美國藥物專利布局與其相應之研究開發與法規活動 - 以諾華藥廠之Gleevec®為例 - 政大學術集成

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(1)國立政治大學科技管理與智慧財產研究所碩士論文. Drug Patent Deployment in the United States of America with the Corresponding Research, Development and Regulatory Activities - A Case of Gleevec® by Novartis Group. 美國藥物專利布局與其相應之研究開發與法規活動以諾華藥廠之 Gleevec®為例. Advisor: Dr. Keith Chan 陳桂恒教授 Student: Eric F.C. Wu 吳豐江 Date: November 2015.

(2) Table of Content ENGLISH ABSTRACT ............................................................................................ III 中文摘要....................................................................................................................... V LIST OF FIGURES ................................................................................................. VII LIST OF TABLES .................................................................................................. VIII CHAPER 1：. INTRODUCTION............................................................................ 1. 1.1. RESEARCH BACKGROUND ...................................................................................................... 1. 1.2. RESEARCH OBJECTIVE ........................................................................................................... 2. 1.3. RESEARCH METHOD............................................................................................................... 4. 1.4. RESEARCH RESTRICTION AND LIMITATION ............................................................................. 5. 1.5. ABBREVIATED TERMINOLOGIES ............................................................................................. 6. CHAPER 2：. PATENT RIGHTS IN BIOTECHNOLOGY AND. PHARMACEUTICAL INDUSTRY ........................................................................... 8 2.1. INTELLECTUAL PROPERTY RIGHT ........................................................................................... 8. 2.2. PATENT ................................................................................................................................... 9. 2.3. DRUG PATENTS ..................................................................................................................... 11. 2.3.1. COMPOUND PATENTS ............................................................................................................ 12. 2.3.2. FORMULATION PATENT ......................................................................................................... 14. 2.3.3. METHOD/ PROCESS PATENT .................................................................................................. 14. 2.3.4. USE PATENT.......................................................................................................................... 15. CHAPER 3：. RESEARCH AND DEVELOPMENT AND REGULATORY. PROCESS IN BIOTECHNOLOGY AND PHARMACEUTICAL COMPANIES 16 3.1. RESEARCH AND DEVELOPMENT PROCESS ............................................................................ 16. 3.1.1. Drug Discovery............................................................................................................... 17. 3.1.2. Drug Development .......................................................................................................... 22. 3.2. REGULATORY PROCESS OF DRUG APPROVAL ........................................................................ 27. CHAPER 4：. HISTORY OF GLEEVEC ............................................................ 30. 4.1. GLEEVEC .............................................................................................................................. 30. 4.2. RESEARCH AND DEVELOPMENT PROCESS OF GLEEVEC ........................................................ 31. 4.3. REGULATORY PROCESS OF DRUG APPROVAL ........................................................................ 37. CHAPER 5：. THE PATENT DEPLOYMENT OF GLEEVEC IN THE. UNITED STATES ...................................................................................................... 39 i.

(3) 5.1. DEFINE SCOPE OF ANALYSIS ................................................................................................ 39. 5.2. ANALYSIS METHOD & TOOL ................................................................................................ 48. 5.2.1. Software Tool .................................................................................................................. 48. 5.2.2. Tree Diagram Establishment .......................................................................................... 48. 5.2.3. Definition of Patent Preamble Tree Diagram ................................................................. 53. 5.2.4. Definition of Patent Body Tree Diagram ........................................................................ 55. 5.2.5. Categorization of the Claims .......................................................................................... 56. 5.2.6. Output of Figures and Tables.......................................................................................... 61. 5.3. RESULT ANALYSIS ................................................................................................................ 61. 5.3.1. Matrix Analysis ............................................................................................................... 61. 5.3.2. Timeline Analysis ............................................................................................................ 65. CHAPER 6：. DISCUSSIONS ON THE PATENTING STRATEGIES OF. GLEEVEC. 74. 6.1. PATENT TYPES IN PROTECTING THE DRUG............................................................................ 74. 6.2. RELATIONSHIPS BETWEEN PATENT FILING TIME AND R&D AND REGULATORY EVENTS ....... 82. 6.3. PATENT FAMILY .................................................................................................................... 85. 6.4. OVERALL DISCUSSION ......................................................................................................... 87. CHAPER 7：. CONCLUSION .............................................................................. 88. REFERENCE ............................................................................................................. 93 APPENDIX ................................................................................................................. 98 APPENDIX I ......................................................................................................................................... 98 APPENDIX II ..................................................................................................................................... 104 APPENDIX III .................................................................................................................................... 121. ii.

(4) English Abstract Patenting is one of the most important measures in securing the profits of a drug and has gained traction in the pharmaceutical and biotechnology industries for several decades. However, in Taiwan, past experience in obtaining and utilizing patent rights has not been a successful story. In addition, a small biotechnology company is usually in tight budget and needs a cost effective and feasible patenting strategy. With the booming development of biotechnology companies in Taiwan, the study aims to provide Taiwanese companies insights of patenting strategies and delineating the relationships between the patents and the corresponding research and development (R&D) and regulatory activities.. The study focused on the drug patenting strategy in the United States (US) since its patent system is one of the most influential and is the largest pharmaceutical market in the world. Gleevec, which is developed by Novartis group, is a global blockbuster and has accumulated billion dollars of sales around the world. The study takes Gleevec as a case study object and analyzes its patent deployments in US. In terms of the scope of the strategy, the study focuses on the patent types (the subject matter), patent application time, filing time in correspondence with the R&D and regulatory events, and the resulting patent families (including US patents claiming priority of previously filed applications and the same invention filed globally). Patents and independent claims are studied and are categorized into several categories which are predetermined according to the patent types. Literature research is conducted to delineate the timeline of R&D and regulatory events.. The study showed a comprehensive patent deployment of Gleevec in US and the patent deployment is in dynamic relationships with the R&D and regulatory events of a drug. Protecting a drug through patents requires professional understanding of patents and patent systems, close collaboration between R&D team and patent team, and a well-organized deployment strategy. Based on Gleevec patent deployment in iii.

(5) US, the study provides the following insights for a biotechnology companies in Taiwan. First, dedicate capital resources at least in obtaining key patents, mainly compound patents and crystalline form patents. These key patents have the biggest scope of protection of a drug. Second, in general, file patents around one to two years after the first laboratory results and/or preliminary animal study results. This is to insure the validity of the patents and yet won't cut short too much of the sales protection period. However, the filing time is also subject to considerations including the competition status in the same field, the overall scientific development and the commercial potential of the candidates. Third , file the key patents globally in early stages. Obtaining patents in different countries could expand protection geographically. Last, taking advantage of the flexibility of the US patent system. The flexibility gives a company a prolonged period to evaluate the potential of the candidate, defer patent timing and costs and make the final decision.. In summary, patent deployment isn't just applying patents in the patent office. It require a detailed and comprehensive plan. A patent deployment plan needs various professionals who have deep knowledge in drug research, clinical development, regulatory activities and global patent regulations and who are very experienced in utilizing the knowledge. It also requires these professionals to complement their knowledge with other professionals and to work closely. Despite such resources might require a lot of capital resources, these resources are not a lump sum cost, instead, the cost are dispersed throughout the whole product life cycle. If a biotechnology company with limited resources could employ the aforementioned suggestion, it would maximize the cost benefit of patent deployment plan and generate a patent deployment with effectiveness and efficiency.. iv.

(6) 中文摘要專利是各藥廠及生技公司保護藥物利潤的重要手段之一，全世界各國因藥物專利而起的侵權訴訟亦持續增加，也因此專利已成為藥廠及生技公司的必爭之地。過去台灣於美國的專利申請量全世界排名第五，但實際從專利而獲得的利益卻非對等，由此可見過去台灣企業在專利的佈局與利用尚待精進。近年來，台灣藥業及生技業蓬勃發展，許多研發成果亦開始走向臨床階段，然生技公司仍需有更完整專利佈局方能立足全球生技業。因此，本研究透過研究國際諾華大藥廠的基利克膜衣錠之美國專利佈局，以及專利佈局與研究開發時程之對應關係，總體觀察國際藥廠對於一小分子化學藥物所執行之專利佈局情況，並依據其專利佈局結果，歸納、分析及提出適用於台灣生技公司之專利佈局策略。美國的專利制度對於全世界的影響相當廣泛，再且其國內藥物市場亦屬全球最大，因此本研究將專注分析基利克膜衣錠於美國之專利佈局策略。. 本研究係透過研閱、分析與分類與基利克膜衣錠相關之專利及研發資訊，並透過文獻檢索方法彙整其研究與發展之各事件及其時程，及透過分析與拆解專利之申請專利範圍，組織歸納並統計其專利之類型(其主張之標的物)、申請時程、專利申請時程與研發時程的關係，以及其美國專利家族(主張優先權的各種延續案)及各國專利家族之應用狀況。. 本研究結果顯示，諾華大藥廠針對基利克膜衣錠在美國至少提出超逾 40 件以上之專利申請，且其涵蓋面向甚廣，至包含化合物專利、晶形專利、衍生物專利、用途專利、代謝物專利、鹽類專利、合成方法專利以及合併療法專利等，是一相當全面性的專利佈局。此外，本研究亦發現其各類型之專利申請時間點，與其研發成果產出時間點有一定關係。由此現象可見，其研發團隊與智慧財產團隊有緊密的互動關係。依據基利克膜衣錠的專利佈局結果以及考量台灣生技業的資源受限情況，本研究提出下列建議以提供台灣生技業作為其專利佈局策略之思考。 (1) 於有限資源中，仍須投入資源申請關鍵專利，其中關鍵專利至少包含化合物專利以及晶形專利。關鍵專利重要之處在於，其所主張的保護範圍在各種專利類 v.

(7) 型中是最廣的同時也最難迴避。(2) 一般而言，專利的申請可在研發成果產生後的一至二年左右提出。研發成果包含一般實驗室的功能性試驗，以及/或初步動物實驗結果。於此一時點提出是為了確保申請之專利具新穎性及進步性，同時又不因過早提出申請而致使專利期覆蓋藥物實際上市銷售期的時間縮短。然而，專利申請時間尚須考量相同領域的競爭程度、技術發展水平以及標的物商業化之潛力等。(3) 於全球各國提出關鍵專利申請。先於各大醫藥國提出專利申請，後再利用優先權制度擴展專利保護的國家。(4) 利用美國專利制度之彈性。美國專利制度包含臨時案、延續案、分割案等，這些彈性提供了生技公司一段較長的時間來產生更多研發成果、評估是否持續執行研發專案、延後正式專利申請及申請費用、研究競爭對手佈局等，因此對於生技公司而言是一重要手段。. 總結而言，藥物之專利佈局並非僅是向專利局提出申請如此而已，其需要一縝密、多面向且事先規劃的專利佈局。藥物的專利佈局包含的面向相當廣泛，涉及了藥物研發各類資訊與產出的了解、各種法規事件之掌握、全球各國專利制度的深入了解與應用，以及研發團隊與智慧財產團隊之緊密合作等。儘管專利佈局涉及之知識、技能與人員深且廣，然所需投入之資源並非集中於同一時間點，而是遍佈整個藥物的產品生命週期，若能掌握本研究所提出四點架構性建議，台灣生技公司應能在早期研究開發階段，將投入資源所產生的效益最大化，達到同時具有效能與效率的專利佈局。. vi.

(8) List of Figures Figure 1: Types of Drug Patents .................................................................. 12 Figure 2: Research Stage ............................................................................. 32 Figure 3: Development Stage....................................................................... 33 Figure 4: Preamble Tree Diagram ................................................................ 50 Figure 5: Body Tree Diagram ...................................................................... 51 Figure 6: Function Tree Diagram ................................................................. 53 Figure 7: Preamble vs. Body Matrix ............................................................ 62 Figure 8: Preamble vs. Application Date Matrix ......................................... 63 Figure 9: Body vs. Application Date Matrix ................................................ 64 Figure 10: Function in Preamble vs. Application Date Matrix .................... 64 Figure 11: Function in Body vs. Application Date Matrix .......................... 65 Figure 12: R&D Timeline vs. Chemical Claims .......................................... 67 Figure 13: R&D Timeline vs. Functional Claims ........................................ 68 Figure 14: R&D Timeline vs. Orange Book Patent Filing Date .................. 70 Figure 15: Patent Family Application Timeline ........................................... 72. vii.

(9) List of Tables Table 1: Patent Search History ..................................................................... 39 Table 2: Patent List of the Scope of the Analysis ........................................ 42 Table 3: Definition of Nodes in Preamble Tree Diagram ............................ 54 Table 4: Definition of Nodes in Body Tree Diagram ................................... 55. viii.

(10) Chaper 1：. Introduction. 1.1 Research Background Lipitor, Atorvastatin, is a statin drug used to lower cholesterol in blood. Lipitor has accumulated over $ 100 billion dollar sales1 during the period of marketing. In 2010 and 2011, global sales revenue is about $ 11 and 10 billion dollars.2 This record is one of the most successful drug products in the history. However, without patent protection, Pfizer wouldn't be able to secure such a successful sales record. Patents protecting Lipitor across the world expired in November 2011. After the patents expired, Lipitor faced with generic competition globally. In 2012, right after the patent expiration, Lipitor sold only $ 5 billion dollars globally and $ 3 billion dollars in 2013.3 It is clear that patent protection is an important measure to secure the value of a drug.. In 2002, only an accumulated 200 thousand published patent applications was reported. This quantity has then been overwhelmingly outnumbered by 325 thousands in 2012. In such a short period of 10 years, the number of patent application in the United States grew almost double the number in 2002. In addition, in 2013 the numbers of patent disputes in the biotech/pharma industry has climbed to the second largest number in the US4. The above paragraphs examplified the importance of patent deployment in the biotech/pharma industry.. In Taiwan, patent deployment of biotechnological and pharmaceutical 1. 2. 3. 4. 輝瑞藥廠面臨專利懸崖—暢銷藥立普妥(Lipitor)專利到期, http://www.hbmsp.sipa.gov.tw:9090/itri/tw/images/NewsList1010905_06.htm (last visited Nov. 9, 2014). Seeking Alpha, Pfizer: Lipitor Vanishing Revenue, http://seekingalpha.com/article/983801-pfizer-lipitor-vanishing-revenue (last visited Nov. 9, 2014). PMLive, Top 50 pharmaceutical products by global sales, http://www.pmlive.com/top_pharma_list/Top_50_pharmaceutical_products_by_global_sales (last visited Nov. 9, 2014). Chris Barry et al., Patent Litigation Study: Big cases make headlines, while patent cases proliferate, PricewaterhouseCoopers, 2013. 1.

(11) inventions during research and development (R&D) has been largely relied on the experience learned from the Information and Communication Technology (ICT) industry. However, the "experience" is in fact not a good one and the differences between biotech/pharmaceutical industry and ICT industry are neglected. History and statistical data has showed that the patent deployment result of Taiwanese companies in ICT industry is not a successful story5. Taiwanese companies have accumulated around ten thousand US utility patent applications, which was ranked fifth in the US. However, in 2012, the revenue generated by Taiwanese companies' intellectual property is $ 0.92 billion while the payment (the expense) of using others is $4.6 billion6. The data indicated that the patent deployments of Taiwanese companies is somehow flawed. The quality of patents filed by Taiwanese companies has also been criticized7. In addition, there are important differences between biotech/pharma and ICT industries. Drug research and development has been known for its lengthy process and its strict regulatory requirements as compared to that of ICT industry8. All these facts suggest that the patent deployment strategy in ICT industry may not work well in biotech/pharmaceutical industry.. It is clear that Taiwan biotech/pharma industry needs a suitable and well-planned patent deployment strategy. Therefore, this study intends to provide insight for Taiwanese companies to deploy patents of a drug candidate in the largest biotech/pharma market, the United States.. 1.2 Research Objective It is intended of the study to provide biotech/pharma companies in Taiwan 5. 6. May, 台灣企業 IP 智財權利金(技術交易)收支 2012 年 55.3 億美金, 科技產業資訊室, http://cdnet.stpi.narl.org.tw/techroom/pclass/2014/pclass_14_A029.htm (last visited Oct. 2, 2014). Id.. 7. 林上祚, 智財權保護台灣半夢半醒之間, 工商時報, Apr. 22, 2004.. 8. 張淑貞, 專家傳真－新藥智財布局用「智慧」避免「窒慧」，工商時報, Nov. 7, 2014. 2.

(12) insight to patent deployment strategy in the United States, which is based on patent filing, R&D and regulatory activities. This study should provide information on how big biotech/pharma practices patent deployment in order to maximize the value of drug through patents.. In order to provide the information, a successful case and patent portfolio is selected as the analysis target and served as an example. The analysis target, Gleevec, is developed by Novartis AG, a Swiss company. Switzerland, like Taiwan, is a small country yet has a world class drug development environment. Gleevec is one of the top 100 pharmaceutical drugs by retail sales in 2013, which was ranked 25th9 in all drugs and ranked 6th in cancer drugs10. Gleevec has been cited as the most competitively priced drugs in its class11. Gleevec is also one of the first targeted cancer drugs in the twenty-first century12, which corresponds to the trend of current drug development. Its patent strategy is also regarded as a strong protection against generics. The original patent protection of Gleevec compound is due on 4 January 2015 but has been extended to 23 May 201913 through its patenting strategy. Not only the compound patents protect the market of the drug, different types of patent application further extended the protection to 19 December 2021. Therefore, this study analyze the patent deployment strategy of Gleevec in the United States.. 9. Drugs.com, U.S. Pharmaceutical Sales - 2013, http://www.drugs.com/stats/top100/2013/sales (last visited May 2, 2014). 10 Kathlyn Stone , Top 20 Cancer Drugs, http://pharma.about.com/od/SalesandMarketing/tp/Top-20-Cancer-Drugs.htm (last visited May 4, 2014). 11 Robert Langreth, First Million-Dollar Drug Near After Prices Double on Dozens of Treatments, http://www.bloomberg.com/news/2014-04-30/drug-prices-defy-gravity-doubling-for-dozens-of-produ cts.html (last visited May 1, 2014). 12 Frank Stegmeier, et al., Targeted cancer therapies in the twenty-first century: lessons from Imatinib, Clin. Pharmacol. Ther. 87 (5): 543–52 (2010). 13 U.S. Food and Drug Administration, Patent and Exclusivity Search Results from query on Appl No 021588 Product 002 in the OB_Rx list, http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew.cfm?Appl_No=021588&Product_No =002&table1=OB_Rx (last visited Oct. 2, 2014). 3.

(13) 1.3 Research Method The study intends to understand the patent deployment of Gleevec in the United States. The basic structure and method of analysis is adopted from patent analysis method, Intellectual Resources Planning, described in two books14. 15. and is developed by Wispro Technology Consulting Corporation16. The method is further adjusted in this study. During the process of research, a patent analysis software, named Advanced Industrialized Patent SystemTM (AIPS17) developed by Wispro Technology Consulting Corporation, is used.. The study first defines the scope of analysis which is the granted utility patents in the United States that are relevant to Gleevec. The scope of analysis is then narrowed down by keyword search. Among the patent list obtained by the search, the relevance of each patent to Gleevec is determined by reviewing titles, abstracts and claims. Only the relevant patents enter the final scope of analysis list. All search methods and the resulting patents will be objectively recorded and only the official database is used.. The patents in the final list are then studied thoroughly. Given that the independent claims are the broadest scope of protection defined in a patent, only the independent claims of the patents are analyzed. The analysis will be based on the preambles, transitional phrases and bodies of the independent claims. A set of tree diagram will be developed according to the analysis on the claim so that each independent claims can be classified into a corresponding node in the tree diagram. Three tree diagrams, preamble, body and function diagrams, are established accordingly. A detailed analysis steps will be described in Sections 5.1 and 5.2. 14. 15 16 17. Y.P. Jou, Marketing Intellectual Property-Business Model Extracting Value from Intellectual Property (1st ed. 2010). Y.P. Jou, Beyond IP: Intelligence Resources Planning (1st ed. 2006). Wispro IP & Legal, http://www.wispro.com/ (last visited Nov. 9, 2014). Advanced Industrialized Patent System, http://www.patentcloud.com/aips/ (last visited Nov. 9, 2014). 4.

(14) Once the patent claims are classified, each tree diagram will be displayed on a two-dimensional matrix, either on the x or y axis (e.g. Preamble vs. Body). Timeline analysis of these patent applications are also depicted. In order to combine the patent analysis together with R&D process and regulatory activities, R&D and regulatory information are collected based on public accessible information. These data are also analyzed by timeline diagrams. Discussion and results will be based on these matrix and timeline diagrams.. 1.4 Research Restriction and Limitation This study has following restrictions and should be taken into account when interpreting the result: 1.. Gleevec is a small molecule chemical drug, therefore it is not the intention of this study to provide a patent deployment strategy for large molecule drugs or botanical drugs even though the same principle can be used.. 2.. The R&D process and regulatory activity information is collected retrospectively from publically accessible information, such as government official website, news and academic papers, therefore the collected information might be an discrete events and may or may not be a coordinated effort.. 3.. The patent search conducted in this study has tried to collect every possible patents that relates to Gleevec. However, given the official patent database provided by United States government has its limit in the patent search module, the study can only include as many relevant patents as possible. It is still possible that some relevant patents are missed in the analysis scope.. 4.. Licensed-in and acquired patents may not be included in the patent research.. 5.. The study analyzed US patent since US is the biggest pharmaceutical market in the world. Even though the US patent data may not represent the patent deployment in other countries, the result should be representative. 5.

(15) 6.. Patent laws are territorial. Patents filed in different country originally protecting a same invention may have different protection scope since each patent was examined independently by each country according to its corresponding requirements.. 1.5 Abbreviated Terminologies AIPS: Advanced Industrialized Patent System ALL: Acute Lymphoblastic Leukemia API: Active Pharmaceutical Ingredient CFR: Code of Federal Regulations CMC: Chemistry, Manufacturing and Control CML: Chronic Myeloid Leukemia GCP: Good Clinical Practice GIST: Gastrointestinal Stromal Tumors GLP: Good Laboratory Practice GMP: Good Manufacturing Practice ICH: The International Conference on Harmonisation IND: Investigational New Drug IUPAC: International Union of Pure and Applied Chemistry MAD: Multiple Ascending repeated Dose NDA: New Drug Application PCT: Patent Cooperation Treaty PD: Pharmacodynamics Ph+: Philadelphia chromosome positive PK: Pharmacokinetics R&D: research and development SAD: Single Ascending Dose sNDA: Supplemental New Drug Application TRIPS: Trade-Related Aspects of Intellectual Property Rights 6.

(16) U.S.C.: United States Code US: the United States USFDA: U.S. Food and Drug Administration USPTO: United States Patent and Trademark Office WIPO: World Intellectual Property Organization. 7.

(17) Chaper 2：. Patent Rights in Biotechnology and Pharmaceutical Industry. 2.1 Intellectual Property Right Generally speaking, intellectual property is considered to be under the scope of intellectual capital and intellectual asset18. However, in the aspect of financial accounting, intellectual capital of an enterprise is the value difference between its market cap and its tangible assets. Intellectual capital is mainly composed of human capital, structural capital and relational capital19. As for intellectual asset, it is usually referred to a defined, preserved and classified intellectual capital which can be utilized by a company who holds it20. 21. .. Intellectual property however has a more specific definition which is provided by World Intellectual Property Organization (WIPO). It refers to reactions of mind, such as inventions; literary and artistic works; designs; and symbols, names and images used in commerce22. Intellectual property right is thus defined in Trade-Related Aspects f Intellectual Property Rights (TRIPS) to be "the rights given to people over the creations of their minds."23 Intellectual property rights can be divided i) copyright and rights related to copyrights, and ii) industrial property right. Industrial property can further be divided into patent, trade secret, trademark and industrial design.24 Among them, patent right will be. 18. 馮震宇,「智慧財產權」解析——如何有效管理與創造最大價值？, 經理人月刊第 62 期 (2010). 19 Nick Bontis, et al., World Congress on Intellectual Capital Readings (2002). 20 Macmillan Dictionary, Intellectual Assets, http://www.macmillandictionary.com/dictionary/british/intellectual-assets (last visited Oct. 2, 2014). 21 Andreas Hubel, et al., Biopatent Law: Patent Strategies and Patent Management (1st ed. 2012). 22 World Intellectual Property Organization, What is Intellectual Property?, http://www.wipo.int/about-ip/en/ (last visited May 2, 2014). 23 World Trade Organization, Frequently asked questions about TRIPS, http://www.wto.org/english/tratop_e/trips_e/tripfq_e.htm#WhatAre (last visited May 2, 2014). 24 World Trade Organization, What are intellectual property rights?, http://www.wto.org/english/tratop_e/trips_e/intel1_e.htm (last visited May 2, 2014). 8.

(18) the main focus of this study and is thus further introduced.. 2.2 Patent Article I, Section 8, Clause 8 of the United States Constitution stated that the congress shall have power to promote the progress of science and useful arts, by securing for limited times to authors and inventors the exclusive right to their respective writing and discoveries25. To promote the progress of science and useful arts is thus the purpose of the clause. WIPO has also defined patent as an exclusive right granted for an invention, which is a product or a process that provides, in general, a new way of doing something, or offers a new technical solution to a problem26. In general, in order to obtain this exclusive right, that is to be patentable, an invention has to be novel, non-obvious and useful.. First, 35 U.S.C. § 101 defines usefulness requirement. In order to obtain a patent, one has to prove the invention is useful and industrially applicable. Second, according to 35 U.S.C. § 102, if the invention was described in a patent, a printed publication or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention, it shall not be entitled to the patent. Last, 35 U.S.C. § 103 defines non-obviousness. An invention might pass the novelty test but still fails non-obviousness requirement. Before the effective filing date of an application, if the claimed invention is obvious over prior arts for a person having ordinary skill in the art at the time of the invention was invented, then the claimed invention is obvious, thus fail the obviousness requirement.. Even though intellectual property rights are territorial, the basic nature and. 25 26. U.S. Const. I. 8. World Intellectual Property Organization, What is a patent?, http://www.wipo.int/patents/en/ (last visited May 4, 2013). 9.

(19) concept are the same across countries. The claimed inventions can be categorized into four category. They are utility patents, model utility patents, plant patents and design patents. However, in the United States, there is no model utility patent, only utility patents. Utility patents can further be divided into four types which is defined in 35 U.S.C. § 101 and they are process, machine, manufacture and composition of matter. To illustrate, a process patent can be a method to kill weeds, a synthesis process of a chemical compound or a manufacturing process of a drug. A machine patent can be a diagnostic device. A manufacture patent and a composition of matter patent is hard to distinguish. For example, a manufacture of a yeast without other bacteria can be both a manufacture patent and/or a composition of matter patent. A composition of matter patent can also be a chemical composition, a pharmaceutical composition for treating diseases, or a gene-engineered plant.. In the United States, there are four types of utility patent applications in terms of an US patent family. They are Provisional Application, Continuation Application, Continuation-in-part Application and Divisional Application. A provisional application is an application which is filed under 35 U.S.C. §111(b). Such application requires only a complete specification and application form and does not require a formal patent claim or an oath or declaration. A provisional application provides the means to establish an early effective filing date in a later filed non-provisional patent application claiming priority to the provisional application.27 Filing a provisional application would give applicants and inventors a year to consider whether to file a non-provisional application while obtaining an earlier effective filing date.. A continuation application is a second application for the same invention.28 an application claiming the priority to a earlier-filed pending patent application 27. United States Patent and Trademark Office (USPTO), Provisional Application for Patent, http://www.uspto.gov/patents/resources/types/provapp.jsp (last visited Oct. 10, 2014). 28 USPTO, Manual of Patent Examination Procedure (MPEP) 201.07 (2013). 10.

(20) (the parent application). The continuation application is limited to the scope of the specification of the parent application. Usually, a continuation application would have a same specification as the parent application but with a different set of claims. Filing a continuation application gives applicants and inventors an opportunity to pursue a new set of claim scope which is disclosed in the specification but not claimed in the parent application.. A continuation-in-part application is an application filed during the lifetime of an earlier non-provisional application, repeating some substantial portion or all of the earlier non-provisional application and adding matter not disclosed in the said earlier non-provisional application.29 If the inventor of an earlier non-provisional application continues to research the invention and results in some addition important features of the original invention, he can file a continuation-in-part application to obtain an early priority date on the original invention and a later filing date of the newly added features.. A divisional application is a later-filed application with an independent or distinct invention disclosed in an earlier-filed pending application.30 Only one distinct invention can be claimed in a patent application. Therefore, when an applicant claim two inventions in a single patent application, patent examiners will request election of the disclosed inventions and restrict the application to one single invention. In that case, the inventor and applicant can file a divisional application claiming the non-elected invention and can still obtain the priority of an earlier-filed pending application.. 2.3 Drug Patents Generally, patents that protecting a drug product and its underlying 29 30. USPTO, MPEP 201.08 (2013). USPTO, MPEP 201.06 (2013). 11.

(21) technologies can be categorized into several different technological fields. There are different analogies to the classification of drug patents. Karin Beukel et al identified six patent types in a conference paper31, including patents that protect the method of identifying new products, the core structure of a product, the specific application of the core structure of the product, the methods of utility, the method of manufacturing and the method of delivery. In a book published by Philip W. Grubb et al.32, the author divided the inventions of chemical and pharmaceutical products into compounds, new salt forms, new physical forms, new synthetic processes, analogy process, new composition and mixtures, new uses and new application processes. Accordingly, this study re-organize these types of inventions as in Figure 1. The types of drug patents are compound, formulation, method/ process and use. Some can be further divided and each are discussed below. The following Section 2.3 contents are mainly adopted from Philip W. Grubb's book unless otherwise noted.. Figure 1: Types of Drug Patents Source: Compiled by the study. 2.3.1 Compound Patents Compound patents, as its literal meaning, protect compounds themselves. Compound patents can be further divided into at least patents 31 32. Karin Beukel, et al., How Patent Types effect Patent Value, (2011) PhilipW. Grubb and Peter R. Thomsen, Patents for Chemicals, Pharmaceuticals, and Biotechnology (5th ed. 2010). 12.

(22) protecting chemical entity of known structure, chemical entity of unknown structure, salt form, physical form and composition. A chemical entity of known structure patent usually protects a group of chemicals with the same backbone and different sets of substitutes. This type of patent is rather straight forward and recites a chemical structure in the claim. The chemical formula is the backbone and the different functional groups are the different sets of substitutes.. Another type of chemical patents is for complex mixture with unknown chemical compounds. A chemical entity of unknown structure is usually written in product-by-process or fingerprint languages. A product-by-process claim usually describes end products produced by a defined process. A product-by-process claim is common in protecting botanical drugs since in some cases the end products is an extract of herbs and the structures of the end products is still unknown. On the contrary, a fingerprint claim is usually directed to a single compound where the structure is unknown or uncertain.. A compound may have different salt forms and may each have a unique feature. Patents protecting such compounds is a salt form patent. The claim usually recites a compound and a specific salt form. Salt form patents are less since pharmaceutically compatible salts are usually known and limited. The known and limited drug compatible salts might lead to lack of inventive step when applying the patents and thus lead to less salt form patents.. A physical form patent protects a compound in different particle sizes, racemic forms, enatiomers and crystalline forms. It is known that certain crystalline form of a compound may have unexpected features and may be patentable.. A drug is usually composed of active ingredients and other active or 13.

(23) inactive supplements such as excipients, diluents, and pharmaceutical carriers. The formula and the ingredients of the final drug product is the pharmaceutical composition. A pharmaceutical composition claim may recites active and inactive ingredients and some may further include ratios of the composition.. 2.3.2 Formulation Patent Formulation is the design of dosage form.33 It is a mixture or structure of a drug product prepared by a specific formula. Samples of formulation of a drug includes emulsion, liposome, capsule, pill, tablet, injection and syrup. A formulation patent protects the dosage form, the formula of mixture and the structure of the drug product. Such formulations contributes a lot in the drug's bioavailability and is a patentable invention. Usually, such formulation patent may recite a specific formulation that is suitable for many chemicals or recite a specific compound in a specific formulation in which combination generates desirable outcomes.. 2.3.3 Method/ Process Patent Method and process patents can be divided into two other categories. One is manufacturing process and the other is methods of drug delivery. Patents of manufacturing process of an ingredient of a drug protect the process to prepare, extract, generate or synthesize the ingredients. The claim usually recites steps and materials to prepare the ingredients. Though manufacturing process is a patentable subject matter, keeping the process as a trade secret is also a choice. By patenting the process, the steps of the process are disclosed to the public including competitors. Patenting a process is not 33. Bassam Abdul Rasool Hassan, Pharmaceutical Formulation, Pharmaceut Anal Acta, 3:10 (2013). 14.

(24) all bad since a patent holder might suit a competitor using the same manufacturing process. However, keeping the process as a trade secret might increase the burden of competitors to produce the same product since the competitors will have to develop a manufacturing process from the scratch.. A delivery method patent protects a drug delivery method such as methods of using special injections, cartridges, inhalers, sprays, patches, oral thin film or any other drug-releasing mechanism. A delivery method patent usually recites steps of how to apply the delivery system and deliver drugs into body systems.. 2.3.4 Use Patent An use patent protects inventions of applications of existing compounds or new compounds. An use patent is drafted as a method or process patent but since this type of patent protects indications of a drug, it is distinct from other method and process claims and is therefore discussed separately in this section. A drug may have several different indications and thus may have several use patents covering the uses of the drug. Such patents usually recite methods or process of using a compound to treat a certain disease.. 15.

(25) Chaper 3：. Research and Development and Regulatory. Process in Biotechnology and Pharmaceutical Companies Marketing of a drug involves a certain drug product and complicated regulatory activities. The creation of drug product can be divided into two large main stages, drug discovery and drug development. Drug discovery stage is from a therapeutic concept to a drug candidate. Drug development stage is from the drug candidate to a registered product. The process of obtaining a marketing approval includes regulatory activities starting from the development process and to the end of the sales. Though research and development and regulatory activities are inter-connected tightly, each stage and process are divided into sub stages and are described separately below.. 3.1 Research and Development Process It is commonly recognized that a R&D process can be divided into pre-discovery, discovery, preclinical, and clinical trials.34 In pre-discovery stage, scientist dedicated in understanding a disease. Underlying casual mechanism of a disease is delineated in order to identify potential targets of the drugs.35 Once the casual mechanism is identified and that the potential targets of drugs are clear, the process proceeds to the next stage, the drug discovery. In this stage, first scientists choose a target that is modifiable, which is the target identification. By employing all kinds of experiments, researchers try to identify the potential of the target to change the pathogenic process and make sure the target has the potential to be a drug target, the target validation. Next, scientists search for lead. 34. Pharmaceutical Research and Manufacturers of America (PhRMA), Drug Discovery and Development (2007), http://www.phrma.org/sites/default/files/pdf/rd_brochure_022307.pdf (last visited Jun. 1, 2015). 35 Pharma Knowledge Base, Process of Drug Discovery, http://hosted.comm100.com/knowledgebase/Process-of-Drug-Discovery_A134.aspx?id=134&siteid= 95439 (last visited Aug. 10, 2014). 16.

(26) compounds that have the potential to act on the identified target, the lead finding. Then researchers try to modify and optimize the lead compound, the lead optimization. Once the lead compound has been proved to be preliminarily safe and useful, research enters the preclinical phase. In this phase, in vitro and animal studies are conducted to obtain further proves on whether the target is safe to be tested in human.. All previous stages including pre-discovery, discovery and preclinical collectively are defined as a Research Phase. After research phase, it is called a Development Phase. The first event of a development phase is an Investigation of New Drug (IND) application. If fortunately the lead compound, or now called a drug candidate, passed the preclinical stage, an IND application would be filed to the regulatory authority of each country such as the U.S. Food and Drug Administration (USFDA) to request the Government approval to conduct human clinical trials. At this stage, the major concern is the safety of the test human subjects. After approved, the drug candidate will go through clinical trials which are subdivided into three phases, Phase I, II and III. In Phase I study, a small group of healthy volunteers are tested to provide safety, pharmacokinetics (PK), pharmacodynamics (PD) and side effect profiles of the drug candidate. In Phase II study, a medium size group of targeted patients are employed to study the side effects, the overall risk and the efficacy of the drug candidate. In Phase III study, a large number of patients are included to prove the safety and efficacy of the drug candidate to a specified indication. All stages and processes are described further below.. 3.1.1 Drug Discovery. A drug works by acting on a disease target and thus drug discovery include compound discovery and target discovery. Both discoveries starts 17.

(27) with unknown goals or targets, and requires mainly scientific researchers to explore the potential drug candidates.. Based on the methods used in drug discovery, it can be categorized into two approaches, irrational and rational approaches.36 Irrational approach is a conventional method. A scientist scans compounds that are isolated from natural sources for a potential target that might have an effect on a certain assay. This approach requires scanning of thousands of compounds in order to find one that works. Scientist then researched on the underlying mechanism of the target. The screening process is long and random and the failure risk is high.37 However, with the advancement of technology, scientists are now able to delineate the causal mechanism of a disease and identify a potential drug target. Then, scientist design a compound that would affect the target by interacting with the target. With the advanced knowledge and tools, current discovery usually employs the rational approach. The approach is typically divided into target identification, target validation, lead compound identification and lead optimization phase.. Target Identification and Validation. A disease is a condition which alters or interferes with the normal state of an organism and is usually characterized by the abnormal functioning of one or more of the host's systems, parts or organs38. Therefore, to understand the cause of a disease, scientist must elucidate the underlying mechanism and, if possible, identify the specific molecules that go wrong. Target identification is to identify the origin of a disease and the potential targets for intervention.39 There are several methods to identify potential targets but 36. Rick Ng, Drugs: From Discovery to Approval 20 (2nd ed. 2009). Id. 38 Raymond G. Hill, Humphrey P. Rang, Drug Discovery & Development 20 (2nd ed. 2013). 39 F. Hoffmann-La Roche Ltd, Drawn to Science: Target identification in drug discovery, http://www.roche.com/media/roche_stories/roche-stories-2013-09-11.htm (last visited Oct. 19, 2014). 18 37.

(28) two are major types. The first approach starts with the understanding of the pathway causing the disease phenotype and to the selection of drug targets. In other words, this approach starts with the study of patients who have the same phenotype, understanding the underlying cause of the disease of these people and then searching for the drug candidates. This approach involves analysis of the pathway that leads to disease first, and is therefore called backward approach.40 Another approach is so called forward approach. The forward approach starts by studying a certain signaling pathway and genotype, changing the pathway, and see how the changed pathway affected the disease phenotype. This new approach becomes possible because of the highly developed DNA sequencing technology and human genome project. With the understanding of the human genome and the ability to manipulate genes, scientists now can alter specific genes and create a specific genotype in a mouse model. By studying the phenotype of the specific genotype, scientists can delineate the relevant biological pathways and identify a potential drug target.41. Once the drug target is identified, researchers need to find direct evidence that shows the validity of the potential target to be a successful drug target. Target validation is a series of experiments. In this phase, scientists are trying to understand the functions and importance of the target. In addition, validation studies can involve in vitro and/or in vivo tests. By in vitro studies, scientists evaluate and validate the target at molecular level while by in vivo studies, scientists can validate the target at biological and phenotypic level.42 In this phase, scientists also research on potential indicators that shows the effect of a drug to interact with the target and develop assays that are used to validate desirable interaction between a compound and the target.. 40 41 42. Supra note 38, at 65-67. Supra note 36, at 23. Supra note 36, at 28-30. 19.

(29) Therefore, in target identification and target validation phases, there is generally still no drug compound actually involved in the research.. Lead Identification. Once the target is selected, scientists try to identify compounds that intervene with the selected target and molecular characteristics of the compounds are also evaluated at this phase. Several approaches are used to identify lead compounds, including existing drugs, natural ligands, natural products, focused screening, rational structure-based design, knowledge-based design, fragment screening virtual screening, high-throughput screening, etc.43 Among all, high-throughput screening is one of the most employed approaches to identify lead compound. It is conducted by experimenting on large numbers of compounds for their biological activity against the drug target. Identification of lead compounds can involve several tiers of screening. Primary screening provides initial positive and active compounds. These compounds are then tested in a secondary screening assays to confirm their activity and are studied for their potency and early specificity of the target.44 The compound hits filtered by secondary screening are studied for their structure-activity relationship and the target specificity. Structure-activity relationship (SAR) aim to study the chemical structure and its biological activity. With SAR information, a medicinal chemist would have a preliminary understanding of the amendability of the compounds and preliminary target specificity, and is capable of synthesizing a small group of compounds with structure similar to the compound hits. The pool of the compound hits and the small group derivatives are the leads identified.45. 43 44 45. Supra note 38, at 123. Supra note 38, at 97-98. Id. 20.

(30) Advanced technology development has made the lead identification more productive and efficient. The technologies include X-ray crystallography, nuclear magnetic resonance spectroscopy, computational chemistry, combinatorial chemistry and bioinformatics.46 These technologies either increase the pool of compound library, improve the quality of lead identification or help scientists better understand SAR.. Lead Optimization. With SAR information and previous biological activity data, medicinal chemists can modify the compounds in order to improve properties that are required for pre-clinical development. The major required properties to screen the lead compounds and the modified compounds are selectivity, potency and absorption, distribution, metabolism and excretion (ADME) properties.47 Medicinal chemists provide modified lead compounds to biologist for biological property testing (mainly in vitro testing). Results of the biological testing are feedbacked to medicinal for further SAR evaluation and structural modification. The process keeps repeating until several optimized compounds are identified. Only a few optimized compounds enter in vivo animal studies for further ADME evaluation.48 In most cases, exploratory toxicity and safety profile are also studied at this phase.49 The final identified compounds would have good efficacy, safety and ADME profiles and are ready for pre-clinical studies. These identified compounds are the optimized lead compounds or called the drug candidates.. Drug discovery starts from cultivating a therapeutic concept to generating drug candidates. This process takes a very long time to identify. 46 47 48 49. Supra note 36, at 60-71. Supra note 38, at 126. Supra note 36, at 58. Supra note 38, at 128-129. 21.

(31) few promising but still risky drug candidates. It involves scientists in different fields to select an estimated 250 drug candidates out of 5000 to 10000 compounds.50 The drug discovery stage not only provides drug candidates, the experiments and the results also serve an important indicators for establishing pre-clinical study design.. 3.1.2 Drug Development. Drug development is a process which the goal is rather clear, to bring the drug through clinical development and into the markets. The whole process involves three aspects, technical, investigative and managerial issues. The technical aspects involves mainly the development of production, quality, formulation and delivery of the drug candidates. The investigative aspect involves the safety and efficacy clinical development. Together, the technical and investigational issues explore the three main issues that USFDA scrutinizes, safety, quality and efficacy of a drug. The last, managerial aspects involves the coordination of all development activities and control the go or no-go decision at every step at the development stage.51. Drug Development stage is categorized into three main phases, preclinical development, clinical development and regulatory approval. All phases are discussed below.52. Pre-Clinical Development. Before clinical studies, safety assessment of a drug candidate is necessary. A preliminary toxicology profile has already been studied 50 51 52. Supra note 34. Supra note 38, at 203-204. Supra note 34. 22.

(32) previously in the drug discovery stage, during which a short period of toxicity study and some in vitro studies are employed. These preliminary studies require no good laboratory practice (GLP) and could provide clues for further toxicology studies.53 If a pharmaceutical company is seeking approval to enter human clinical trials, it must conduct comprehensive toxicology studies under GLP regulation. Such safety assessment studies are also called pre-clinical studies.54. 55. In pre-clinical phase, safety is assessed in both pharmacology and toxicology studies. These studies in the United States are currently in compliance with International Conference on Harmonization (ICH) guidelines. In pharmacology studies, PK and PD are evaluated. PK is the study of ADME while PD is the study of dose response effects.56. Toxicology studies focus mainly on the chronic toxicity of repeated administration. It provides long term effect on animal as well as dose range information. Other toxicity profiles are also evaluated at appropriate times corresponding to clinical phase of the studies, including genotoxicity, carcinogenicity, reproductive toxicology, mutagenicity and special toxicity tests. Both pharmacological and toxicological studies are mostly performed by in vivo animal tests in order to provide references for human clinical studies.57. Together, the pre-clinical studies could provide references for doses and dosing regimens in clinical trials. Once the toxicology profiles of the drug candidates are explored and proven promising, the results will be submitted to USFDA for an IND review which will be reviewed in Section 3.2. 53 54 55 56 57. Supra note 38, at 212. Supra note 38, at 211. Supra note 36, at 137-139. Supra note 38, at 213-216. Id. 23.

(33) Clinical Development. According to the ICH, the definition of a clinical trial is any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects on an investigational product, and/or to identify any adverse reactions to an investigational product, and/or to study absorption, distribution, metabolism, and excretion of an investigational product with the object of ascertaining its safety and/or efficacy.58. In general, clinical development can be divided into at least three stages, clinical trial phase I, clinical trial phase II and clinical trial phase III. In most cases, there is post-market clinical studies known as phase IV trial. Each phase has a primary aim. Phase I clinical trials assess mainly the safety profile of a drug in healthy human subjects, usually accompanied with PK and tolerability assessment. Phase II trials study the efficacy and safety in a small group of patients and explore the appropriate dose range. Phase III trials explore the efficacy and safety in a large population. Phase IV trial evaluate the safety and efficacy of a drug after the drug is on the market. Each phases are further discussed below.59. 60. Clinical Trial-Phase I. A typical Phase I study takes around a year and 10 million USD to develop.61 Usually, around 100 healthy subjects are enrolled in the study. In some cases, patients in critical conditions may be recruited in this phase if. 58 59 60 61. ICH Guidelines, Section 7.11. Supra note 38, at 240. Supra note 36, at 181-186. Supra note 36, at 182. 24.

(34) the benefits outweigh risks after cautious evaluation.62. In this phase, safety, tolerability and PK of a drug in an intended formulation is evaluated.63 Trial design includes single ascending dose (SAD) and multiple ascending repeated dose (MAD) studies.64 The primary objective of the SAD and MAD studies is to provide initial safety and tolerability information of a drug. Secondary objective, including PK, is also evaluated in most cases. If patients are included, initial efficacy data may be collected.. Information collected in this phase, including dosing, maximum tolerable dose, PK profile, adverse events and PD profile, are crucial and determinative in designing the next phase, Phase II clinical trial.65. Clinical Trial-Phase II. A typical Phase II clinical trial takes around one to two years and 20 million USD to complete. About 50 to 500 patients are enrolled in the study.66. In this phase, safety and efficacy of the drug is again studied. However, unlike in Phase I which testing is focused on safety, Phase II safety and efficacy studies are indication oriented.. Phase II studies are used to explore the safety, efficacy, dose-response relationships, dose selection and dosing regimens. Tolerability and adverse side effects are also evaluated in patients. Phase II results are necessary for 62 63 64 65 66. Supra note 60. Supra note 38, at 240-244. Id. Id. Supra note 36, at 183. 25.

(35) Phase III trial designs.67. 68. Clinical Trial-Phase III. A typical Phase III clinical trial takes around three to five years and 50 to 100 million USD to complete. Patient numbers may range from several hundreds to thousands.69. In this phase, trials are designed to resemble to how the drug mighty be used after approved. The primary aim of this phase is to study the drug's effectiveness in statistical aspects. In order to reach statistical significance under a pre-determined power, hundreds or thousands patients might be needed.70 Trials are usually conducted in several different centers and hospitals so that the results might also provide population-specific information. In addition, two Phase III trials are usually required.71 The results of trials determines the dosage, dosing regimens and target patients.. If the results of the trials are positive, a new drug application will be prepared to submit to the USFDA to see marketing approval. Once the drug is approved and hits the market, a Phase IV study is triggered.. Clinical Trial-Phase IV. In Phase IV study, treated patients are monitored for their adverse side effects. This post market surveillance is set to protect patients from risks unidentified in all previous development. Serious adverse side effects shall be reported to USFDA. If necessary, USFDA may decide to recall the drug or 67 68 69 70 71. Supra note 38, at 241. Supra note 36, at 182-183. Supra note 36, at 183. Supra note 36, at 183. Id. 26.

(36) change labels.72. 3.2 Regulatory Process of Drug Approval Evaluation of a new chemical compound on human subjects is risky. Therefore, it is necessary for the government to gain control of such activities. In the United States, USFDA is the concerned authorities which oversees the pharmaceutical markets and has the ultimate power to decide on a drug's marketing approval. USFDA are concerned with scientific matters of a drug and its clinical studies. During the drug development, a pharmaceutical company needs to communicate, negotiate and obtain different kinds of permission in order to proceed to the next phases of development. The requirements that the pharmaceutical company need to comply include at least general practice requirement, investigation new drug and new drug application.. Good Practice Requirement. Good practices are overseen by USFDA and include at least GLP, GCP and good manufacturing practice (GMP).. The primary aim of GLP is to ensure the experiment results of pre-clinical animal studies are qualified and are reliable. GLP requires the pre-clinical studies on animals to follow certain quality-ensuring practice, including at least organization, personnel, laboratories, facilities, protocols, records and reports. It is necessary to comply with GLP in order to submit an IND.73 In the United States, GLP is regulated under 21 CFR 58.. As previously described, all clinical trials are subject to GCP requirements. The primary aim of GCP is to ensure the ethics and quality of human studies. 72 73. Supra note 36, at 186. Supra note 38, at 169. 27.

(37) GCP regulates across participant entities, regulatory documents, protocols and procedures. Currently, GCP in the United States is regulated under 21 CFR Parts 50, 56 and 312.74. The aim of GMP is to ensure the consistent quality of manufacturing the drugs. GMP requirements also cover personnel, building and facilities, manufacturing equipments, documents and records, protocol and procedures, laboratory controls, validation and storage and distribution. GMP in the United States is regulated under 21 CFR Parts 210, 211, 600 and 610.75. Investigational New Drug (IND). Once a pharmaceutical company decides to enter clinical trial stage based on the pre-clinical data, it must file and IND application to the USFDA. The primary aim of obtaining an IND approval is to ensure the safety of patients in the following clinical trials. An IND application mainly comprises designed protocols of clinical trials, chemistry, manufacturing and control (CMC) data and pre-clinical pharmacology and toxicology data.76 Generally, within 30 days after the submission of an IND application, USFDA would inform the applicant whether it approves the application or that further information is required in order to obtain permission to conduct clinical trials.77. New Drug Application (NDA). If the outcome of phase III clinical trial meets the pre-determined criteria, the pharmaceutical company may submit an NDA to seek marketing approval. There are several types of NDA including 505(b)(1) NDA, 505(b)(2) NDA and. 74 75 76 77. Supra note 36, at 187. Supra note 36, at 279-282. Supra note 36, at 233-238. Id. 28.

(38) 505(j) ANDA.78 If the clinical trial is conducted to prove the potentials of a new chemical compound, the NDA would be a 505(b)(1) NDA. Such NDA mainly comprises CMC data, non-clinical pharmacology and toxicology data, clinical pharmacology and toxicology data, labeling and patent information.79 Reviewing of an NDA involves medical, clinical, pharmacology, toxicology, CMC, statistical, clinical pharmacology, biopharmaceutical, bioresearch monitoring reviewers and GMP facility inspectors.. It generally takes around more than 10 months to review an NDA.80 However, in some cases where the NDA is seeking an approval on rare diseases, diseases without proper treatment or other special conditions, the USFDA might grant the NDA with certain designation, such as priority review and accelerated approval. These designations might accelerate the reviewing process as well as the amount of data required.81. Supplement to the New Drug Application (sNDA). If after the approval a pharmaceutical company wants to make changes in a product, it can file an sNDA. Such changes may include changes in a label, new dosage or strength, manufacturing process, manufacturing facilities and other miscellaneous changes.82 An sNDA is a supplement submission to an original NDA and requires USFDA's approval.. 78. Supra note 36, at 240. Supra note 36, at 239. 80 Supra note 36, at 247. 81 Supra note 38, at 299. 82 Drugs@FDA Glossary of Terms, http://www.fda.gov/Drugs/InformationOnDrugs/ucm079436.htm (last visited Nov. 9, 2014). 29 79.

(39) Chaper 4：. History of Gleevec. 4.1 Gleevec Gleevec is a prescription-only oncology drug marketed by Novartis Pharmaceutical. In Canada, South Africa and the United States, it is called Gleevec, while in Australia, Europe and Latin America it is named Glivec. Gleevec and Glivec are the trade names of the Imatinib which is its international nonproprietary name83. The chemical name (IUPAC84) of Gleevec is 4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2 -yl]amino}phenyl)benzamide. While Gleevec was developed in Novartis, it was coded STI571.. Gleevec tablets are indicated for adult and pediatric patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML). They are also indicated for Ph+ acute lymphoblastic leukemia (ALL), KIT-positive gastrointestinal stromal tumors (GIST) and several other oncology diseases.85. Upon the first approval of the Gleevec in CML patients in 2001, Gleevec has been described as the first cancer drug that transform the target cancer into a chronic disease rather than a doomed death. In 2013, Gleevec has sold 1.87 billion dollars86 in the United States and 4.7 billion dollars globally. In 2013, Gleevec ranked the 14th in terms of global sales among all pharmaceutical products87. 83. International nonproprietary name of a drug is an official generic name of a pharmaceutical substance designated by the World Health Organization. 84 IUPAC (International Union of Pure and Applied Chemistry) names are names for chemical compounds. The chemical nomenclature of systematic name is established by IUPAC based on certain rules of chemistry. The IUPAC names are given mainly base on the structure of the chemical compound. 85 Gleevec Official Website, http://www.gleevec.com/index.jsp (last visited Oct. 26, 2014). 86 Supra note 9. 87 PMlive, Top 50 pharmaceutical products by global sales, http://www.pmlive.com/top_pharma_list/Top_50_pharmaceutical_products_by_global_sales (last 30.

(40) 4.2 Research and Development Process of Gleevec R&D events are surveyed and compiled in this study. It is to be noted that information gathered in this study is all public or legally accessible by the author. Best efforts are dedicated in surveying the R&D information but may not be comprehensive due to the limited sources of information. Information of R&D events including event time, R&D stage, event description and event references are compiled in Appendix I and are depicted in timeline figures in Figure 2 and Figure 3.. visited Oct. 26, 2014). 31.

(41) Began first STI571/ Gleevec laboratory studies Chromosome 22 and 9 translocation observed by new staining techniques. Abnormal chromosome 22 found in CML patients. The compound that became Gleevec was synthesized in lab. Began functional tests of STI571 in animal model including Pharm/Tox, CMC, ADME and formulation. Filed IND. 1986 1960. 1973. 1982. 1992 1993. Pre-Discovery Stage. 1982. 1984 ·. Cellular oncogene identified in chromosome 22 translocation. Drug Discovery Stage. Cellular oncogene was identified to be c-ab1. · ·. Found the translocation region on Chromosome 22 and identified the translocated bcr gene; Identified potential protein (tyrosine kinase activity) of cab1 altered protein; BCR-ABL protein identified as possible cause of CML). Preclinical Stage. 1986. · ·. Figure 2: Research Stage Source: Compiled from Appendix I 32. 1996 1998. Transcript of ab1 and bcr genes are detected in CML; mRNA of ab1 and bcr fusion was identified clinically. ·. Bcr-Abl protein identified to be tyrosine kinase (P210) which regulates cell growth and division.

(42) 1999/7. 2000/6. · · ·. rd. 3 Phase II · 2nd line CML therapy · Blast Crisis · 262 patients 1999/7/2. · · ·. 2000/5. 1st Phase II · 2nd line CML therapy · Chronic Phase · 532 patients. Filed IND. 1998/4/9. 1999. · · ·. Approval #21-335 2nd line CML therpay. Approval #21-335 1st line CML therapy 2003/5/20. 1999/8 2000/3 2nd Phase II · 2nd line CML Phase III therapy · CML · Accelerated · 1106 Phase patients · 235 patients 2000/6 2001/1 2000 2001 2001/5/10. 1998/6. · · ·. Approval #21-335 kit+ GIST. · · ·. · · ·. NDA #21-335 2nd line CML therapy. · ·. Approval #21-588. 2002/12/20. 2002/2/1 2002. 2003. 2003/4/18. sNDA #21-335 1st line CML therapy. · · ·. sNDA #21-335; #21-588 Pediatric 2nd line CML therapy. 2000/7. ·. st. 1 line CML therapy: First line therapy (indicated for patients. Phase II · kit+ GIST · 147 patients. · · ·. sNDA #21-335 kit+ GIST. who are newly diagnosed with chronic myeloid leukemia) ·. 2 line CML therapy: Second line therapy (indicated for CML patients who failed a first-line treatment). ·. Pediatric 2nd line CML therapy: Second line therapy (indicated. · · · ·. nd. Figure 3: Development Stage Source: Compiled from Appendix I. for pediatric 2nd CML patients) 33. 2004. 2002/6/28 2003/4/23 2002/12/13. 2001/2/27 2001/10/16. 2000/5. Phase I · 2nd line CML therapy (after IFN-a treatment failed or intolerable) · 149 patients · Explored efficacy and safety. <Indication Specification>. Approval #21-588; #21-235 Pediatric 2nd line CML therapy. NDA #21-588 Capsule to Tablets All indications in #21-335.

(43) The R&D events in Appendix I are further described in the following paragraphs and in the order of the R&D process.. Pre-Discovery Stage. In 1960, abnormal chromosome 22, also called Philadelphia chromosome, was first observed in CML patients by Peter Nowell and David Hungerforsd.88 It is later found that the abnormality of Chromosome 22 was caused by a reciprocal translocation between Chromosome 22 and Chromosome 9 by Janet Rowley89. In 1984, a group of scientists found that the transallocation region of Chromosome 9 disrupted the c-ABL gene and led to a novel gene, BCR, on Chromosome 22. The c-ABL gene was then found to be one of the oncogene in CML. The upstream mechanism of c-ABL gene leading to CML was further delineated in 1984, where the altered c-abl protein was found to affect the tyrosin kinase activity90. Tyrosin kinase is an enzyme that phosphorylate the tyrosin residue of a protein or a peptide. Such phosphorylation of certain proteins would affect the properties of transcription factors and upregulate mitogenesis and mitosis in a cell. Therefore, tyrosin kinase participates in cell growth and differentiation. In 1985, transcript of ABL and BCR genes are confirmed to be detectable in CML human patients91, and an abl and bcr fusion RNA transcript was detected clinically in CML patients92, which together proved that ABL and BCR are linked to human CML disease. Such fusion RNA transcript was quickly identified to produce a phosphoprotein P210, a tyrosine kinase that regulates cell growth and division.93. 88. Peter Nowell, and David Hungerford, Chromosome studies on normal and leukemic human leukocytes, J. Natl. Cancer Inst. 25:85–109 (1960). 89 Janet D. Rowley, A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 243:290–293 (1973). 90 James B. Konopka, et al., An alteration of the human c-abl protein in K562 leukemia cells unmasks associated tyrosine kinase activity, Cell. 37:1035–1042 (1984). 91 Emma Shtivelman, et al., Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature. 315:550–554 (1985). 92 Kees Stam, et al., Evidence of a new chimeric bcr/c-abl mRNA in patients with chronic myelocytic leukemia and the Philadelphia chromosome. N. Engl. J. Med. 313:1429–1433 (1985). 93 Yinon Ben-Neriah, et al., The chronic myelogenous leukemia-specific P210 protein is the product of the bcr/abl hybrid gene, Science. 233:212–214 (1986). 34.

(44) Drug Discovery. Since the tyrosine kinase, the abl-bcr fusion protein, has been proved to be one of the casual reasons of the CML patient with Philadelphia chromosome, a research program of searching for specific tyrosine kinase inhibitors was established in 1986.94 In 1988, Dr. Nick Lydon and Alex Matter, both in Novartis's Oncology Division at that time, were in charge of the research of tyrosine kinase inhibitor.95 Latter on in 1990, Dr. Lydon and Dr. Matter appointed Dr. Jurg Zimmermann and Dr. Elisabeth Buchdunger a research program which aimed to find a tyrosine kinase that selectively targets the Bcr-Abl kinase activity.96 The appointed project focused on a 2-phenylaminopyrimidine derivatives synthesized by Dr. Zimmermann and were then tested in a biological assays by Dr. Buchdunger. After many synthesized 2-phenylaminopyrimidine derivative candidates failed to provide desired biological effect, in August 28, 1992, Dr. Zimmermann synthesized a compound latter on became the known STI571. Early in 1993, Dr. Buchdunger tested on STI571 and found that STI571 was able to suppress Bcr-Abl.97 Four compounds including STI571 entered pre-clinical stage for further testings.. Pre-Clinical. In 1993, Dr. Brian Drucker from Dana Farber Cancer Institute had a CML testing model and was therefore recruited to test on the four compounds provided by Novartis. Protein, cell and animal preclinical studies were carried out to obtain 94. Lana Bozulic, et al., Meeting report: targeting the kinome — 20 years of tyrosine kinase inhibitor research in Basel, Sci. STKE (2007). 95 Benjamin Yang, Executive Summary of a Book: Magic Cancer Bullet, http://www.discoverymedicine.com/Benjamin-Yang/2009/05/23/executive-summary-of-a-book-magi c-cancer-bullet/ (last visited Aug. 10, 2014). 96 PhRMA, The Story of Gleevec, http://www.innovation.org/index.cfm/StoriesofInnovation/InnovatorStories/The_Story_of_Gleevec (last visited Aug. 10, 2014). 97 Id. 35.