引言 Introduction
1984年的《药物价格竞争和专利期修正案》 (Drug Price Competition and Patent Term Restoration Act，即熟知的Hatch-Waxman法案) 确立了仿制药的申请途径ANDA (Abbreviated New Drug Application，简略新药申请)；2003年，美国国会颁布的《医疗保险处方药改进和现代化法案》 (Congress Enacted The Medicare Prescription Drug, Improvement, And Modernization Act) 进一步修订了与180天独占权相关的条款。2011年9月，《美国发明法案》 (America Invents Act,) 出台了解决专利争议的快速通道-双方复议 (Inter Partes Review, IPR)。在这个过程中，FDA也逐步制定了一套完善的仿制药管理体系。本文将通过FDA现行法规与指南讨论首仿药的定义与申报流程。
△来源：百度
The Drug Price Competition and Patent Term Restoration Act of 1984 (the Hatch-Waxman Amendments) to the FD&C Act established the ANDA approval pathway for generic drugs. In 2003, Congress enacted the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA), among other things, substantially revised certain statutory provisions related to 180-day exclusivity. In Sep. 2011, IPR (Inter Partes Review) has been raised in America Invents Act (AIA), which is a new way to resolve the patent disputes conveniently, FDA has gradually developed a comprehensive generic drug management system, this article will discuss the definition and application process of first generics based on the current FDA regulations and guidelines.
首仿药 First generics
“首仿药”顾名思义-即首个获得FDA批准上市销售的仿制药。正如“Proposed Criteria for First Generic Submissions for Purposes of ANDA”描述，首仿药可以是任何一个满足以下条件的ANDA：
1. 第一个递交符合获得180天独占权条件（满足该条件的首仿药可以是单个，也可以是一批），或不受到专利/独占权限制的ANDA；
2. 该品种无已获批的ANDA。
△来源：pixabay
“First generics” are just what they sound like—the first approval by FDA which permits a manufacturer to market a generic drug product in the United States. As outlined in the Proposed Criteria for First Generic Submissions for Purposes of ANDA, a first generic application is any received ANDA: (1) That is a first-to-file ANDA eligible for 180-day exclusivity (If only one such ANDA is filed on the first day, there is only one first applicant; if two or more such ANDAs are filed on the first day, the ANDA applicants share first-applicant status), or for which there are no blocking patents or exclusivities; and (2) for which there is no previously-approved ANDA for the drug product. [1].
△首仿药申请流程 Application Process of First Generics
专利声明及独占权Patent Certifications and Exclusivities
仿制药企业在递交ANDA时，必须针对Reference Listed Drug (RLD) 登记在橙皮书中的所有专利做出以下4种声明之一：
Generic drug applicants must include in an ANDA a patent certification described in the act for each patent listed in the Orange Book for the reference listed drug. The applicant must certify one of the following for each patent [2]:
对于PI、PII声明，专利问题不会影响ANDA的批准；递交PIII声明，则表示申请人同意待原研药物相关专利到期后，临时批准转为正式批准。如果申请人希望在专利到期前通过专利挑战来获得ANDA批准上市，即声明该仿制药不会侵犯专利或该专利无效，则必须递交PIV声明给FDA。
If an applicant submits a paragraph I or II certification, the patent in question will not delay ANDA approval. If an applicant submits a paragraph III certification, the applicant agrees to wait until the relevant patent has expired before seeking final approval of its ANDA. If, however, an applicant wishes to seek approval of its ANDA before a listed patent has expired by challenging the validity of that patent, by claiming that the patent would not be infringed by the generic drug product proposed in the ANDA, or by claiming that the patent is unenforceable, the applicant must submit a paragraph IV certification to FDA[3].
△来源：百度
ANDA申请人在提出PIV声明时，必须在提出申请后通知NDA持有人以及所有专利持有人，告知NDA持有人以及所有专利持有人其已向FDA提交了ANDA申请以及PIV声明的详细信息。如需对PIV声明做出回应，专利持有人应在收到该通知45天内向法院提出专利侵权诉讼，则启动30个月遏制期（自任意专利持有人或NDA持有人收到通知之日起，或法院要求的其他时间）；若专利持有人未在45天内提出专利侵权诉讼，则默认为仿制药不侵权。在30个月遏制期内，FDA将会继续审查申请人的ANDA，ANDA符合要求将给予临时批准。如果诉讼判决专利无效或仿制药不构成侵权，则在判决生效之日临时批准转为正式批准，允许上市并获得180天市场独占权。
An applicant submitting a paragraph IV certification to a listed patent must provide the NDA holder and each patent owner with notice of its paragraph IV certification, including a description of the legal and factual basis for the ANDA applicant’s assertion that the patent is invalid, unenforceable, or will not be infringed. In response to notice of a paragraph IV certification, the patent owner or its representative or the exclusive patent licensee initiates a patent infringement action against the ANDA applicant within 45 days of receiving the required notice, approval of the ANDA generally will be stayed for 30 months from the later of the date of receipt of the notice by any owner of the patent or the NDA holder or such shorter or longer time as the court might order. If the patent holder does not initiate a patent infringement action within 45 days, it is assumed that the generic drug is not infringing. During the 30-month stay, the FDA will continue to review the dossier ANDA dossier, and tentatively approval will be granted for the dossier that meet the requirements. If the patent is invalid or that the generic drug is not infringing, the tentatively approval will be converted to formal approval on the effective date of the judgment, allowing for listing and obtaining a 180-day period of exclusivity.
180天独占权触发 180-day exclusivity trigger
FD&C法案规定，任何首仿药申请人的首次商业销售行为（包括销售已上市同品种药物）均会触发180天独占权。FDA对 “包括销售已上市同品种药物”进行了进一步解释，即使首仿药申请人的ANDA尚未获得批准，其商业销售已上市同品种药物的行为仍会触发180天的独占权。
The FD&C Act provides that the 180-day exclusivity period is triggered by “first commercial marketing of the drug (including the commercial marketing of the listed drug) by any first applicant.” FDA has interpreted the statutory phrase “including the commercial marketing of the listed drug” to provide that exclusivity can be triggered by the marketing of an authorized generic by a first applicant, even if that first applicant’s ANDA has not yet been approved [4].
△来源：pixabay
180天的独占权在首仿药申请人商业销售授权仿制药或RLD时会被触发，可以防止NDA持有人与首仿药申请人之间串通破坏既定法规。如果180天的独占权仅在首仿药申请人的ANDA产品商业销售时被触发，则首仿药申请人与NDA持有人达成协议，对授权仿制药或RLD进行商业销售，而不销售其ANDA产品，将会在专利到期前阻止后续ANDA的批准。
Concluding that 180-day exclusivity is triggered upon the first applicant’s commercial marketing of an authorized generic or the RLD prevents potential subversion of the statutory scheme through collusion between NDA holders and first applicants. If 180-day exclusivity were triggered only by commercially marketing the first applicant’s ANDA product, a first applicant that struck a deal with the NDA holder to commercially market the authorized generic or RLD instead of marketing the product described in its ANDA potentially could block approval of subsequent ANDAs until patent expiration.
180天独占权失效 Forfeiture of 180-day Exclusivity
1. 因未开展销售而失效（首仿药申请人未能在获批后75天或ANDA申请递交后30个月（以较早的日期为准）开展销售的，会丧失180天独占权）；
2. 因ANDA撤回后失效；
3. 因改变专利声明类型而失效；
4. 因未获得FDA临时性批准而失效，（申请人在ANDA递交后的30月内未获临时性批准的丧失180天独占权）；
5. 因与其他ANDA申请人或已上市药物持有人或专利持有人达成协议而失效；
6. 因PIV声明相关专利到期而失效。
1. Failure to Market Forfeiture Provision (if the first applicant fails to market the drug by the later of the earlier of the date that is 75 days after the date on which the approval of the application of the first applicant is made effective; or 30 months after the date of submission of the application of the first applicant);
2. Withdrawal of Application Forfeiture Provision;
3. Amendment of Certification Forfeiture Provision;
4. Failure to Obtain Tentative Approval Forfeiture Provision (the application within 30 months after the date on which the application is filed);
5. Agreement with Another ANDA Applicant, the Listed Drug Application Holder, or a Patent Owner;
6. Expiration of All Patents Forfeiture Provision.
参考文献
[1]：Proposed Criteria for First Generic Submissions for Purposes of ANDA.
[2]：Small Business Assistance: New 180-Day Generic Drug Exclusivity Regulations.
[3]：ANDA Submissions – Amendments and Requests for Final Approval to Tentatively Approved ANDAs Guidance for Industry.
[4]：GUI FINAL Requests for Final Approval to Tentatively Approved ANDAs RPMS 9 25-20 1.
供稿人：胡荣荣 虞富龙
END
关于诺泰生物
诺泰生物（股票代码：688076）
2009年成立，2021年科创板上市
聚焦多肽药物、小分子化药
战略布局寡核苷酸药物
自主研发和CDMO业务相结合
总部及研究院位于浙江杭州
在连云港市及杭州建德市分别拥有生产基地
中科院专家领衔，海归博士为骨干的研发团队
建有博士后工作站
今天因为你的分享，让我元气满满！