Etranacogene dezaparvovec

2025年5月，美国联邦巡回上诉法院（CAFC）支持PTAB认定uniQure 关于FIX AAV的两项美国专利无效的决定，驳回上诉，无效挑战者辉瑞赢得了上诉。无效挑战者辉瑞赢得FIX AAV基因疗法的专利诉讼byTiPLab 木桃这一消息对于开发FIX AAV的玩家来说，无疑是个好消息，或许辉瑞帮助扫除了一个潜在的专利障碍。而且有意思的是，辉瑞已经于今年终止了B 型血友病基因疗法 Beqvez的全球商业化，而转向了治疗血友病的抗体药物。另外，该案中关于治疗方法专利的非显而易见性讨论也给了我们一些启示。血友病B是一种由于单基因突变导致的凝血因子IX（FIX）缺乏病症。传统采用高频输注重组FIX蛋白的蛋白替代疗法进行治疗，而近年来以腺相关病毒（AAV）载体为基础的基因治疗成为替代方案，将携带编码FIX蛋白的病毒载体给予患者，从而使患者自身能够持续合成FIX蛋白，降低甚至消除对蛋白替代疗法的依赖。而AAV会引发免疫反应，且达到有效治疗效果的AAV剂量可能使患者出现严重的不良免疫反应。uniQure将FIX蛋白338位的精氨酸（R）替换为亮氨酸（L）获得高活性FIX-R338L突变体，其活性比野生型FIX高8到9倍，通过降低病毒载体剂量降低患者的免疫激活。uniQure利用FIX-R338L开发了HEMGENIX®，已经获得 FDA批准。关注要点：美国专利非显而易见的判断涉案专利为US9,982,248（’248专利）和US10,465,180（’180专利），旨在通过在基因治疗中利用野生型FIX基因的突变版本来解决这一问题，分别保护涉及使用AAV递送FIX-R338L治疗凝血病和包含编码FIX-R338L的AAV载体。其中’248专利关于治疗方法类权利要求非显而易见性的观点值得关注。美国专利非显而易见的判断包括两个要点，本领域技术人员（POSA）是否有动机结合现有技术（motivation to combine）以及结合后是否有成功预期（reasonable expectation of success）。本案中，uniQure承认POSA有结合动机，主要争议点在于利用AAV-FIX-R338L基因疗法治疗血友病B是否具有合理的成功预期。’248的权利要求1： 1. A method of treating a coagulopathy in a human patient, comprising administering a vector to the human patient, wherein: a. the vector is an adeno-associated virus; b. the vector comprises a nucleic acid encoding a modified FIX polypeptide, the modified FIX polypeptide comprising at least 70% identity to SEQ ID NO: 2 and a leucine in position 338 of SEQ ID NO: 2; and c. the vector comprises promoter sequences and transcription termination and control elements; thereby treating the coagulopathy.’248 专利的独立权利要求1要求通过向人类患者施用载体来治疗凝血病，其中该载体是AAV，包含编码修饰的 FIX 多肽的核酸，其中338位是亮氨酸。PTAB认为，Stafford、Manno 和 Schuettrumpf 的组合，将使 POSA 获得合理的成功预期，即可以利用 AAV-FIX-R338L 载体治疗血友病 B。Stafford 向 POSA 证明了使用 FIX-R338A 所取得的结果也有望通过使用 FIX-R338L 实现： Stafford在实施例中明确证明了FIX-R338A的凝血活性相比于野生型提高了2-3 倍。根据权利要求，FIX-R338L 是三个明确优选的变体之一，也是单独要求保护的两个变体之一。Manno 和 Schuettrumpf 证明了 AAV 基因疗法治疗血友病 B可以成功实现： Manno 报道用 AAV递送野生型FIX 可成功实现对于血友病B的治疗； Schuettrumpf 教导了 AAV-FIX-R338A 在给小鼠注射时产生的蛋白质活性是野生型 FIX 的六倍。另外，uniQure ’248 专利描述丙氨酸（A）和亮氨酸（L）是“同源氨基酸”，并且它们之间的替换“不会改变蛋白质的表型”。CAFC观点根据CAFC最终的观点，可以概括出判断合理成功预期的两个要点1）治疗用途的合理成功预期不总是需要临床数据uniQure尝试争辩基因治疗的不可预测性，以及现有技术缺乏针对 AAV-FIX-R338L 的疗效数据。CAFC指出“在治疗方法权利要求中证明合理的成功预期不必依赖临床数据，也不必包括证明该治疗在每种情况下都会成功的确定性。“Our case law makes clear that a showing of a reasonable expectation of success in a method of treatment claim need not rely on clinical data . . . nor must it include a demonstration of certainty that the treatment would be successful in every instance.”CAFC还认为“并不总是需要体内有效性数据来证明合理的成功预期”，本案中，辉瑞的专家证人已证明“FIX 水平与临床症状有很好的相关性”，这足以构成合理的成功预期。2）保守氨基酸替换可能合理预期其效果相似性uniQure尝试争辩难以预期氨基酸替换会产生具有可预测结构和功能的突变体。CAFC认同辉瑞专家证人的观点，即 POSA应该理解丙氨酸和亮氨酸都是不带电荷、非极性、脂肪族和疏水性氨基酸，能够预期在 FIX-R338 处用亮氨酸替换丙氨酸，而不会损失凝血活性。此外，’248 专利也描述基于结构相似性，将丙氨酸和亮氨酸描述为彼此的保守替换。因此，当以多肽作为其治疗作用的分子时，如果仅是对现有蛋白质进行氨基酸保守替换在创造性上存在挑战，特别是现有技术已经披露氨基酸结构的相似性与其功能存在对应关系时。TiPLab小贴士对于治疗方法类权利要求，1）当适应症的机理比较明确时，且现有技术已经公开其类似产品的体外效果或小鼠效果，在创造性中争辩不具有“合理的成功预期”存在一定难度，比如，仅通过取得较好的临床效果争辩创造性可能还不够，可以考虑通过产品的区别特征带来的难以预期的效果和临床上其他未公开的效果，比如：更低的副作用来争辩。2）也可以通过预料不到的技术效果来争辩非显而易见，但需注意要证明其与权利要求的关联性，明确指出该预料不到的效果是由本申请的发明点带来的。在本案中uniQure指出AAV-FIX-R338L满足了长期未满足的临床需求或取得了预料不到的疗效等。CAFC认同PTAB的观点，即上述效果与权利要求缺乏足够的关联，认为该效果主要是由 Stafford 中披露的 FIX-R338L所带来的，且没有明确证明该效果由本专利保护的 AAV-FIX-R338L所带来的。3）在撰写专利文本时，描述现有技术部分需要谨慎评估对于自身创造性的影响，特别是涉及到一些已知机理描述，防止给未来授权或确权过程中埋雷。* 以上文字仅为促进讨论与交流，不构成法律意见或咨询建议。© 作为一家专业服务公司，TiPLab坚持原创的系统的研究，注重系统性知识积累与专业影响力。欢迎读者个人分享转发，各专业平台媒体如需转载请联系TiPLab获得授权。 TiPLab提供基于研究的核心知识产权服务FTO：技术商业化实施的侵权风险防范TiPLab通过对细分技术领域内核心技术和重要专利的长期研究，结合自身在数据检索和分析方面的专长，致力于帮助客户深入了解、积极应对潜在的专利侵权风险。Due Diligence：商业活动中的知识产权尽职调查在企业许可交易、融资、并购、上市等过程中，TiPLab帮助企业和投资方了解目标技术/产品的专利保护强度及产品商业化过程中潜在的专利侵权风险，从而为商业谈判和决策提供支持依据。Patenting：全球范围内高价值专利资产的创设TiPLab熟知全球主要国家和地区的法律实践和细分领域内的前沿技术进展情况，通过前瞻性的专利布局策略，帮助客户通过创设有价值的专利资产而获取、保持和巩固独特的竞争优势。

~ Alignment with FDA continues to support Accelerated Approval pathway ~ ~ BLA submission planned for first quarter of 2026 ~ ~ Conference call today at 8:30 a.m. ET ~ LEXINGTON, Mass. and AMSTERDAM, June 02, 2025 (GLOBE NEWSWIRE) -- uniQure N.V. (NASDAQ: QURE), a leading gene therapy company advancing transformative therapies for patients with severe medical needs, today provided a regulatory update on AMT-130, its investigational gene therapy for the treatment of Huntington’s disease. Following recent Type B meetings and further guidance from the U.S. Food and Drug Administration (FDA), the Company has reached alignment with the FDA on several key components of the statistical analysis plan and Chemistry, Manufacturing and Controls (CMC) information that will support a Biologics License Application (BLA) submission expected in the first quarter of 2026. “We are very pleased with our continued, productive engagement with the FDA and the progress we’ve made toward a planned BLA submission for AMT-130 in the first quarter of 2026,” said Walid Abi-Saab, M.D., chief medical officer of uniQure. “We are pursuing an accelerated approval pathway supported by multiple years of clinical data – a rigorous and differentiated approach that reflects the urgent need in Huntington’s disease and our commitment to delivering the first disease-modifying treatment for people affected by this devastating disease. We are grateful to the FDA for their continued engagement and look forward to sharing three-year top-line data in the third quarter of 2025.” Statistical Analysis Plan In the second quarter of 2025, the Company held a Type B meeting with the FDA to discuss the proposed use of external control data and the prospectively defined statistical analysis plan (SAP) in support of the planned BLA submission for AMT-130. The FDA continued to support its prior agreement that the composite Unified Huntington’s Disease Rating Scale (cUHDRS) may serve as an acceptable registrational, intermediate clinical endpoint for accelerated approval. The FDA agreed that the primary efficacy analysis for the BLA will evaluate the 3-year change in cUHDRS in high-dose AMT-130 patients compared to a propensity score-adjusted external control arm. The Company plans to use propensity score-weighted external control derived from the ENROLL-HD dataset for the primary analysis and to submit certain sensitivity analyses, including one using a propensity score-matched external control, as additional support. The FDA also agreed that ENROLL-HD – a large, prospective, longitudinal, natural history study of patients with Huntington’s disease – may be acceptable as the external control dataset for the primary analysis of the trial data along with additional sensitivity analyses using the TRACK-HD/TRACK-ON and PREDICT-HD datasets. To date, approximately 33,000 patients have enrolled in ENROLL-HD. Compared to previously used natural history studies like TRACK-HD and PREDICT-HD, ENROLL-HD offers a substantially larger sample size, lower attrition rates, and longer average patient follow-up. The Company expects the larger sample size to reduce variability in the external control data and enhance the robustness of the SAP. The Company plans to submit an updated SAP consistent with discussions from the recently held Type B meeting to the FDA in the second quarter of 2025. Chemistry, Manufacturing and Controls (CMC) In the first quarter of 2025, the Company held a Type B meeting with the FDA to discuss CMC requirements in support of the planned BLA submission for AMT-130. The FDA agreed that validation of the AMT-130 manufacturing process should be possible using experience and prior knowledge from the etranacogene dezaparvovec-drlb (HEMGENIX®) process, complemented with additional full-scale AMT-130 GMP batches and a single Process Performance Qualification (PPQ) batch. The FDA also agreed with the Company’s proposed drug product release testing plan, including the proposed potency assay, pending completion of qualification and specification setting activities. Next Steps for the Planned BLA Submission Based on these recent Type B meetings with the FDA, the Company continues to prepare for a BLA submission for AMT-130 in the treatment of Huntington’s disease. Certain key next steps and expected timing include: Q2 2025: submit updated SAP to the FDAQ3 2025: initiate PPQ run and present topline Phase I/II data per the SAPQ4 2025: hold pre-BLA meeting with the FDAQ1 2026: submit BLA with a request for priority review designation Investor Conference Call and Webcast Information uniQure management will host an investor conference call and webcast today, Monday, June 2, 2025 at 8:30 a.m. ET. The event will be webcast under the Events & Presentations section of uniQure’s website at https://www.uniqure.com/investors-media/events-presentations, and following the event a replay will be archived for 90 days. Interested parties participating by phone will need to register using this online form. After registering for dial-in details, all phone participants will receive an auto-generated e-mail containing a link to the dial-in number along with a personal PIN number to use to access the event by phone. If you are joining the conference call, please dial in 15 minutes before the start time. About the Phase I/II Clinical Program of AMT-130 uniQure is conducting two multi-center, dose-escalating, Phase I/II clinical studies to explore the safety, tolerability, and exploratory efficacy signals of AMT-130 for the treatment of Huntington’s disease. In the U.S. study, a total of 26 patients with early manifest Huntington’s disease were randomized to treatment (n=6 low dose; n=10 high dose) or an imitation (sham) surgical procedure (n=10). Treated patients received a single administration of AMT-130 through MRI-guided, convection-enhanced stereotactic neurosurgical delivery directly into the striatum (caudate and putamen). The study consists of a blinded 12-month core study period followed by unblinded long-term follow-up of treated patients for five years. An additional four control patients crossed over to treatment. The European open-label Phase Ib/II study of AMT-130 enrolled 13 patients with early manifest Huntington’s disease (n=6 low dose; n=7 high dose). A third cohort enrolled an additional 12 patients across sites in the U.S. and EU. This cohort was randomized to explore both doses of AMT-130 in combination with immunosuppression, using the current, established stereotactic administration procedure. Additional details are available on www.clinicaltrials.gov (NCT0543017, NCT04120493) AMT-130 has been granted the FDA’s Regenerative Medicine Advance Therapy (RMAT) designation and Breakthrough Therapy designation, the first therapy for Huntington’s disease to receive an RMAT designation. About Huntington’s Disease Huntington’s disease is a rare, inherited neurodegenerative disorder that leads to motor symptoms including chorea, behavioral abnormalities and cognitive decline resulting in progressive physical and mental deterioration. The disease is an autosomal dominant condition with a disease-causing CAG repeat expansion in the first exon of the huntingtin gene that leads to the production and aggregation of abnormal protein in the brain. According to 2021 study in Neuroepidemiology, approximately 70,000 people have been diagnosed with Huntington’s disease in the U.S. and Europe, with hundreds of thousands of others at risk of inheriting the disease. Despite the clear etiology of Huntington’s disease, there are currently no approved therapies to delay the onset or to slow the disease’s progression. About uniQure uniQure is delivering on the promise of gene therapy – single treatments with potentially curative results. The approvals of uniQure’s gene therapy for hemophilia B – an historic achievement based on more than a decade of research and clinical development – represent a major milestone in the field of genomic medicine and ushers in a new treatment approach for patients living with hemophilia. uniQure is now advancing a pipeline of proprietary gene therapies for the treatment of patients with Huntington's disease, refractory temporal lobe epilepsy, ALS, Fabry disease, and other severe diseases. www.uniQure.com uniQure Forward-Looking Statements This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. All statements other than statements of historical fact are forward-looking statements, which are often indicated by terms such as "anticipate," "believe," "could," “establish,” "estimate," "expect," "goal," "intend," "look forward to", "may," "plan," "potential," "predict," "project," “seek,” "should," "will," "would" and similar expressions and the negatives of those terms. Forward-looking statements are based on management's beliefs and assumptions and on information available to management as of the date of this press release. Examples of these forward-looking statements include, but are not limited to, statements concerning: the availability of accelerated approval pathways and the need for additional pre-approval studies for AMT-130; the Company’s anticipated timing of the BLA submission; the Company’s plans to submit a revised SAP and CMC information to the FDA; the Company’s ability to deliver a potentially life-changing therapy to people living with Huntington’s disease and related timeline for doing so; the potential clinical and functional effects of AMT-130; the Company’s plans to continue clinical development of AMT-130; the Company’s plans to share clinical data of AMT-130 in the third quarter of 2025; and the utility of the ENROLL-HD patient dataset with respect to Phase I/II study. The Company may not actually achieve the plans, intentions or expectations disclosed in these forward-looking statements. Furthermore, the Company’s actual results could differ materially from the plans, intentions and expectations anticipated in these forward-looking statements for many reasons. These risks and uncertainties include, among others: risks related to the Company’s Phase I/ll clinical trials of AMT-130, including the risk that interim data from the trials may not be predictive of later data readouts that will serve as a basis for further regulatory interactions, may not support BLA submissions or accelerated approvals, may not be satisfactory to the FDA and other regulators, and new analyses of existing data and results may produce different conclusions than established as of the date hereof; risks related to the Company’s current and future interactions with regulatory authorities, which may affect the initiation, timing and progress of clinical trials, its BLA submission plans and pathways to regulatory approval; risks related to the Company’s ability to pursue business development efforts with respect to AMT-130; risks related to the Company’s use of propensity-weighted external controls in connection with its statistical analysis of clinical outcomes to date; uncertainties as to the FDA’s and other regulatory authorities’ interpretation of the data from the Company’s Phase I/ll clinical trials of AMT-130 and acceptance of the Company’s clinical programs and the regulatory approval process; later developments with the FDA and other regulators that could be inconsistent with the feedback received to date; and whether regulatory authorities will accept the Company’s approach as a basis for accelerated approval; risks related to the Company’s use of nominal p values as a basis for its statistical analyses; whether the measurements that the Company is evaluating continue to be viewed as robust and sensitive measurements of disease progression; whether RMAT designation or any accelerated pathway, will lead to regulatory approval; the Company’s ability to continue to build and maintain the infrastructure and personnel needed to achieve its goals; the Company’s effectiveness in managing current and future clinical trials and regulatory processes; the Company’s ability to demonstrate the therapeutic benefits of its gene therapy candidates in clinical trials; the continued development and acceptance of gene therapies; the Company’s ability to obtain, maintain and protect its intellectual property; and the Company’s ability to fund its operations and to raise additional capital as needed and on acceptable terms. These risks and uncertainties are more fully described under the heading "Risk Factors" in the Company’s periodic filings with the U.S. Securities & Exchange Commission (SEC), including its Annual Report on Form 10-K filed with the SEC on February 27, 2025, its Quarterly Reports on Form 10-Q filed May 9, 2025, and in other filings that the Company makes with the SEC from time to time. Given these risks, uncertainties and other factors, you should not place undue reliance on these forward-looking statements and, except as required by law, the Company assumes no obligation to update these forward-looking statements, even if new information becomes available in the future. uniQure Contacts: FOR INVESTORS:FOR MEDIA: Chiara RussoTom MaloneDirect: 617-306-9137Mobile: 617-306-9137Mobile: 617-306-9137Mobile:339-223-8541c.russo@uniQure.comt.malone@uniQure.com