University of Macau / Institute of Chinese Medical Sciences

本論文研究主題係針對生物技術專利的要件的探討外，更探討跨學科領域的結合所形成的專利制度，如何透過實務的見解來具體化專利的要件，本文希望嘗試透過探討法律層面的專利取得要件及專利審查基準的認定外，更進一步希望透過法院實務的見解，來具體化專利要件之內涵，架構其中一段完整生物技術專利要件之評估，除作為本論文探討的具體內容。

知識經濟時代的來臨，代表知識早已經取代勞力、土地、資本，成為最重要的生產要素，而知識創造的具體果實就是智慧財產，此項無形資產占企業財產的重要性已遠超過有形資產。個人、企業和國家唯有專注在智慧財產的創造、保護、管理和運用上，方可成為知識經濟下的大贏家。 近年來，隨著人類科學知識與生活智慧的增長與演進，與人類日常生活和生命安全息息相關的生物醫學技術日益突破且其重要性與日俱增，國際間生技產業發展迅速，並帶領生技產業走向多元化的發展；除此之外，生技產業也是台灣兩兆雙星計畫中所追求的新興產業之一。然而，台灣在這股趨勢洪流中，整體生技產業的發展上並不蓬勃。歸根究柢，生技產業乃為典型的高附加價值、知識導向型產業，智慧財產的重要性不言可喻並且更加突顯。智慧財產如同其他企業資產一樣，需要善加管理與運用才能發揮其價值，若企業擁有大量之智慧財產，但對該智慧財產欠缺有效之管理運用，亦無法為公司創造任何價值。因此，如何為智慧財產尋求正確的運用管道，應是智慧財產所有人最為關心的議題。由於生物技術產業十分重視技術的掌握與應用，故本論文研究將焦點放在與技術知識保護有關的「專利授權與技術移轉」上，並特別針對屬於智慧財產行銷管理層面的策略進行探討。 《時代》雜誌年度風雲人物華裔科學家何大一曾說過要用人才賭生技，其需要的是什麼樣的人才?又該如何賭?本論文研究希望能提出相對應之見解，藉由個案研究方法分析找出台灣生技企業在「專利授權與技術移轉」上的策略思考邏輯，並更加釐清智慧財產行銷管理對產業發展影響的角色與位置。 由於台灣生物技術公司目前本身先天條件不佳且資源不足，無法透過商品化與產業化之智慧財產實施方式來創造最大利益，因此透過智慧財產交換方式乃是其最佳模式，而考量相關環境條件後，其中又以「專利授權與技術移轉」為最具經濟效益且最可能成功之智慧財產商業模式與型態，因此本論文研究便針對此方面進行深入探討，以提供產業後續發展之參考借鏡。 本論文研究目的包括：1.探討推動台灣生物技術產業公司發展過程中，考量「專利授權與技術移轉」的重要因素。2.瞭解台灣生物技術產業公司目前在「專利授權與技術移轉」方面的運作機制。3.介紹台灣生物技術產業公司之指標性個案，分析其智慧財產行銷策略，歸納其關鍵成功因素，以茲其他業者參考。4.了解智慧財產行銷策略的核心結構，提出智慧財產行銷策略規劃上的建議。5.綜合研究結果，提出對台灣生物技術產業公司「專利授權與技術移轉」策略之建議，並分析該產業之潛在問題與可能限制。 本論文研究提出理論強調台灣生物技術產業公司必須考量智慧財產行銷的六大要素(6P)，以『主導產業鏈』、『控制價值鏈』、『分配供應鏈』等三鏈為目標，因而決定採取「專利授權與技術移轉」之正確的智慧財產商業模式後，站在目標被授權人的立場思考，透過「策略九說」來作檢驗，以找出最適合的智慧財產行銷之執行策略，並在執行時確實考量組織行銷之特性。 本論文研究方式採用個案研究法以及質化研究法，獲得以下結論： 1. 「專利授權與技術移轉」必須著重於專利品質，以更貼近產業與市場需求，進而強化技術移轉之成效。 2. 「專利授權與技術移轉」是屬於相當複雜且專業性高的領域，與市場互動至關密切。 3. 任何產業的任何公司當其智慧財產行銷策略之方向目標正確，且手段方法合理，則成功便是可以預期的。 4. 一旦擬定正確的智慧財產行銷策略，則後續的執行力，便成為是否成功之唯一重點。 / The coming of Knowledge-based Economy Era indicates the fact that knowledge had taken the place of labor, land and capital to become the most important production factor. The results of knowledge creation are Intellectual Property (IP). The Intangible Assets are much more important than Tangible Assets for industries in nowadays. It becomes crucial for individuals, industries, and countries to achieve success in the Knowledge-based Economy Era to concentrate on the creation, protection, management and application of intellectual property. In the recent years, because of the developments of scientific knowledge and life wisdom, the progress and importance of the biomedical technology which closely related to human life and safety advances rapidly. Besides, the biotechnology industry is also one of the booming industries of Taiwan “Two Millions, Two Stars” projects. However, the Taiwan Biotechnology Industry does not follow the trend well. The biotechnology industry is a typical high value added and knowledge oriented industry, and the importance of IP is much more distinct. Same as other corporation’s property, intellectual property needs to be managed and put to use well to manifest its value. If a corporation owns a lot of IP without effective management and application, none value or benefit will be produced for the corporation from the IP. Therefore, for the IP owner, how to find out the correct application ways of IP will be the most important concern. Since technology familiarity and application is a highly emphasized issue for biotechnology industry, this study will focus on the technology knowledge protection concerning “Patent Licensing and Technology Transferring,” especially on the IP Marketing Management Strategy. David Ho, a Chinese American scientist and the Man of the year 1996 of “Time” magazine, once said that “we have to bet on biotechnology with talents”. The question is what talents are needed, and how to bet? This study aims to provide some corresponding thoughts and find out the strategy of “Patent Licensing and Technology Transferring” for Taiwan biotechnology corporation through case study. Furthermore, the study will manifest how IP Marketing Management will influence industry development. Due to the immature company structure and small business size of Taiwan biotechnology corporations, these corporations are unable to create the best profit through IP commercialization or industrization. Thus, the best model for them will be through IP Exchange and the “Patent Licensing and Technology Transferring” will be the most effective and feasible IP Business Model given the conditions of Taiwan biotechnology industry. This thesis will concentrate on this aspect and provide advices for industrial developments. The purposes of this study include: a. the important factors and the significnace of “Patent Licensing and Technology Transferring” in the promotion of Taiwan biotechnology corporation development; b. the current mechanism of “Patent Licensing and Technology Transferring” of Taiwan biotechnology corporation; c. a case study of Taiwan biotechnology corporation, including the IP Marketing Strategy analysis and the key successful factors as reference for other corporations; d. the core structure of IP Marketing Strategy and IP Marketing Strategy planning; and e. strategy suggestions for “Patent Licensing and Technology Transferring” and the potential problem analysis of the industry to Taiwan biotechnology corporation. This study proposes that the Taiwan biotechnology corporation must put the 6P factors of IP Marketing into consideration and target to dominate Industry Chain, to control Value Chain, and to allocate Supply Chain. They should also take the correct IP Business Model of “Patent Licensing and Technology Transferring”, and then think in the position of the targeted licensee through the examination of “9 Theories of Strategy” to find out the most suitable IP Marketing strategy. They should also take the characteristics of “Organizational Marketing” into consideration in practice. This study comes to the conclusions below with case study and qualitative methods: a. The quality of patents is always important in “Patent Licensing and Technology Transferring” to meet the industry and market demand and thus to reinforce the technology transferring achievement. b. “Patent Licensing and Technology Transferring” is complicated, highly professional and closely related to the market. c. The success of any corporation of any industry lies on a correct IP Marketing Strategy and a legitimate method. d. Once the correct IP Marketing Strategy is settled, the only key factor to success will be how to enforce the strategy.

有鑑於生物科技成為科技趨勢，以及其創造出的龐大價值，近年來台灣也開始大力推動生技產業的發展。產業是企業的組合，企業的成長與否正是驅動產業生態變化的主要原因。本研究主要探討台灣生技藥物研發公司的創業過程，希望透過研究成果對台灣生技公司的發展有所貢獻。 　　本研究的研究架構以Timmons Model做為主軸，以機會、資源、團隊做為主要的研究構面，先對個案公司進行靜態的研究構面探討，然後分析其發展的動態平衡過程。 / Because biotechnology sets a trend and creates great value, Taiwan government tries to develop his own biotechnology industry. However, an industry will bloom if most of companies related to the industry are operated well. The objective of this study is to observe and analyze the entrepreneurial process of biomedical R&D companies in Taiwan. 　　The research bases on Timmons Model that was developed by Timmons for analyzing an entrepreneurial process of a company and consists of three driving forces, opportunity, resource, and team. Every entrepreneurial process of companies in the thesis is observed first according to the three driving forces. Then it is analyzed by using the idea of constant balancing.

生物科技為目前世界各國極力投入之新興產業，此產業無需大量天然資源及低污染的特性，同時又能解決人類的醫療問題並提昇生活水準的未來發展空間，更使得此一新興產業吸引了眾人的眼光。 　　本論文提出一個評估的模式，讓此產業之技術、產品或專利之價值能夠經系統化的分析後完整呈現，並可基於此分析結果作出策略上之判斷，並以GnRH vaccine技術為例。因為GnRH分子之序列早已發表，經本研究分析得兩種常用的專利保護策略，第一種是將GnRH與不同的載體進行結合，而新生成一個嵌合化合物，並申請此新化合物之專利；第二種是進行GnRH分子結構上之改變以取得新序列的專利保護，取得效果優於自然設計之分子，或藉以增加與免疫載體之結合率。經分析後發現，GnRH疫苗應用理論已經相當成熟，未來幾年應該會有成熟產品通過上市之審核過程；再隨著新科技的進步，可預期將會有更多的新產品會上市，而進一步地有效提昇產品功效並降低製造成本。 　　本研究最後針對GnRH未來在人用藥品及動物用藥之未來市場加以分析，並對於以重複免疫原在重組型疫苗製備法之開發提出行銷、財務、通路、價格、推廣、臨床實驗之建議，以期能經由策略規劃的角度將生物技術的價值作最大化的管理。 / Biotechnology attracts high attentions among many countries recently. New biotechnology will provide a key solution to cure diseases and potentially will be able to increase human life quality without damaging the environment and consuming massy natural resources. 　　In this thesis, we presented a possible process, which involved in academic, marketing and patent information analysis, to effectively evaluate the feasibility and potential of any novel biological technologies, so as to provide the managerial and strategic suggestions based on the analysis. GnRH repeat immunogens vaccine development was taken as an example to demonstrate if the proposed process can be executed adequately. After discretly cross examining the collected information, we concluded that many independent GnRH vaccine patents are available but will not be effective enough to stop to new competitors to get in this sector because GnRH sequence was disclosed in very early research and nobody held the patent for it and most of GnRH patents were granted to either different GnRH-Carrier chimeras or the GnRH analog sequences. Analysis results show that there is only one company closely approaching the final product approval at this moment. However, any improved technology can easily employed to provide a better product with higher effectiveness and lower cost following the first product's upcoming marketing clearance and then make the future market very complicated. 　　Based on those findings, we further analyze the Taiwanese current environment and provide a few managerial suggestions to maximize the value of a novel GnRH vaccine preparation technology.

隨著產品生命週期的縮短，大量的廢棄物對人類生存環境開始造成威脅，各國開始正視廢棄物管理的議題，紛紛立法來規範廢棄物的回收管理。企業為了成本、企業形象、法律規定等因素開始將逆物流(reverse logistic)納入其營運規劃。但在逆物流資訊難以取得以及具備大量的不確定因素下，許多企業選擇將逆物流外包給專業的逆物流業者，以專注在其核心能力之上。 在單純的外包模式下，企業時常面臨回收商無法穩定供給再生物料之問題，若再生物料使用比率無法達到法規要求，則需繳納高額的回收規費，部分企業甚至以新產品分解為新再生物料來補足再生物料短缺以迴避高額的回收規費；回收商則會面臨企業再生物料需求數量不穩定或是數量不足，單次運輸成本大幅提高，使其表現出只願回收退回商品取得回收補貼，但不分解販售再生物料，而是堆放退回商品於集散處的傾向。 本研究提出一綜合回收商及製造商之緊密營運模式，考量連續時期、利潤共享的條件下，建立一數量決策模型，以整體利潤最大化為目標，探討不穩定因素下之每期穩健再生物料分配決策。因應大環境之不穩定因素，將以建構情境為基礎之穩健最佳化模式求得穩健解。 / In recent year, enterprises consider reverse logistic in their processing because of cost, corporate image and government policy. But there are lots of uncertainty factors in the reverse logistic, in order to focus on enterprise’s professional skills, more and more enterprises outsource their reverse logistics. Both enterprise and professional reverse logistic processor have to spend more costs to keep their cooperation in recent outsourcing model. Thus, this thesis builds a model which combine enterprise's business model and professional reverse logistic processor's business model. In this model, assumes that profit should be share between both of them, and apply Robust optimization methods to solve uncertainty factors in reverse logistic. The thesis finds out the best distribution ratio of regeneration materials in each period.

University of Macau / Faculty of Education

在生態學與生物學上，物種數常作為生物多樣性的指標，以估計單一群體物種數為例，較知名的方法首推Good (1953)以在樣本中出現一次的物種為基礎，提出的物種數估計方法堪稱的先驅，隨後許多文獻延伸Good的想法，發展出許多的估計方法，例如Burham and Overton (1978)的摺刀估計法，Chao and Lee (1992)則以涵蓋機率方式估計。相對而言，兩群體的共有物種數的研究少有人探討，目前以Chao et al. (2000)的估計式較為知名。 本研究參考Good (1953)提出估計未發現物種出現機率的想法，估計未發現共有物種的機率，並以Burham and Overton (1978)中應用摺刀法估計物種數的概念，建立一階摺刀估計式與變異數，且另行以多項分配公式推導變異數估計式，進行電腦模擬與實際資料驗證並與Chao et al. (2000)提出的共有物種估計式比較。最後根據Rasmussen and Starr (1979)以抽樣成本建立最適停止規則的概念，應用於本研究所提出的估計式，並經由電腦模擬找出抽樣成本與物種分佈均勻程度的關聯，可作為設定停止規則的依據。 / The number of species is often used to measure the biodiversity of a population in ecology and biology. Good (1953) proposed a famous estimate for the number of species based on the probability of unseen species. Subsequently, many studies applied Good’s idea to create new estimation methods, For example, the Jackknife estimate by Burham and Overton (1978), and the estimate by using the sample coverage probability in Chao and Lee (1992) are two famous examples. However, not many studies focus on estimating the number of shared species of two populations, except the method by Chao et al. (2000). In this study, we modify Good’s idea and extend the Jackknife method of Burham and Overton (1978) to develop the estimate for the number of shared species of two populations. In addition, we also establish the variance formula of the estimator by using the multinomial distribution. Subsequently, we use computer simulation and real data sets to evaluate the proposed method, and compare them with the estimator by Chao et al. (2000). Finally, we adapt the idea of optimal stopping rule by Rasmussen and Starr (1979) and combine it with the proposed jackknife estimate. We found that using the sampling cost as the stopping rule is a feasible approach for estimating the number of shared species.

生物科技產業，是一個被預期將於未來使人類在醫學、製藥、材料、糧食乃至於能源、生態等各方面所面臨的問題，獲得重大突破的產業；也是被公認為二十一世紀最具發展潛力的重點產業！世界上各個先進國家莫不競相投入大量資源，積極進行生技產業的培植與發展。研究單位與大專院校，一向被稱為所謂的「知識引擎」。照理說，在良好的智財管理之下，理當成為智慧財產生產之重鎮，並經由技術轉移實際地應用在產業界，協助提昇企業的競爭力，進而強化國家整體的經濟能量。 本研究藉由各方相關之文獻、著作加以分析，先從美國與我國在科技或技術移轉相關法規的介紹，再整理生物技術與生技製藥產業的特性，和我國目前的現況與問題，最後由商品化角度歸納出技術移轉在各階段的組成要素，再參考美國麻省理工學院技術移轉中心實例。與國內產學成功之案例-「寶齡富錦PBF1681專案」及「陽明大學新藥中心」對照，從中比較出國內學校與產業之間的交流，哪一環節出了問題？在探討我國大學生技製藥產學合作機制上，本研究採用的架構主要是從國內外大學負責產學合作單位的「運作流程」開始瞭解在智慧財產權、技術推廣、技術移轉過程與移轉後的回饋監控機制等。 交相比較之後，建議國內大學之技術移轉中心需擬定明瞭易懂之政策 設計簡單易填之表格、重視商品化流程、經驗豐富之授權人才引進、設置「成功故事」區，來激勵想要新創公司之人。另外，也對國內生技製藥產業建議，台灣的切入點以植物藥為迅速且花費少、成功機會高，這是值得投入之領域。而產業之結構也應有所調整，台灣藥廠規模小，無法與國外大廠競爭開發新藥。開發新藥需投入大量時間及金錢，故國外藥廠之產業結構為垂直整合，亦即是將上市前所有試驗及上市後行銷一手包辦。國內藥廠需仿照科技業一般，將整個產業作水平分工，將核心能力保留，其餘皆可外包。這樣不但節省時間，也可減少對不熟悉領域之摸索，由仿製之學名藥廠，走向新藥開發，進而與國外大廠相互抗衡。 / The universities are long taken as the “knowledge engine” for industries. Through a well-designed cooperation or licensing system, that is, the academic-industry liaison, those intellectual property produced from academic researches should be applied in the industry and industrial competency can thus be improved. However, the academic-industry liaison concerning biotechnology and drug in Taiwan is deficient. This thesis compares the cases of “Panion & BF Biotech Inc. PBF1681 Project,” “Research Center for Drug Discovery in National Yang-Ming University” in Taiwan with the Technology Licensing Office (TLO) of MIT in the U.S. Through the comparison, it can be found that techonology transfer office of universities in Taiwan needs to design a more friendly procedesure for licensee applicants and focuses on technology commercialization. Moreover, the pharmaceutical industry needs to invest more in herbal drug development. The industry itself needs corporate reengineering. The structure of the industry should be a horizontal division instead of the vertical integration. They should focus on their core competency and strengthen the mutual cooperation between companies to form a network of efficient production divisions. Key word: academic-industry liaison, biotechnology, drug discovery, pharmaceutical, Technology Licensing Office (TLO)

摘 要 本研究主要是探討利用新式生物反應器以固定化細胞培養技術生產日本腦炎病毒(Japanese encephalitis virus；JEV)之研究，首先根據所培養細胞的生長特性與原有生物反應器之缺點，利用已改良設計之新式生物反應器，評估此新式生物反應器適用性、效能，以及所培養細胞之生長代謝情形與病毒力價。整個實驗過程大致分為幾個階段，第一個階段探討細胞固定化培養之最適化培養條件與生長代謝情形，第二個階段找出細胞固定化培養於此新式生物反應器中最佳生長狀態，最後一個階段為病毒的培養。實驗後發現Vero細胞經固定化貼附於FIBRA-CEL®載體上，可擴大培養於新式生物反應器，Vero細胞最佳生長量達到6.6×106cells/mL。希望藉由此改良之新式生物反應器提供細胞與病毒一個良好之生長培養環境，獲得高產量、品質穩定一致之細胞生物製品，以提供ㄧ設備簡單與製程操作容易、低成本、低能源消耗之細胞製品生產基座。 / Abstract In this study, we investigated the production of Japanese encephalitis virus (JEV) by the immobilized cell technology in a novel bioreactor. According to the disadvantages of original bioreactor and growth characteristics of cell culture, we evaluated the suitability and efficiency of a design-improved novel bioreactor as well as the growth and metabolic situation of cultured cells and titers of JEV. All studies including three major stages: (1) investigation of the optimal conditions and metabolic situation for the growth of immobilized cells, (2) finding the optimal conditions for the growth of immobilized cells in this novel bioreactor, and (3) growth of JEV using immobilized cells in this novel bioreactor. Our results showed that after immobilization on the FIBRA-CEL® carries, Vero cells can grow on the novel bioreactor up to the density of 6.6 × 106 cells/mL. Hopefully, the improvement of the novel bioreactor will provide an optimal growth condition for both the cells and viruses. Furthermore, it will also provide the basis for the production of cell products with advantages of simple-equipped, easy-to-operate, low cost, and low energy consumption. / 目 錄 誌謝------------------------------------------------- i 中文摘要 -------------------------------------------- ii 英文摘要 -------------------------------------------- iii 目錄 -------------------------------------------- iv 表目錄 -------------------------------------------- v 圖目錄 -------------------------------------------- vi 第一章 緒論---------------------------------------- 1 第二章 文獻探討------------------------------------ 3 第一節 日本腦炎病毒疫苗---------------------------- 3 第二節 動物細胞的培養------------------------------ 4 第三節 載體上動物細胞的培養------------------------ 5 第四節 動物細胞培養於生物反應器-------------------- 7 第三章 材料與方法---------------------------------- 10 一 細胞株的培養-------------------------------- 10 二 細胞冷凍保存與解凍培養---------------------- 10 三 細胞滾瓶培養-------------------------------- 11 四 病毒株的培養-------------------------------- 12 五 固定化載體材料製備-------------------------- 12 六 載體上細胞數的測定-------------------------- 12 七 細胞貼壁率的計算---------------------------- 13 八 生物反應器結構特性與固定化細胞培養---------- 13 九 日本腦炎病毒力價測定------------------------ 19 十 葡萄糖的測定-------------------------------- 19 第四章 結果與討論---------------------------------- 20 一 固定化載體材料比例對Vero細胞生長的影響------ 20 二 細胞貼附固定化時間對Vero細胞生長的影響------ 23 三 細胞接種量對Vero細胞生長的影響-------------- 24 四 生物反應器培養系統對Vero細胞生長的影響------ 25 五 新鮮培養基更換對Vero細胞生長的影響---------- 27 六 最適化細胞生長條件培養日本腦炎病毒---------- 29 第五章 結論與建議---------------------------------- 30 參考文獻 -------------------------------------------- 31 附錄一 PBS配製方法--------------------------------- 62 附錄二 Medium 199配製方法-------------------------- 62 附錄三 MEM medium配製方法-------------------------- 62