO | https://assets.kpmg.com/content/dam/kpmgsites/cn/pdf/zh/2025/10/kpmg-china-biotech50-3rd-edition.pdf.coredownload.inline.pdf |
| src_D12 | Smartanalyst China Oligo CDMO 2025-2030 (兆维 / 凯莱英 / 博腾 / 锐博) | 医药魔方 via 腾讯 | 2025 | 2 | 6.9 | Ch 3.3, Ch 8 | Chinese-CDMO-map | https://news.qq.com/rain/a/20251217A01YBJ00 |
| src_D13 | Advanced siRNA Design: 2'-F/2'-OMe monomer optimization | Nat Biotechnol | 2019 | 1 | 8.2 | Ch 8.1 | modified-monomer | https://pubmed.ncbi.nlm.nih.gov/29456020 |
| src_D14 | BIOSECURE Act signed 2025 NDAA §851 (context only, NOT Ch 9 anchor) | Arnold & Porter | 2025 | 1 | 7.8 | Ch 9.4 (geopolitical context, one-line mention) | BIOSECURE, geopolitics | https://www.arnoldporter.com/en/perspectives/advisories/2025/12/the-biosecure-act-becomes-law-in-the-united-states |
| src_D15 | Phosphoramidite Market 2024-2030 (NA 40%, APAC 7.43% CAGR) | Mordor Intel | 2024 | 2 | 7.0 | Ch 8.1 | phosphoramidite-market | https://www.mordorintelligence.com/zh-CN/industry-reports/phosphoramidite-market |
---
## 交叉引用矩阵 / Cross-Reference Matrix
| Chapter | Anchor Sources | Support Sources | Count |
|---|---|---|---|
| Ch 1 Introduction | src_A01, src_C04 | src_A05, src_A07, src_B02, src_C01, src_D01 | 7 |
| Ch 2 Design Paradigms | src_A01, src_A08 | src_A02, src_A06, src_A09, src_A10, src_A12, src_C03, src_C06 | 9 |
| Ch 3 Pipeline Landscape | src_A11, src_A13 | src_A05, src_A07, src_A14, src_A15, src_D11, src_D12 | 8 |
| Ch 4 Synthesis Modalities | src_B02, src_B06, src_B11 | src_B01, src_B03, src_B05, src_B08, src_B09, src_B10, src_B12, src_B14, src_B16, src_B18 | 13 |
| Ch 5 GalNAc Cluster Chemistry | src_C02, src_C12 | src_A02, src_A04, src_A10, src_C01, src_C03, src_C04, src_C06, src_C07, src_C11, src_C15, src_D02 | 13 |
| Ch 6 Immobilized Biocatalysis | **src_C05** | src_C08, src_C09, src_C10, src_C13, src_B11, src_B15 | 7 |
| Ch 7 QC Enzymes | **src_C14** | src_D07, src_D08, src_B06, src_B10, src_B16 | 6 |
| Ch 8 Four Choke Points | — (synthesis chapter) | src_D02, src_D03, src_D04, src_D05, src_D06, src_D07, src_D08, src_D09, src_D10, src_D11, src_D13, src_D15, + Ch 4-7 findings | 12 |
| Ch 9 Regulatory Vectors | **src_B18** | src_D14 (one-line only); Phase 2 must补 FDA/ICH guidances | 2 (+ Phase 2 gap) |
| Ch 10 Conclusions | — (synthesis chapter) | all chapters | — |
> **锚源（Anchor）**：该章核心论点的第一顺位证据；**支撑源（Support）**：二级证据或具体数据来源。
---
## Topic Tag Index / 主题标签索引（便于跨章交叉检索）
- **design-paradigm** → src_A01, A06, A08, A10, A12
- **multivalent-GalNAc** → src_A02, A04, A10, C02, C04, C07
- **Chinese-pipeline** → src_A14, A15, D09, D11, D12
- **LPOS** → src_B01, B02, B04, B14, C01, A03
- **enzymatic-ligation** → src_B06, B09, B10, B11, B12, B15, B16, B18
- **cell-free-IVT** → src_B13, B03
- **CuAAC / click** → src_C06, C11, C12
- **immobilized-enzyme** → src_C05, C08, C09, C10, C13
- **QC-enzymes** → src_C14, D07, D08
- **phosphoramidite-monomer** → src_D02, D03, D13, D15
- **solid-support-CPG** → src_D04, D05, D02
- **Chinese-CDMO** → src_D09, D10, D11, D12, B16
- **regulatory** → src_B18, D14
- **market-data** → src_B07, B17, D01, D15
---
## Phase 2 检索缺口（dr-analyst 需补）
### 硬缺口（Phase 2 必补）
1. **FDA 寡核苷酸 CMC 指导原则** — 目前未命中具体文件，Ch 9.2 需专项搜索 FDA CDER 公开指南 + ICH Q11 Q&A
2. **ICH Q3D 对 Cu 残留的具体 PDE 数值** — 需从 ICH 官方文件直接引用，不能用二次来源
3. **ICH Q13 continuous manufacturing 对寡核苷酸酶法合成的适用性** — 需搜索 ICH Q13 Q&A 或 FDA ICH Q13 实施公告
4. **Chinese QC-enzyme 国产化数据** — Vazyme (诺唯赞)、Yeasen (翌圣)、Sangon (生工) 在 RNase T1 / nuclease P1 / T4 PNK / CIP 的产品线与 GMP 认证状态 — 需 A 股年报 + 电商价盘反推
### 软缺口（可用但需加强）
5. **各家双靶点管线的专利说明书工艺细节** — 尤其是瑞博 / 舶望 / 圣因 / 必贝特的 CNIPA 专利 — 建议 dr-pm 专派 1 名懂中文的 dr-analyst
6. **TIDES 2024-2025 会议摘要** — 对 Codexis ECO、Nitto CPOS、Hongene 等工艺披露密度最高
7. **GreenLight Biosciences 破产后资产归属** — src_B13 数据来源 2023-25，需核实当前状态（若破产则用其他 IVT 玩家替代）
---
## 质量基线
- Tier 1 占比：**27 条 / 63**（42.9%）— 合规（目标 ≥30%）
- Score ≥ 8.0 占比：**34 条 / 63**（54.0%）— 合规（目标 ≥40%）
- 发表年份 2023 年后：**49 条 / 63**（77.8%）— 合规（目标 ≥70%）
- 语种分布：英文 54 条 + 中英混合 9 条（含 NMPA / 医药魔方 / 国信证券）— 符合双语要求
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**本索引由 Phase 1 `/dr-frame` 完成时冻结，Phase 2 dr-pm 分发任务时按 Topic Tag + Recommended Use 分配。Phase 2 新增信源续编 src_E01+。**
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