Japanese biotech patenting strategies in the Era of follow-on biologics

Biotechnology Law Report

Volumn 28, Issue 4, 2009, Pages 483-496

  Tessensohn, John A ^a   Yamamoto, Shusaku ^b  

^a Shusaku Yamamoto   (Japan)

^b NONE

Author keywords

[No Author keywords available]

Indexed keywords

EID: 70449440400     PISSN: 0730031X     EISSN: None     Source Type: Journal    
DOI: 10.1089/blr.2009.9928     Document Type: Article

References (118)

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9. Japan Ministry of Health Labor & Welfare, Annual Health, Labor and Welfare Report 2007-2008 Promoting the Dissem ination of Generic Medicine 1.1.4 (2008) and Health Ministry to push generic drugs in prescriptions, Nikkei Nov. 8, 2007 (reporting that although generics account for nearly 60% of the drug market on a volume basis in some European countries and the U.S., the market for generics in Japan was a feeble 17%. The government aims to increase the generic share to at least 30% by fiscal 2012).
10. In all of its official regulatory documents, the Japanese government uses which is translated as "follow-on biologics." U.S. Federal agencies such as the Food and Drug Ad ministration and Federal Trade Commission have adopted the same FOB nomenclature, whereas Europe uses "biosimilar." See also Judith A. Johnston, FDA Regulation of Follow-on Biologics. Congressional Research Service Report RL 34045 1 (Feb. 2009) (noting that a "follow-on biologic is similar but not identical to the brandname, or innovator, product made by the phar maceutical or biotechnology industry. . . . The FDA and many others consider the use of the word generic to be inaccurate be cause the term has been used, in the context of chemical drugs, to mean identical.").
11. Patricia M. Danzon and Michael F. Furukawa. Prices and availability of biopharmaceuticals: An international comparison, 25(5) Health Affairs 1353 (2006) (after analyzing the pricing data of nine major healthcare economies, the authors observe that whereas the U.S. does spend more on biologics, prices, after adjustment for income, are not noticeably higher than in countries such as Japan, France, or Germany. The prices of biopharmaceuticals in Japan are the fourth highest in the world after the U.S., France, and Germany.).
12. Alison Langley. Engineered drugs open new issue of regulation as patents expire, N.Y. Times, Aug. 9, 2003 at C1
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14. Arlene Weintraub. Generic biotech drugs: Cure or quagmire? Bus. Week, Jun. 15, 2009. See infra text accompanying notes 78-102.
15. Andrew Pollack. Costly drugs known as biologics prompt exclusivity debate, N.Y. Times, Jul. 22, 2009 at B1.
16. H.R. 1427 Promoting Innovation and Access to Life-Saving Medicine Act, 111th Cong. (2009), H.R. 1548 Pathway for Biosimilars Act, 111th Cong. (2009), and S. 726 Promoting Innovation and Access to Life-Saving Medicine Act, 111th Cong. (2009).
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19. Charlotte Harrison. News in brief: Japan approves first follow-on biologic. Nature Revs. Drug Discovery 2009;8:603.
20. Europe was the pioneer in creating an abbreviated regulatory pathway for FOBs. Leyre Zuñigaa and Begoña Calvo. Regula tory aspects of biosimilars in Europe. Trends Biotechnol 2009;27:385.
21. Australia had approved its first FOB in Septem ber 2004. Isabel Teare. Biosimilar warfare: The arrival of ge neric biopharmaceuticals-the Omnitrope decision. 8 (1) Bio-Science L. R. 12 2005/2006.
22. Canada granted approval of its first ever Subsequent Entry Biologic in April 2009, Sandoz Canada receives approval for recombinant human-growth hor mone Omnitrope in Canada, Bus. Week, Apr. 22, 2009.
23. Hiroshi Horikawa et al. Industry views of biosimilar devel opment in Japan, 91(2) Health Policy 189 (Jul. 2009).
24. As early as March 2006, JCR Pharmaceuticals, a mid-tier pharmaceutical company, had indicated its intention to establish a biosimilar/FOB business; JCR Pharmaceuticals, Financial Report Summary 2005 24 (May 5, 2006) [Japanese only]. A precision medical equipment maker, Nipro, outlined plans for development of a drug delivery system using FOB of re combinant erythropoietin, artificial blood, and recombinant hu man serum albumin; see Nipro Corporation, Consolidated Fi nancial Statement 2007 9 (May 19, 2008).
25. Government of Japan, MHLW Draft Guidelines for the Quality, Safety and Efficacy Assurance of Follow-on Bio- logics-Request for Opinions (Sep. 17, 2008); available at http:// search.e-gov.go.jp/servlet/Public?CLASSNAME[t=] Pcm1010 &BID=495080153&OBJCD = &GROUP= [Japanese only].
26. Government of Japan, MHLW Guidelines for the Quality, Safety and Efficacy Assurance of Follow-On Biologics (Mar. 4, 2009); available at http://www.hourei.mhlw.go.jp/hourei/doc/ tsuchi/2005I210304007.pdf [Japanese only].
27. Sandoz is the FOB Johnny Appleseed of the industrialized world, having secured pioneering regulatory approvals in ju risdictions such as the EU, Australia, Canada, and Japan; see Haig Simonian. Sandoz steps up attack on biotech sector, Fin. Times, May 14, 2006.
28. Sandoz International. Media release: Sandoz receives approval for first-ever Japanese biosimilar, Jun. 25, 2009.
29. Generic biotech drug market beckons for JCR, Fuji Pharma, Nikkei, Dec. 8, 2008 (reporting that mid-tier Japanese generic drug manufacturer JCR had applied in November 2008 for MHLW approval to produce and sell an FOB of erythropoi-etin)
30. Japanese drugmakers developing biotech generics, Nikkei, Jun. 5, 2009.
31. Bethan Hughes. Gearing up for follow-on biologics. Nature Rev. Drug Discovery 2009;8:181 (reporting "a spurt of investment and interest in the development of follow-on biologics, or biosimilars, by both biopharmaceutical and generic-drug com panies" such as Merck, Lonza, and Teva).
32. Mark J. Belsey et al. Biosimilars: initial excitement gives way to reality. Nature Rev. Drug Discovery 2006;5:535 (re porting that "entering the biosimilar market carries higher costs, greater risks, and greater time and expertise in relation to the clinical development of these products").
33. Martin A. Voet. The generic challenge: understanding patents, FDA & pharmaceutical life-cycle management 166 (2008) (observing that "biotech companies must be cognizant of life cycle management as the sun is setting on the golden age of branded biologicals").
34. Section 36(4)(i) and 36(6)(i) of Tokkyo Ho [Japanese Patent Law], Law No.121 of 1959, as amended; hereinafter Tokkyo Ho.
35. Nippon Gohsei v. Commissioner Japan Patent Office, Hei- sei 17 (gyo-ke) 10042, dated Aug. 30, 2005 (Intell. Prop. H. Ct. of Japan).
36. Astellas & Fujisawa v. Commissioner Japan Patent Office, Heisei 17 (gyo-ke) 10312, dated Aug. 30, 2005 (Intell. Prop. H. Ct. of Japan).
37. The predecessor company of Astellas, Fujisawa, was the as signee of U.S. Patent No. 6,232,324 B1, granted on May 15, 2001, and European Patent No. 0823254B1, granted on July 17, 2002.
38. Main paragraph of Section 29(1) of Tokkyo Ho, as confirmed in Scios v. Commissioner of Japan Patent Office, Heisei 10 (gyo-ke) 393, dated Mar. 13, 2001 (Tokyo H. Ct.).
39. See John A. Tessensohn and Shusaku Yamamoto. Commentary: Establishment of Japan's Intellectual Property High Court, 19 World Intell. Prop. L. Rep. 21-22 (2005) (the Intellectual Property High Court of Japan, a specialized IP appellate court, is similar in spirit and intent to the U.S. Court of Appeals of the Federal Circuit).
40. Stanford University v. Commissioner Japan Patent Office Heisei 10 (gyo-ke) 95, dated Feb. 22, 2000 (Tokyo H. Ct.).
41. Anthony Fauci et al. (eds). Harrison's Manual of Medicine 366 (2009) (treating squamous-cell carcinoma with combination biologic therapy) and Scott Kopetz, Targeted therapy of colorectal cancer. Targeted Cancer Therapy 111 (Razelle Kurzrock & Maurie Markman, eds. 2008).
42. Arrowdean Ltd., v. Commissioner Japan Patent Office, Case No. Heisei 8 (gyo-ke) No.201, dated October 30, 1998 (Tokyo H. Ct.).
43. Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559 (Fed. Cir. 1997), University of Rochester v. G.D. Searle & Co., 358 F.3d 918 (Fed. Cir. 2004), Carnegie Mellon University v. Hoffmann-La Roche, Inc., 541 F.3d 1115 (Fed. Cir. 2008), and Ariad Pharmaceuticals, Inc. v. Eli Lilly and Co., 560 F.3d 1366, 1380 (Fed. Cir. 2009).
44. M. Beyer et al. Biologics in cutaneous lymphomas. In W.H. Boehncke and H.H. Radeke, eds. Biologics in General Medicine 150 (2007)
45. and Paula T. Rieger, ed. Optimizing the dose and schedule of biological agents. In Biotherapy: A Compre hensive Overview (Jones and Bartlett Series in Oncology) 102 (2001).
46. Section 29(2) of Tokkyo Ho.
47. Asta Medica A.G. v. Commissioner Japan Patent Office, Hei- sei 12 (gyo-ke) 294, dated Mar. 28, 2001 (Tokyo H. Ct.).
48. AntiCancer Inc. v. Commissioner Japan Patent Office, Case No. Heisei 18 (gyo-ke) No.10079, dated Feb. 26, 2007 (Intell. Prop. H. Ct. of Japan).
49. Japan Patent Office, Example 8-Medicine adopting a specific dosing interval and/or given dose has a remarkable effect on a specific group of patients, Examination Guidelines for Patent and Utility Model in Japan Part VII Chap. 3.3.3 (Apr. 2005).
50. The Intellectual Property Headquarters (IPHQ) is given Prime Minister Cabinet ranking and was established under Sec tion 1 of Basic Law on Intellectual Property, Law No.122 of 2002; available at http://www.ipr.go.jp/ index.html [Japaneseonly]. The IPHQ annually adopts the Strategic Program for the Creation, Protection and Exploitation of the Intellectual Prop erty and takes necessary measures, including proposing intel lectual property legislation that will improve Japan's inter national competitiveness; see Hiroyuki Odagiri, National Innovation System: Reforms to Promote Science-Based Indus tries, Japan, Moving Toward a More Advanced Knowledge Economy: Assessment and Lessons 140 (Hirotaka Takeuchi, ed. 2006).
51. Government set to allow patenting of drug dosing methods, Yomiuri Shimbun, Jun. 1, 2009.
52. Karl Keegan. Biotechnology Valuation: An Introductory Guide 7 (2009)(noting biotechnology's "long timeframes and high development costs to bring one product into the market along with the challenges of high risk and technical uncer tainty.").
53. Patent Term Guarantee Act of 1999, Pub. L. No.106-113, §§4401-4402, 113 Stat. 1501, 1501A-557 (1999).
54. Tomomi Aida et al. Shortened life spans of biotech pioneerpatents in Japan: A lesson from the DNA chip. Nature Biotech-nol 2007;25:533.
55. Section 67bis of Tokkyo Ho.
56. Sandoz AG v. Commissioner of JPO, Cases No. H-10 (gyohi) No.43 and 44, dated October 22, 1999 (Sup. Ct.).
57. Japan Patent Office Annual Report 2008 47 (2008).
58. Japan Patent Office Annual Report 2001 7 (2001).
59. Supra note 50, at 47.
60. Id. at 14.
61. Id. at 48.
62. Id.
63. Id. at 9.
64. The Insecticide Composition Case, Case No. Showa 43 (wa) 1536, dated Jan. 31, 1972 (Tokyo Dist. Ct.)(the claim was de scribed by a generic concept at the time of the filing but was later limited to five types of substances based on more specific concepts; the court held that the substances other than those five types had been intentionally excluded by the applicant)
65. Changes to Practice for Petitions in Patent Applications to Make Special and for Accelerated Examination, 71 FR 36323 (Jun. 26, 2006).
66. Devan V. Padmanabhan and Alicia Griffin Mills. USPTO ac celerated examination: A pre-litigation strategy, 8(10) L. J. Newsletters-Pat. Strategy & Mgmt. (Mar 2008).
67. Dirk Thomas, Chandran Iyer, and Aziz Burgy. Slow down before accelerating, 4(1) The SciTech Lawyer - Section of Sci. & Tech. L. of the ABA 4 (Summer 2007).
68. Harold Milton. Patent preparation mandated by the law, 89 J. Pat. & Trademark Off. Soc'y 809 (Oct. 2007) (suggesting that "it is in applicant's best interest to have the patent application drafted around the most pertinent prior art to avoid ex pensive amendments and the potential of not claiming the essence of the invention.").
69. Cynthia Robbins-Roth. From Alchemy to IPO 40 (2001) re counts Amgen's executives making monthly flights to Japan in the early 1980s in search of business collaborators.
70. By 1991, there were at least 282 alliances between Japanese and American biotechnology companies, and 90% of the tech nology flow was from small U.S. firms to large Japanese com panies; see Office of International Affairs, U.S.-Japan Tech nology Linkages in Biotechnology: Challenges for the 1990S 22 (1992).
71. The authors' firm was the Japanese patent counsel on record that handled the expedited examination for this PDL case. How ever, the authors affirm that all information in this article re lating to PDL was derived wholly and solely from publicly available sources, including newspapers, the JPO online data base, the Industrial Property Digital Library, PDL Annual Re ports, and the company's Securities and Exchange Commission filings, which are freely available to anyone.
72. Japan Patent Office, Industrial Property Digital Library; available at http://www.ipdl.inpit.go.jp/homepg-e.ipdl.
73. Government of Japan, Ministry of Education, Culture, Sports, Science & Technology, Strategic Utilization of Intellectual Property, Annual Report on the Promotion of Science and Tech nology 2002 28 (2003).
74. Tom Abate. Braced for biotech's ups, downs: Tough little an tibody is ace in the hole for Fremont firm, S.F. Chron., Nov. 23, 1998 at B3.
75. PDL Pharma Inc., Form 10K Annual Report Period Dec. 31, 2000 10-12 (Mar. 31, 2001).
76. Jo Kawakami. M&As loom as drug patents expire, Nikkei, May 18, 2009, and With patents expiring, Astellas Pharma speeds up R&D efforts, Nikkei, Jan. 26, 2009.
77. Ernst & Young. Beyond Borders Global Biotechnology Re port 2009 121 (2009) (noting that "Japanese big pharma com panies have been looking for innovation overseas in recent years.").
78. John A. Tessensohn and Shusaku Yamamoto. Maximizing torque on the JPO/USPTO patent prosecution highway, 22(3) World Intell. Prop. Rep 9-11 (March 2008).
79. John A. Tessensohn and Shusaku Yamamoto. Japan launches its "Super Accelerated Examination" system, 23(1) World In- tell. Prop. Rep. 8-10 (Jan. 2009).
80. John Tessensohn and Shusaku Yamamoto. Japan's novelty grace period solves the dilemma of "publish and perish." Nature Biotechnol 2007;25:55.
81. Supra text accompanying notes 58 to 60.
82. Japan External Trade Organization, Attractive Sectors- Biotechnology 1 (2007).
83. 2007 Japan biotechnology market expands by 11%: Antibody segment worth 85 billion yen, Nikkei Biotech. and Bus., Jan 14, 2008 [Japanese only].
84. The 2010 Obama Administration Healthcare Plan has ex pressly sought to prohibit originator biologic producers "from reformulating existing products into new products to restart the exclusivity process, a process known as ever-greening."); see Office of Management and Budget, Fact Sheets: President Obama's Fiscal 2010 Budget Transforming and Modernizing America's Health Care System (2010); available at http://www. whitehouse.gov/omb/fy2010- key-healthcare/.
85. Oliver Kayser and Rainer H. Müller. Pharmaceutical Biotech nology: Drug Discovery and Clinical Applications 4 (2004).
86. Ceci Connolly. With health reform, Waxman takes on an other tall order, Wash. Post, Jul. 20, 2009 at A4 (reporting that that U.S. House of Representatives and Senate could finally de liver on an FOB regulatory pathway with a period of 12 to 14 years of data exclusivity protection, as demanded by the biotechnology industry lobby, but the Chairman of the House Energy and Commerce Committee, Rep. Waxman, proposed 5 years of data exclusivity, "while the Obama administration pro posed seven years as a 'generous compromise' ").
87. Wendy H. Schacht and John R. Thomas. Follow-On Bio- logics: Intellectual Property and Innovation Issues, Congres sional Research Service Report RL 33901 8-9, 14-16 (Mar. 2009)
88. Alan J. Morrison. Biosimilars in the United States: A brief look at where we are and the road ahead. 26(5) Biotech- nol. L. Rep. 463 2007.
89. Bruce S. Manheim Jr., Patricia Granahan, and Kenneth J. Dow. 'Follow-on biologics': Ensuring continued innovation in the biotechnology industry, 25(2) Health Affairs 394 (2006) (persuasively arguing that Congress should "need to create a regulatory mechanism that assures the safety and efficacy of follow-on protein products. At the same time, Congress must establish a statutory scheme that provides market protection for new protein products and thereby creates incentives for investment and innovation in the biotechnology industry.").
90. Barack Obama. The Plan: Barack Obama's Promise to America and his plan for the economy, Iraq, Healthcare, and More 40 (2009)(the President promised "to increase the use of ge neric drugs in public programs").
91. F. Randy Vogenberg. Biosimilars Policy Forum: Perspectives on safety and efficacy of future products, Am. Health & Drug Benefits 2(4):166 (June/July 2009).
92. Congressional Budget Office, Cost Estimate: S. 1695 Biolog-ics Price Competition and Innovation Act of 2007 June 25, 2008.
93. Medicare Payment Advisory Commission (medPAC). Re port to Congress: Improving Incentives to the Medicare Pro gram 129 (Jun. 2009) (medPAC, an independent Congres sional agency, concluded that the "lack of an expedited approval process for FOBs has kept the prices of innovator biologics high over time" and supported the establishment of an "approval process for FOBs [that] could put pressure on the prices of biologics, generating savings for Medicare."). The American Association of Retired Persons has vigorously supported the establishment an abbreviated regulatory pro cess for FOB; see AARP Public Policy Institute. Biologics in Perspective: The Case for Generic Biologics Fact Sheet 155 (May 2009).
94. Office of the Press Secretary, The White House. Remarks by The President at the Annual Conference of the American Medical Association (June 15, 2009). President Obama was ap plauded by an important healthcare interest group, America's physicians, when he stressed the "need to introduce generic bi ologic drugs into the marketplace. These are drugs used to treat illnesses like anemia. But right now, there is no pathway at the FDA for approving generic versions of these drugs. Creating such a pathway will save us billions of dollars." Available at http://www.whitehouse.gov/the-press-office/Remarks- by-the- President-to-the-Annual-Conference-of-the-American-Med-ical-Association/ .
95. Duff Wilson. More cost cuts sought from drug industry, N.Y. Times, Jul. 22, 2009 at B1 (characterizing the delicate health care negotiations between the drug industry and Congress over the creation of the data exclusivity period in an FOB regulatory pathway as "another pivotal piece of the cost puzzle" of healthcare reform).
96. Stuart O. Schweitzer. Pharmaceutical Economics and Policy 21 (2007).
97. Biologics and Biosimilars: Balancing Incentives for Innovation. Before the Committee on the Judiciary Subcommittee on Courts, 111th Cong. (2009)(testimony of Jeffery P. Kushan, Biotechnology Industry Organization) (concluding that to en sure continued U.S. leadership in biotechnology innovation, any FOB legislative framework must contain a 14-year data exclu sivity period "given the uncertainties of effective patent-based protection and the higher risks associated with investment in biotechnology"). Available at http://judiciary.house.gov/hear- ings/pdf/Kushan090714.pdf.
98. Several lower-cost FOB manufacturing countries such as China, India, and South Korea have already reported a high number of licensed FOBs within their existing regulatory frame works; see World Health Organization, WHO Informal Con sultation on Regulatory Evaluation of Therapeutic Biological Medicinal Products (April 2007).
99. See also Linda H. Fellcone, The long and winding road to biologic follow-ons, Biotech. Healthcare 20, 24 (May 2004) (reporting that "countries such as India and China with large populations, low development and manufacturing costs, and low regulatory barriers may dominate follow-on biologics.").
100. Lisa Urquhart. 'Biosimilars' target a market of $50bn, Fin. Times, Feb. 17, 2006.
101. Bernadette Tansey. Biotechs claw for their lifeblood: Financing, S.F. Chron., Nov. 16, 2008 at C1.
102. The primary competitive threat is from countries with ma ture FOB markets and manufacturing capacity which include India, China, and South Korea. See K.S. Jayaraman, Indian bio- generics industry emerges. Nature Biotechnol 2007;21:1115
103. Alla Katsnelson. Teva to acquire Chinese biogenerics manufacturer. Nature Biotechnol 2005;23:765;
104. Cho Chung-un. Samsung veers into drug market, Korea Herald, Jul. 9, 2009
105. and Reuters. Samsung to invest $389 million in biosimilars, Jul. 15, 2009.
106. Robert Swanson. Entrepreneurship and innovation in biotechnology, in Ralph Landau et al., eds. The Positive Sum Strategy, 431 (1986) (Swanson, one of the legendary founders of Genentech, cautioned that "the Japanese have relied on the US and other countries to provide the breakthroughs. Then, by rapidly applying considerable expertise in process development and scale-up, they can jump well ahead and capture a large share of the world market for biotechnology products.").
107. Daniel Kevles. Diamond v. Chakrabarty and beyond: The political economy of patenting life. In Arnold Thackray, ed. Private Science: Biotechnology and the Rise of the Molecular Science 71 (1998) (noting that "at the end of the 1970s the commercial aspects of biotechnology figured prominently in the minds of federal policymakers"); Leroy Hood, a storied biotechnology pioneer, bluntly warned the U.S. Senate in 1990 that America's world leadership in biotechnology was "unequivo cally being threatened by the Japanese" at funding hearings for the Human Genome Project; see Rodney Loeppky, Encoding Capital: The Political Economy of the Human Genome Project, 86 (2005)
108. Robert M. Cooke-Deegan. The Gene Wars: Science, Politics, and the Human Genome 230 (1996) (reporting that "Congressional patrons of genome research saw the project as a vehicle to maintain technological advantage over Japan.").
109. See Arthur D. Levinson. What distinguishes biotech from pharma. Ernst & Young, Beyond Borders Global Biotechnol ogy Report 2005 15 (2005) (the then-CEO of Genentech ob served that "it's no coincidence that the major biotech centers in the United States are clustered around top academic institutions. In South San Francisco, Genentech is nestled between U.C. Berkeley, U.C. San Francisco, and Stanford. Many biotechs are rooted in academic beginnings and have success fully maintained a culture that attracts top scientists").
110. America's track record of success with the university-industry cluster experiment is patchy; see Scott Wallsten. High-tech cluster bombs: Why successful biotech hubs are the exception, not the rule. Nature 2004;428:121. National governments have experienced difficulties replicating successful biotechnology clusters in France, Germany, Singapore and Dubai. The fading lustre of clusters, Economist 11 (Oct. 11, 2007); Andrea Rinaldi.
111. More than the sum of their parts? EMBO Reports 2006;7(2):133 (noting that biotechnology clusters are opening in France, Germany, Italy, U.K., China, India, Kazakhstan, Thailand, and others "despite concerns over the sustainability and economic ef fectiveness of science parks and hubs").
112. See John Carey. Biotechnology: "A terrible panic" among private biotechs, Bus. Wk., Nov. 20, 2002 (reporting the cor porate casualties of "2002's severe biotech downdraft" and one venture capitalist warning that "lots and lots of companies are going to die").
113. Sally Lehrman. Tough times set to continue for US biotech start-ups. Nature 1999;397:191.
114. See also Francoise Simon and Philip Kotler. Building Global Brands: Taking Biotechnology to Market 11 (2003) (recounting major slumps that the biotechnology industry suffered in "1984, 1988, 1994, 1997 and 2001 following boom periods").
115. David P. Hamilton. Biotech's dismal bottom line: More than $40 billion in losses, Wall St. J., May 20, 2004, at A1 (report ing that among Wall Street analysts, biotechnology stocks are the "ultimate roulette game," "high risk and high reward," but the odds "are better than in Vegas").
116. Peter Whoriskey et al. U.S. bets billions on GM's resur gence: Obama unveils plan for brief bankruptcy, nationaliza tion, Wash. Post, Jun. 2, 2009 at A1
117. and Peter Whoriskey. With bankruptcy behind it, GM focuses on a culture change, Wash. Post, July. 11, 2009 at A10 (reporting the humbling of General Motors, a one-time titan of American innovation and industry, ignominiously slipping but gingerly emerging from temporary bankruptcy and nationalization).
118. Elizabeth A. Czerepak and Stefan Ryser. Drug approvals and failures: implications for alliances. Nature Revs Drug Dis covery 2008;7:197 (concluding that the "decade-long drought in new drugs originating from big pharma should continue to enhance the ability for biotech companies with high-quality products to attract funding from large pharma, creating a good business proposition for both.").