BPCIA在2010年三月生效後，生物相似藥廠商開始可以利用簡化的文件向美國食品和藥物管理局（FDA）申請藥品許可證，這個新醫療法賦予FDA決定如何落實法案的權力。基於不同生物製劑之間缺乏比較性這個已知的事實，加上公眾安全的考量，在還沒有累積大量經驗可以歸納出哪些是比較分析必要的資訊之前，FDA會保守的要求生物相似藥廠商以BPCIA提出申請時，必須提供臨床試驗資料來證明與參照藥品之間沒有臨床上有意義的差異。 雖然BPCIA給出了解決專利糾紛的框架，俗稱專利舞蹈(patent dance)，依照目前聯邦巡迴上訴法院對BPCIA的解釋，認為BPCIA法案不強制生物相似藥申請者遵循其規定之專利糾紛解決程序，雖然就目前的最新發展來看，迴避專利舞蹈可以避免一些程序上的麻煩，但真正參照藥品廠商和生物相似藥公司的輸贏仍是在訴訟戰場上見真章。 美國FDA在2015年3月6日核准了的一個生物相似藥-Zarxio( filgrastim-sndz)，目前尚不清楚均等論這種不確定性在生物相似藥上影響的程度，但藉由簡化新藥申請上市的小分子藥物所涉入的侵權訴訟做有限度的推論可以發現，小分子藥物的均等謬論案件是牽涉到外圍專利，當專利不再提供足夠的誘因去激勵專利權人時，學名藥廠商就會贏得均等論謬論案件。因為生物製劑是一種製程決定的產物，因此其專利通常是集中在製程。以BPCIA和專利法為框架來分析過去的相關侵權訴訟，可以預測生物相似藥廠商在轉化前步驟、轉化步驟、調劑、或包裝做改變，其成功的機會較大，而在細胞培養會純化步驟做改變，成功的機會最小。然而，最終還是要看法院將來如何解決生物相似藥的侵權問題，各方都要意識到科學與法律議題的複雜性，及妥適解決侵權訴訟的重要性。 台灣廠商要進入生物相似藥的領域，是困難重重的。生物相似藥的開發及法規成本，不如想像中低，鑒於蛋白質藥『產能』一直被看作是市場發展受阻的主要原因，藥廠委外合作(CRO、CMO或NRDO) 的模式能快速與國際藥廠接軌，逐步奠定台灣在藥物開發的供應鏈合作利基並提昇國際知名度。 / The Biologics Price Competition and Innovation of 2009 was activated on March in 2010. Now the US Food and Drug Administration (FDA) can approve biosimilars and was empowered to how to practice. Given the known issues with lack of comparability between different biologics preparations, and the Agency’s strong interest in protecting public safety, it is probable that, until it has developed a body of experience with regards to the amount and kind of data needed to make comparability evaluations, the FDA will adopt a conservative approach and require at least some clinical studies before approving biologics under BPCIA. Though BPCIA provide the frame for resolving patent issues, that is so-called patent dance, Federal Circuit said that parties were not compelled to dance. Thus the law uncertainty was shifted to patent infringement. FDA approved the first biosimilar, Zarxio (filgrastim-sndz), on 6, March, 2015. It is unclear how biosimilar will be treated in court based on doctrine of equivalence. Based on the experience from generics, courts tends to adjust the scope of equivalents to improve the correspondence between patent scope and desired patent incentives. In contrast, biologics is path depended. That is to say process decided what biologics would be. Both the BPCIA and patent law guide the shape of infringement suits. Follow-on biologics companies will be most successful when they make a change in the pretransformation process, the transformation process, the formulation, or the packaging. They will be least successful when they make a change in the cell culture conditions or the purification process. It remains to be seen how courts will address issues of infringement for follow-on biologics, but all parties should be aware of the complexity of the scientific and legal issues and the importance of addressing them properly. The cost for development and the complexity of regulation in biosimilars were tremendously high. Thus it is difficult for biopharmaceutical industries in Taiwan to enter this field. In the light of unmet production capacity in protein drug, pharmaceutical industries in Taiwan could apply the mode of CRO, CMO or NRDO to integrate into global biopharmaceutical community.

生物藥品是很多先前具致命性和難以治療的疾病領域，像是癌症、自體免疫疾病及神經系統疾病內最被看好的現行新穎療法。近年來，隨著探索出突破性小分子藥物愈趨困難，加上生物藥品在新藥研發過程中有較低的折損率與較高的成功產出率，使得越來越多藥廠紛紛轉向開發利潤豐厚的大分子生物產品。此外許多暢銷生物藥品專利期即將屆至，從而帶來對相對價廉、通常被稱為原廠生物藥品仿製版本之「生物相似性藥品」的龐大治療需求。然而，由於生物藥品和小分子藥物在分子大小及結構複雜程度方面存在截然不同的特性與本質差異，因此建立一套專屬於生物相似性藥品的上市許可規範勢在必行。 作為於2010年3月23日正式簽署公告之「患者保護及可負擔照護法案」中的一部分，美國國會通過了「生物藥品價格競爭與創新法」(BPCIA)。BPCIA的生效被視為製藥產業最重要的變革之一，旨在藉由競爭達到維護公眾健康、促進生物技術創新和控制醫療支出之目的，同時取得適當之三方利益平衡。BPCIA即以Hatch-Waxman法案下的化學學名藥核准途徑為模版，創建生物藥品簡易上市申請程序。 本論文的結構主要區分為兩大部分進行研究，其一提供了製藥產業概觀與全球生物藥品市場的發展趨勢，其二則聚焦在BPCIA新建立的核准前專利爭端解決程序下，生物相似性藥品面臨「專利舞蹈」時的法律評估及智慧財產權管理。 論文的第一部分係根據從各種市場研究報告收集、整理而成的統計數據，以系統性的方式深入介紹全球製藥產業，並分析生物相似性藥品的市場機會和潛在隱憂。另外此部分亦詳細說明了生物相似性藥品的生理活性、知識斷層與製程依賴性之間的關係、分析技術對生物產品做完整定性的不足以及生物相似性藥品的開發流程。 論文的第二部分則以討論BPCIA的重要條文規定為主，包括專利舞蹈制度和上市審查要求，諸如生物相似性之證明、可互換性之認定與適應症外推。其他相關議題，包含參考藥品的法定專屬權保護期長度、生物相似性藥品自動替換之立法化、專利資訊交換機制的可能濫用及原廠與生物相似藥廠達成反競爭協議之風險皆會予以進一步探討。除此之外，本部分也介紹了歐盟和台灣生物相似性藥品上市法規的沿革與現況。 本文試圖透過對生物相似性藥品的全方位綜合研究成果，提出可行的市場進入方案及善用專利和營業祕密優勢之智慧財產權保護佈局策略。 / Biologics represent many of the most promising novel therapies for previously deadly and intractable disease areas like cancer, autoimmune disease and neurological disorders. As discovery of breakthrough small-molecule drugs becomes more difficult, together with lower attrition rate and higher productivity of biologics in the new drug research and development (R＆D) process, pharmaceutical companies are increasingly turning to develop lucrative large-molecule biological products in recent years. In addition, the patents on numerous blockbuster biologics treatments will soon expire, bringing soaring demand for relatively inexpensive generic versions of originator biologics, generally known as “biosimilars.” However, due to contrasting characteristics and natural differences in terms of size and structural complexity between biologics and small-molecule drugs, it is necessary to create a regulatory pathway solely for biosimilars. As part of the Patient Protection and Affordable Care Act which was officially signed into law on March 23, 2010, the U.S. Congress passed the Biologics Price Competition and Innovation Act (BPCIA). The BPCIA is considered one of the more significant overhauls to the pharmaceutical industry, aiming to strike a proper balance among securing public interests, stimulating biotechnology innovation and controlling healthcare expenditure through competition. It established an abbreviated approval pathway for biosimilars modeled closely after the Hatch-Waxman Act’s approval process for generic chemical drugs. The structure of this thesis is divided into two major parts, of which the first part provides an overview of pharmaceutical industry and trends in the global biologics market, whereas the second part focuses on the legal assessment and intellectual property management of biosimilars under BPCIA’s new pre-approval patent dispute resolution process, the “patent dance”. The first part starts from the in-depth systematic introduction of global pharmaceutical industry based on statistics collected from various market research reports, then analyzes the market opportunities and potential concerns for biosimilars. Moreover, this part illustrates the physiological properties, the relationship between “knowledge gap”and manufacturing path-dependence, the insufficieny of analytical techniques in fully characterizing biological products, and the development process of biosimilars in details. The second part discusses key provisions of the BPCIA, including the patent dance procedures and regulatory requirements, such as demonstrating biosimilarity, interchangeability and extrapolation. Other relevant issues include the length of statutory exclusivities granted to reference products, legislations on biosimilar automatic substitution, potential abuses of patent information exchange mechanism and risks of reaching anti-competitive agreements between pioneers and biosimilar manufacturers will be further discussed. Besides, this part describes the timeline and status quo of EU and Taiwan’s biosimilar approval regulations. With comprehensive study on multiple aspects of biosimilars, this article tries to propose feasible market access plans and robust intellectual property protection strategies capitalizing upon patents and trade secrets.