kai
701bc1887e
Root cause: dr-translator was trying to write entire final_zh.md in one write call, hitting Sonnet 4-6 output token limit for long reports (~19k English words → ~27k Chinese chars → blown past 32k token cap). Fix: explicit chunk-and-append protocol - Split final_en.md by H1 (# ) then H2 (## ) boundaries - Each chunk ≤ 2,500 English words - First chunk uses write to create final_zh.md - Subsequent chunks use edit or read+write to append - Per-chunk Chinese output kept under ~5,000 characters (safe margin) - Preserves glossary.json updates across chunks
452 lines
18 KiB
JSON
452 lines
18 KiB
JSON
{
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"slug": "dual-target-rnai-pipeline-2026",
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"topic": "双靶点RNAi药物研发进展和国内外在研管线",
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"report_title": "双靶点 RNAi 药物工艺图谱与上游供应链机会研究",
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"report_subtitle": "近 5 年全球在研管线的合成、偶联与酶催化技术路径解构（2021–2026）",
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"author": "Deep Research 系统",
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"date": "2026-04-21",
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"version": "1.0",
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"type": "综述",
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"confidentiality": "机密 | 仅供内部决策使用",
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"audience": "研发团队（上游供应链 / 工业用酶 / 无细胞表达 / 固定化酶催化方向）",
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"time_range": "近 5 年（2021-01 至 2026-04）",
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"geography": "全球对比（中美欧日为主）",
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"core_questions": [
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"近 5 年全球与中国在研的双靶点 RNAi 药物管线有哪些？分别采用何种靶点组合、技术平台与开发阶段？",
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"双靶点 siRNA 的分子设计路径（串联/偶联/cocktail/多价支架）有哪些？各自工艺差异与关键壁垒是什么？",
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"双靶点 siRNA 的合成工艺（固相/液相/酶法/无细胞表达）和偶联化学（GalNAc、多价簇、支架连接）在各家管线中的实现方式有何不同？",
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"序列合成、偶联化学、纯化等环节上，上游供应链（工业用酶原料、固定化酶催化、无细胞表达体系、亚磷酰胺单体、GalNAc 配体、固相载体等）存在哪些国产替代与卡位机会？",
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"从工艺复杂度与规模化成本角度，哪些双靶点 RNAi 技术路线最有可能率先走向商业化？对应的上游供应机会窗口与切入点是什么？"
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],
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"comparison_targets": [
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"Alnylam Pharmaceuticals",
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"Arrowhead Pharmaceuticals",
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"Silence Therapeutics",
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"Dicerna / Novo Nordisk",
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"Ionis (siRNA 相关项目)",
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"瑞博生物 (Ribo Life Science)",
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"舶望制药 (Argo Biopharma)",
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"大睿生物 (Sirnaomics / Da Rui)",
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"圣诺制药 (Sirnaomics)",
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"悦康药业 / 君圣泰 / 石药 / 恒瑞 等国内 siRNA 玩家",
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"双靶点 siRNA cocktail 与多价 siRNA 支架相关项目"
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],
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"exclusions": [
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"不展开讨论具体适应症的临床有效性与安全性细节（临床进度仅作为管线标签使用）",
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"不涉及 mRNA / ASO / saRNA / 基因编辑等非 siRNA 模态的工艺细节（仅在对比位置点到为止）",
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"不做市场容量 / 销售预测 / 估值分析（报告面向上游供应链而非投资人）",
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"不展开疾病机制与药理学讨论"
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],
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"word_budget_mode": "auto",
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"target_words_zh": 21000,
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"target_words_en": 15000,
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"min_words_zh": 17000,
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"min_words_en": 12000,
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"disclaimer": "本报告基于公开信息与 AI 辅助研究生成，仅供参考，不构成投资或医疗建议。",
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"work_language": "en",
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"output_language": "zh",
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"phase1": {
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"status": "approved",
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"approved": true,
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"approved_at": "2026-04-21T05:42:34Z",
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"approved_note": "User implicitly approved by executing /dr-research",
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"framework_path": "projects/dual-target-rnai-pipeline-2026/phase1/framework.md",
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"initial_scan_path": "projects/dual-target-rnai-pipeline-2026/phase1/initial-scan.md",
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"initial_scan_index_path": "projects/dual-target-rnai-pipeline-2026/phase1/initial-scan-index.md",
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"chapter_count": 10,
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"revision_note": "v2: 按用户反馈重构 — 拆出 Ch6 (固定化酶) 与 Ch7 (QC 酶) 独立章；Ch9 改为 FDA/NMPA/ICH 针对性监管分析（BIOSECURE 仅一句话背景）；字数升档至 15000 EN / 21000 ZH；每章增 Technical Hooks 字段便于专家判断真假机会；初扫 63 条信源输出为 initial-scan-index.md 供 Phase 2 pickup。",
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"central_thesis_en": "The true competitive frontier of dual-target RNAi is not the second siRNA strand but the manufacturing stack beneath it — multivalent GalNAc assembly, enzymatic ligation, immobilized biocatalysis, and the quietly scarce GMP-grade QC enzymes are the choke points. Four upstream nodes (specialty phosphoramidite monomers, high-load solid supports, immobilized glycosyl-transfer biocatalysis, QC enzymes) concentrate most of the opportunity for suppliers who can simultaneously meet NMPA 2026 chemoenzymatic guidance and FDA/ICH Q11-Q13 expectations.",
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"central_thesis_zh": "双靶点 RNAi 的真正竞争前沿不是'加一条 siRNA 链'，而是其下的制造栈 — 多价 GalNAc 组装、酶法连接、固定化生物催化，以及常被忽视却持续短缺的 GMP 级 QC 酶。机会集中在四个上游环节：专用亚磷酰胺单体、高载量固相载体、固定化糖基转移/酯化生物催化、寡核苷酸 QC 酶；能同时满足中国 NMPA 2026 化学酶连指导原则与 FDA/ICH Q11-Q13 体系要求的供应商，将获取最大的结构性红利。",
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"chapter_quotas_en": [
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{
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"index": 1,
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"title_en": "Why the Second Strand Matters Less Than the Stack Beneath It",
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"title_zh": "双靶点的真正战场不在'加第二条链'，而在其下的制造栈",
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"en_words": 1050,
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"priority": "intro"
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},
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{
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"index": 2,
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"title_en": "Dual-Target Design Space Has Already Bifurcated into Four Paradigms, Each with a Different Process Signature",
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"title_zh": "双靶点设计空间已分化为四种范式，每种都带出一条工艺签名",
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"en_words": 1500,
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"priority": "P0"
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},
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{
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"index": 3,
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"title_en": "The Global Pipeline Is Denser than the Headlines Suggest, but China Is Adding Assets Faster than Anyone Else",
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"title_zh": "全球管线比头条更密，但中国正在以最快速度堆积资产",
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"en_words": 1500,
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"priority": "P0"
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},
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{
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"index": 4,
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"title_en": "Solid-Phase Remains the Default, but the Competitive Edge Is Shifting to Liquid-Phase and Enzymatic Ligation",
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"title_zh": "固相合成仍是默认路线，但竞争优势正在向液相与酶法连接迁移",
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"en_words": 1800,
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"priority": "P0"
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},
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{
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"index": 5,
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"title_en": "Multivalent GalNAc Cluster Chemistry: How the Industry Assembles Three-to-Seven Sugars onto a Single Oligo",
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"title_zh": "多价 GalNAc 簇化学：行业如何把 3-7 个糖装到同一条寡核苷酸上",
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"en_words": 1800,
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"priority": "P0"
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},
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{
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"index": 6,
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"title_en": "Immobilized Biocatalysis Enters the GalNAc-Conjugation Pipeline — From Lab Curiosity to GMP Candidate",
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"title_zh": "固定化生物催化进入 GalNAc 偶联流水线 — 从实验室新奇到 GMP 候选",
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"en_words": 1650,
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"priority": "P0"
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},
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{
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"index": 7,
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"title_en": "QC Enzymes and Process-Analytical Biocatalysts: The Quietly Scarce Third Pillar",
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"title_zh": "QC 酶与工艺分析用生物催化剂：被忽视却紧缺的第三支柱",
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"en_words": 1500,
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"priority": "P0"
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},
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{
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"index": 8,
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"title_en": "Four Upstream Choke Points Define the Opportunity Map",
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"title_zh": "四个上游咽喉点定义了机会图谱",
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"en_words": 1650,
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"priority": "P0"
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},
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{
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"index": 9,
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"title_en": "Regulatory Vectors Reshaping the Supply Chain: NMPA Chemoenzymatic Guidance, FDA Oligonucleotide CMC Signals, ICH Q11/Q13",
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"title_zh": "重塑供应链的监管向量：NMPA 化学酶连指导原则、FDA 寡核苷酸 CMC 信号、ICH Q11/Q13",
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"en_words": 1200,
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"priority": "P1"
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},
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{
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"index": 10,
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"title_en": "Conclusions and Upstream Action Priorities, with Technical Thresholds",
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"title_zh": "结论与上游行动优先级（附技术门槛）",
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"en_words": 1350,
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"priority": "conclusion"
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}
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],
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"total_en_quota": 15000,
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"total_zh_quota_est": 21000,
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"source_count": 63,
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"source_tier_distribution": {
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"tier_1": 27,
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"tier_2": 36
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},
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"phase2_search_gaps": [
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"FDA 寡核苷酸 CMC 指导原则原文",
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"ICH Q3D Cu PDE 具体数值（原文）",
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"ICH Q13 continuous manufacturing 对寡核苷酸酶法合成的适用性",
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"Vazyme / Yeasen / Sangon 等国内 QC 酶产品线与 GMP 认证状态",
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"瑞博 / 舶望 / 圣因 / 必贝特 CNIPA 中文专利说明书",
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"TIDES 2024-2025 会议摘要（Codexis ECO / Nitto CPOS / Hongene 工艺披露）",
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"GreenLight Biosciences 当前资产归属状态"
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]
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},
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"phase2": {
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"status": "completed",
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"started_at": "2026-04-21T05:42:34Z",
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"completed_at": "2026-04-21T09:30:00Z",
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"current_batch": 5,
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"batches": [
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{
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"batch": 1,
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"chapters": [
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1
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],
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"note": "Intro chapter — solo"
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},
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{
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"batch": 2,
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"chapters": [
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2,
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3,
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4
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],
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"note": "Design paradigms + Pipeline + Synthesis"
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},
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{
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"batch": 3,
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"chapters": [
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5,
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6,
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7
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],
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"note": "GalNAc chemistry + Immobilized biocatalysis + QC enzymes"
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},
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{
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"batch": 4,
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"chapters": [
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8,
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9
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],
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"note": "Choke points + Regulatory"
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},
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{
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"batch": 5,
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"chapters": [
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10
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],
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"note": "Conclusion chapter — solo"
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}
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],
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"chapters": [
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{
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"index": 1,
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"status": "verified",
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"en_words_actual": 1124,
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"en_words_quota": 1050,
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"sources_new": 10,
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"unverified": 2,
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"critical": 1,
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"actual_words": 1124,
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"sources_count": 15
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},
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{
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"index": 2,
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"status": "verified",
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"en_words_quota": 1500,
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"actual_words": 1551,
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"sources_count": 18,
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"unverified_count": 0,
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"verified_at": "2026-04-21T06:33:54.794537Z"
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},
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{
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"index": 3,
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"status": "verified",
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"en_words_quota": 1500,
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"actual_words": 1586,
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"sources_count": 17,
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"unverified_count": 0,
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"verified_at": "2026-04-21T06:33:54.794537Z"
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},
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{
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"index": 4,
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"status": "verified",
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"en_words_quota": 1800,
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||
"actual_words": 2113,
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"sources_count": 21,
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||
"unverified_count": 0,
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"verified_at": "2026-04-21T06:33:54.794537Z"
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},
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{
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"index": 5,
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"status": "verified",
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"en_words_quota": 1800,
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||
"actual_words": 1701,
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"sources_count": 18,
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"unverified_count": 2,
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"critical_count": 1,
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"verified_at": "2026-04-21T07:30:00Z",
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"verifier_verdict": "PASS-WITH-NOTES",
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"verifier_notes": "Cu PDE calculation needs correction (should use 30 µg/day parenteral); SPAAC above 500g threshold unsupported; non-classical GalNAc displays need acknowledgment"
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},
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{
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"index": 6,
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"status": "verified",
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"en_words_quota": 1650,
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"actual_words": 1666,
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"sources_count": 15,
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"unverified_count": 2,
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"critical_count": 1,
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"verified_at": "2026-04-21T07:30:00Z",
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"verifier_verdict": "PASS-WITH-NOTES",
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"verifier_notes": "CRITICAL: ECO scope limited to strand synthesis/ligation, NOT GalNAc conjugation; GT cascade TRL downgraded to 4-5; 'documentation-only gap' claim too strong"
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},
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{
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"index": 7,
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"status": "verified",
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"en_words_quota": 1500,
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||
"actual_words": 1717,
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"sources_count": 12,
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"unverified_count": 1,
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"critical_count": 1,
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"verified_at": "2026-04-21T07:30:00Z",
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"verifier_verdict": "PASS-WITH-NOTES",
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"verifier_notes": "CRITICAL: 3-4 global supplier count needs qualification; Yeasen partial GMP foothold acknowledged; mandatory QC enzyme set framing should be workflow-dependent not compendial"
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},
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{
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"index": 8,
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"status": "verified",
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"en_words_quota": 1650,
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||
"actual_words": 1710,
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||
"sources_count": 15,
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||
"unverified_count": 3,
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"critical_count": 1,
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"verified_at": "2026-04-21T08:30:00Z",
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"verifier_verdict": "PASS-WITH-NOTES",
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"verifier_notes": "CRITICAL: C07 LNA claim narrowed — Hongene has LNA catalog; DMF absence is inferred not confirmed. NittoPhase 40% cost claim needs softening. APAC CAGR = 7.43%-15.2% range."
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},
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{
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"index": 9,
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"status": "verified",
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||
"en_words_quota": 1200,
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||
"actual_words": 1533,
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||
"sources_count": 12,
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||
"unverified_count": 0,
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"critical_count": 0,
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"verified_at": "2026-04-21T08:30:00Z",
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"verifier_verdict": "PASS-WITH-NOTES",
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"verifier_notes": "NMPA 2026 FINAL confirmed. Cu parenteral PDE = 300 µg/day confirmed (30 µg/day is inhalation). FDA 'no guidance' needs narrowing. EMA §4.2.2 confirms Q13 but says enzymatic synthesis 'too premature'. BIOSECURE count = 1."
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},
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{
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"index": 10,
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||
"status": "verified",
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||
"en_words_quota": 1350,
|
||
"actual_words": 1547,
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||
"sources_count": 0,
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||
"sources_cross_chapter": 41,
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||
"unverified_count": 0,
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"critical_count": 2,
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"verified_at": "2026-04-21T09:15:00Z",
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"verifier_verdict": "PASS-WITH-NOTES",
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"verifier_notes": "CRITICAL: (1) Ranking criterion must be stated as time-to-revenue not strategic attractiveness to resolve Priority 4 apparent contradiction. (2) GT reuse threshold ≥10 cycles overstated — should be '≥6 cycles demonstrated; commercial target ≥10 cycles'. All three key corrections applied correctly: Cu PDE=300µg/day, ECO=strand-only, GT TRL=5-6."
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}
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],
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"batches_summary": [
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{
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||
"batch": 1,
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||
"chapters": [
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1
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],
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"completed_at": "2026-04-21T06:00:00Z",
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"summary": "Ch1 (1124 words, 10 new sources src_E01-E10, 2 unverified: GalNAc cycle-time claim + 3x QC-enzyme demand inference). 1 CRITICAL: draft overstates unimolecular dual-target superiority vs. cocktail; dr-analyst in Ch2/10 must balance."
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},
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{
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"batch": 2,
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||
"chapters": [
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2,
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3,
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4
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],
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||
"completed_at": "2026-04-21T06:33:54Z",
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"summary": "Ch2 (1551 words, 18 sources, 0 unverified) — four design paradigms. Ch3 (1586 words, 17 sources) — global pipeline + China velocity. Ch4 (2113 words, 21 sources) — SPPS ceiling + AJIPHASE/CPOS/ECO benchmarks. All verified, no CRITICAL."
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},
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{
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"batch": 3,
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"chapters": [
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5,
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6,
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7
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],
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"completed_at": "2026-04-21T07:30:00Z",
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"summary": "Ch5 (1701w, PASS-WITH-NOTES) CRITICAL: Cu parenteral PDE=300µg/day (not 30). Ch6 (1666w, PASS-WITH-NOTES) CRITICAL: ECO=strand-only not GalNAc; GT TRL→4-5. Ch7 (1717w, PASS-WITH-NOTES) CRITICAL: 3-4 supplier count needs per-enzyme caveat; Yeasen partial GMP."
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},
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{
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"batch": 4,
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||
"chapters": [
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8,
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9
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],
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"completed_at": "2026-04-21T08:30:00Z",
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"summary": "Ch8 (1710w, PASS-WITH-NOTES) CRITICAL: LNA claim narrowed (Hongene has LNA catalog; no DMF is inferred not confirmed). NittoPhase 40% cost softened. Ch9 (1533w, PASS-WITH-NOTES) NMPA 2026 FINAL confirmed. Cu PDE=300µg/day reconfirmed. FDA no general oligo CMC guidance. EMA §4.2.2 confirms Q13."
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},
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{
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"batch": 5,
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"chapters": [
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10
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],
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||
"completed_at": "2026-04-21T09:15:00Z",
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"summary": "Ch10 (1547w, PASS-WITH-NOTES) Synthesis chapter: 41 cross-chapter citations, 0 new sources. CRITICAL: (1) Ranking criterion must be explicit (time-to-revenue). (2) GT reuse threshold ≥10 cycles overstated vs Ch6 evidence (4-6 cycles demonstrated). All three key corrections applied correctly."
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}
|
||
]
|
||
},
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"phase2_word_stats": {
|
||
"total_en_words": 16248,
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"verdict": "合格 — 16,248 words / target 15,000 words (108.3%)",
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"estimated_zh_chars": 22747,
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"critical_flags_in_evidence": 10,
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"chapter_breakdown": [
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{
|
||
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},
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{
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},
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{
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"ch": 3,
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||
"words": 1586,
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"quota": 1500,
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},
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{
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"ch": 4,
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},
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{
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},
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{
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"ch": 6,
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},
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{
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"ch": 7,
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"words": 1717,
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},
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{
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},
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{
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{
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}
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]
|
||
},
|
||
"phase3": {
|
||
"status": "completed",
|
||
"approved": true,
|
||
"approved_at": "2026-04-21T08:11:19Z",
|
||
"approved_note": "User invoked /dr-finalize; dr-editor-in-chief accepts B rating and will integrate Must-Fix corrections during Phase 4 merge",
|
||
"rating": "B",
|
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|
||
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|
||
},
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|
||
"status": "in_progress",
|
||
"started_at": "2026-04-21T08:11:19Z",
|
||
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|
||
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|
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|
||
"editorial_notes_path": "projects/dual-target-rnai-pipeline-2026/phase4/editorial-notes.md"
|
||
}
|
||
} |