1
國立交通大學
科技法律研究所
碩 士 論 文
Patentability of Human Genes:
The Myriad Case and Beyond
人體基因是否可為專利保護標的:
由 Myriad 案為起點
研 究 生：謝宗穎
指導教授：王立達 博士 、林欣柔 博士
中 華 民 國 一○二 年 一月
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Patentability of Human Genes: The Myriad Case and Beyond
人體基因是否可為專利保護標的:由 Myriad 案為起點
學生：謝宗穎 Student: Tsung-ying Hsieh
主指導教授：王立達 博士 Advisor: Dr. Li-Dar Wang
共同指導教授：林欣柔 博士 Co-advisor: Dr. Shin-Rou Lin
國 立 交 通 大 學
科 技 法 律 研 究 所
碩 士 論 文
A ThesisSubmitted to Institute of Technology Law College of Management
National Chiao Tung University in partial Fulfillment of the Requirements
for the Degree of Master
in
Technology Law January 2013
Hsinchu, Taiwan, Republic of Taiwan
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人體基因是否可為專利保護標的:由 Myriad 案為起點
學生:謝宗穎 主指導教授: 王立達 博士 共同指導教授: 林欣柔 博士國立交通大學科技法律研究所碩士班
摘 要
專利制度藉由賦予研發者或投資者排他權，以達鼓勵研發之目的。此排他權 可使投資者與發明者回收研究資金成本，甚至得到額外的報酬。過去三十年來， 基因相關專利急速的增加，代表基因關聯發明的重要性日益增加，但也因基因專 利排他的特性而對現有的科學研究產生了不良影響。例如有些基因研究因他方的 專利之阻礙，無法順利進行研究。這通常涉及支付相關專利授權費用而導致基因 研究的時間延長與成本提高。再從病人的角度言，當僅有專利權人可實施該技術 時，可能剝奪病人獲得第二意見(second opinion)的權利。所謂的第二意見係指為 了確定先前診斷報告準確性而去尋求其他意見。這些問題與專利制度鼓勵創新的 本質產生了衝突，也是近期 Myriad 案之所以受到廣泛關注的原因之一。本案的 主要爭點為人體基因是否可為專利保護標的，原告主要為受到基因研究專利所帶 來的負面影響的研究機構與正接受臨床治療的病人，他們透過主張人體基因係非 專利適格標的而使基因專利無效。本案判決代表了美國聯邦上訴法院對基因專利 的最新見解，突顯出 Myriad 案的重要性。本論文之研究重點是分析美國以往專 利適格標的之重要案件，並與最新 Myriad 案比較，希望藉此了解法院判斷專利 適格標的之標準，哪些是一致的，而哪些是有改變的。最後，針對此判決對研究 機構、病人、發明人與投資者所造成的影響，本論文將提出可行的解決方案。 關鍵字: 專利適格標的, 基因專利, 基因序列4
Patentability of Human Genes: The Myriad Case and Beyond
Student: Tsung-ying Hsieh
Advisor: Dr. Li-Dar Wang
Co-advisor: Dr. Shin-Rou Lin
Institute of Technology Law
National Chiao-Tung University
ABSTRACT
The drastic increase of patent filing and applications on genes for past thirty years has shown the increased importance gene related inventions. One primary motivation of setting up the patent system is to provide an incentive to invent by insuring the investors and prospect inventors a possible return or gain of the research cost. But this exclusivity offered by gene patents has produced some adverse consequences such as the inaccessibility to genes for research, increase cost in diagnostic cost or deprive the opportunity for second opinion for patients. These are some reasons why the issue on the patentability of human genes has attracted more concern since the instigation of the Myriad case. The plaintiffs of this case are mainly research groups and patients that have “negatively” affected by the gene patent and therefore, hope to invalidate the patent by challenging the gene sequence not a patentable subject matter. The uniqueness and the complexity of gene patents are related to the unidentified functions in genes or broad wordings used in claims. As a result, granting gene patents may stifle the future genetic research and development of diagnostic test such as parallel sequencing and whole genome sequencing. In addition, lack of clear standards when determining patentable subject matter is also another sophisticated issue that needs to be solved when granting gene patents. Thus, the major focus of this thesis is to analyze different standards used in the precedent cases in U.S. and compare these standards with the standards used in the Myriad case. Thus, hope to understand Federal Court’s recent view on this issue. Furthermore, discuss the implications of these new holdings on the public, investors and prospect inventors. Lastly, with different problems arise from the granting of gene patents and propose some possible solutions to help solving the current and future situation on gene patents.
5 Acknowledgement 終於要畢業了!!這條路走下來真的很辛苦，但這一切都是值得的。在這段期 間中，交大科法所紮實的課程設計與各位老師細心的照顧指導，讓學生有機會不 斷的學習與成長。也由於這個機會，認識了一群知心的朋友。 首先要謝謝我們科法所的每一位老師，這一路走來受到你們每一位的幫助與 指教，讓學生成長許多。首先要謝謝立達老師這段期間的細心指導，讓我有機會 回頭檢視自己的弱點，改進了我的寫作能力。老師，謝謝你。接下來，學生要謝 謝欣柔老師的一路的指導與耐心鼓勵，your encouragement is important to me。敏 銓老師，謝謝您從最初認識至今的所有一切幫助與教導。謝謝劉老師與倪老師的 平時教導。謝謝建中老師的給予的所有對學生協助與支持。謝謝志潔老師與鋕雄 老師平時的細心照顧與熱情的教導。最後更要感謝李素華老師給予學生的所有的 義務幫助。各位老師，辛苦了，學生真的非常感謝你們。 書瑋、靜雅、Grace、珮珍、洗碗精、秉志、樗寧、語青、俊雯、于柔、郁 之、昱婷、小涵、書瑜、以及我在科法所的每一位朋友，謝謝你們。能與你們做 朋友真是我的榮幸。 最後要感謝我一路支持我的家人，使我無後顧之憂。爸、媽，妹妹、謝謝你 們。
6 Index Chinese Abstract………..……… 3 English Abstract………... 4 Acknowledgement………... 5 Index……….……… 6 Chapter 1 – Introduction 10 1.1 Motive of the Research………...………. 10
1.2 Research Scope, Method and Structure of the Thesis... 13
1.2.1 Purpose and Scope of the Research……….……… 13
1.2.2 Research Method………... 14
Chapter 2 - Background to Gene Patent 14 2.1 Fundamental Knowledge on DNA and Genome Sequence………..………….. 14
2.1.1 DNA and It’s Roles……….………. 2.1.2 Protein Synthesis……….………….... 2.1.3 Duplication of DNA………... 2.1.4 Study of Defective Gene………...………... 2.1.5 Cancer Genes………...…… 2.1.6 Importance of BRCA1/2 Gene………... 2.1.7 DNA Sequencing………...…... 2.1.8 cDNA Sequencing………... 2.1.9 Whole Genome Sequencing………... 14 16 16 17 17 18 19 19 20 2.2 Different Categories of Gene Patents………... 2.2.1 Therapeutic Protein………..… 2.2.2 Gene Therapy……….……….. 2.2.3 Diagnostic Testing………..……. 20 20 21 22 2.3 What Is a Patentable Invention?... 23
2.3.1 Process…..……….……….. 2.3.2 Machine………..…. 2.3.3 Manufacture………... 2.3.4 Composition of Matter………... 24 24 24 24
2.4 Gene Patent and It’s Different Perspectives……… 2.4.1 Definition of Gene Patent………..….. 2.4.2 Incentives to Invest………..… 2.4.3 Patient Access………..…… 2.4.4 Research Access………. 25 25 26 30 32
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3.1. Well Accepted Standard Prior to the Myriad Case 35
3.1.1 Exceptions to Patent Act
Case 1 - Funk Bros. Seed Co. v. Kalo Inoculant Co.
(1948)………
Case 2 - Gottschalk v. Benson (1972)………... Case 3 - Diamond v. Chakrabarty (1980)……….
3.1.2 Application of a Law of Nature or Mathematical Formula May Deserve Patent Protection……….
Case 1 – Mackay Radio & Tel. Co. v. Radio Corp. of Am. (1939)… Case 2- Funk Bros. Seed Co. v. Kalo Co. (1948)……….. Case 3- Diamond v. Diehr (1981)……….
35 35 36 36 38 38 38 39
3.2 Issues at Debate Prior to the Myriad Case 39
3.2.1 Standard for the Distinction between Product of Nature and Human-made Invention
3.2.1.1 - Natural Product in General
Case 1 - Hartranft v. Wiegmann (1887)……….… Case 2 - Parke-Davis v. Mulford Co. (1911)……….. Case 3 - American Fruit Growers v. Brogdex Co. (1931)……... Case 4 - Funk Bros. Seed Co. v. Kalo Co. (1948)………... Case 5 – In re Marden (1998)………. 3.2.1.2 – Gene Patent in Specific
Case 1 - Diamond v. Chakrabarty (1980)………. Case 2 - Amgen, Inc v. Chugai pharmaceutical co. (1991)……
Case 3 -Schering Corporation and Biogen v. Amgen Inc.(2000) Case 4 - Genzyme Corp and Mount Sinai School of Medicine
of New York University v. Transkaryotic Therapies, Inc. (2004)
39 39 40 41 41 42 43 43 44 45
3.2.2 Standard for Determining the Patentability of Method or Process Claim in Gene Patent
Case 1- Gottschalk v. Benson (1972)……….. Case 2- Parker v. Flook (1978)………... Case 3- Diamond v. Diehr (1981)………... Case 4- In re Bilski (2008)……….. Case 5 –Prometheus v. Mayo (2009)………... Case 6 - Bilski v. Kappos (2010)………. Case 7 – Mayo v. Prometheus (2012)………..
46 46 47 48 50 51 52 53
3.3 Summary Table 1 – Well Accepted Standard Prior to the Myriad Case……….. 3.4 Summary Tables – Issues at Debate Prior to the Myriad Case……….………...
54 55
8
3.4.1 Standard for Qualifying the Distinction between Product of Nature and Human-made Invention………. 3.4.2 Standard for Determining the Patentability of Method or Process
Claim in Gene Patent……….. 3.5 Overall Summary………...
55
58 61
Chapter 4 – The Myriad Case 66
4.1 Background Information Related to the Case………...…………... 4.1.1 Information on Myriad Genetics, Inc. ……….. 4.1.2 History of Patents in Suit………... 4.1.3 BRCA1 and BRCA2 Tests Offered by Myriad Genetics, Inc. …... 4.1.4 Patent in Suit Table………...
66 66 69 69 70
4.2 District Court’s Decisions……….... 4.2.1 Table – Amici Curiae in District Court’s Decisions on Granting the Patent for Human DNA Sequences………... 4.3 Federal Court’s Earlier Decisions………... 4.4 The Federal Court’s Decisions in the Recent Remanded Myriad Case
4.4.1 Issue 1 – Who Has the Standing for Claiming the Declaratory
Judgment?... 4.4.2 Issue 2 – Do the Organization Plaintiffs Have Standing to Invoke
Declaratory Judgment?... 4.4.3 Issue 3 – Whether or Not the Composition Claims Covering Isolated
DNA Sequences Directed to Patent-eligible Subject Matter?... 4.4.4 Issue 4 – Whether or Not cDNAs Are Eligible for Patent?... 4.4.5 Issue 5 – Whether or Not the Method Claims for Comparing or
Analyzing Isolated DNA Sequences Are Patentable?... 4.4.6 Issue 6 – Whether or Not the Method Claims for Screening Potential
Cancer Therapeutics via Change in Cell Growth Rates Are Patentable?... 4.5 Concurring and Dissenting Opinions……….. 4.6 The Comparison between the Two Federal Court
Decisions………. 4.6.1 Majority’s Opinion on the Issue of Invoking Declaratory Judgment Standing………... 4.6.2 Majority’s Opinion on the Issue of Composition Claims- Isolated DNA Molecules……….. 4.6.3 Majority’s Opinion on the Issue of Method Claims……….……… 4.6.4 Comparison of Judge Moore’s Opinion……….………..
72 75 80 80 81 83 83 86 87 89 90 93 93 93 95 96
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4.6.5 Comparison of Judge Bryson’s Opinion……….………. 99
Chapter 5 – Assessing the CAFC’s Decisions in the Myriad Case
5.1 Assessment of Judge’s Opinions as Delivered in the Myriad Case……….…… 5.1.1 Issues Solved: Test Method Claims in Gene Patents………... 5.1.2 Unsolved Issues: Composition Claims in Gene Patents……….. 5.1.3 Do the Decisions in the Myriad Case Derailed from the Precedent Cases and the Statute? ……….
100 100 100 102
105
5.2 How Do the Decisions of CAFC in This Case Affect the Research Access,
Patient Access and Incentives to Invest?... 106
Chapter 6 – The Possible Solutions to Gene Patenting
6.1 Alternatives in Solutions……….………. 6.1.1 Compulsory Licensing……….… 6.1.2 Research Exception……….………. 6.1.3 Granting of the “Function-specific” Patent………. 6.1.4 Patent Pool……….…….. 110 110 110 111 114 116 Chapter 7 - Conclusions 117 References 120 Cases Cited 126
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Chapter 1- Introduction
1.1- Motive of the Research
The framers of the U.S. Constitution created incentives for technological invention by drafting Intellectual Property Clause.1 One of major goals of the patent law is to disclose the newest scientific discoveries information to the public and to enlighten the public as to how these discoveries can benefit society.2 However, since the first gene patent issued to Regents of the University of California in 1982
regarding a bacteria containing plasmid that expresses a chronic somatomammotropin gene3, the debate over the protection of human gene sequence has sparked a long debate whether human genes should be treated as a patentable subject matter. One of the major concerns is the limited access to testing and diagnosis where patients are unable to confirm or verify the accuracy of the diagnostic test with another diagnostic facility when the patentee is the sole provider of the gene test.4 Another concern relates to the potential of impeding the future researches which contradict with the original purpose of setting patent system and that is to stimulate innovation.5
Since the instigation of human gene research, the outcomes of the various researches have played pivotal roles in treating and preventing genetically inherited diseases. Starting in late 1970s, scientific researchers began to view genetic material as a means of developing treatment options for a variety of human diseases.6 As the gene researches become prevalent, there is an increase trend of seeking for patent protection. Human gene sequences are now widely used in different clinical and research areas such as gene therapy, diagnostic genetic testing, and purified protein production. With the advancement of pharmaceutical industry, the relationship
1
The Constitution gives Congress the 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 Writings and Discoveries.” U.S. Const. art. I, § 8, cl. 8.
2 Bonito Boats, Inc. v. Thunder Craft Boats, Inc., 489 U.S. 141, 151 (1989). 3
Gene Patents and Global Competition Issues, available at http://
www.genengnews.com/articles/chitem.aspx?aid=1163&chid=0 (last visited April. 15, 2012). 4
David H. Ledbetter, Gene patenting and licensing: the role of academic researchers and advocacy
groups, 10GENETICS IN MED.314,314(2008). 5
Kate Murashige, Patents and Research--An Uneasy Alliance, 77ACAD.MED. 1329(2002)
(evaluating the claim that patents such as gene patents inhibit scientific progress). 6
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between drugs and gene product has become closer compared to a few decades ago.7 For example, the completion of the Human Genome Project in 2003, identifying nearly 25,000 genes and 3 billion base pairs in the human body that setup a complete human gene database.8 One of the aims of this technology is to transfer the
information to private sectors, thereby facilitating diagnoses of disease and
pharmaceutical development.9 This caused a drastic increase in the number of patent applications for human genes over past few decades.10 The number of applications increased more than double from approximately 16,000 applications in 1990 to 33,000 applications in 2000.11 Today, close to two thirds of new drugs that reach the market have been influenced by genetic research,12 and genetic material has been linked to more than 850 human diseases.13 The average life expectancy of U.S. citizens has elongated and quality of life have greatly enhanced over the past century, and this largely due to the improvement of pharmaceutical and genetic innovations.14 Nearly twenty percent of human genes are patented under United States law15 and a
7
GREGORY J.HIGBY, FROM COMPOUNDING TO CARING:AN ABRIDGED HISTORY OF AMERICAN
PHARMACY IN PHARMACEUTICAL CARE 19,36-37 (Knowlton H. Calvin & Richard P. Penna eds., 2d ed. 2003).
8
Battelle Technology Partnership Practice, Economic Impact of the Human Genome Project (2011), http://battelle.org/docs/default-document-library/economic_impact_of_the_human_genome_project.pd f?sfvrsn=2.
9 Id. 10
Richard Willing, Gene Patent Gets Tougher, USATODAY, Nov. 15, 2000, at 14A.
11 Id. 12
Andrew Pollack, The Genome at 10: Awaiting the Genome Payoff, N.Y.TIMES, June 15, 2010, at B1, available at http://www.nytimes.com/2010/06/15/business/15genome.html (indicating that the Research and Development President at Bristol-Myers Squibb and the Research Executive Vice President at Roche have both proclaimed that two-thirds of newly developed drugs have been influenced by genetic research).
13
Nicholas Wade, A Decade Later, Gene Map Yields Few New Cures,N.Y.TIMES, June 13, 2010, at A1, available at
http://www.nytimes.com/2010/06/13/health/research/13genome.html?pagewanted=1&ref=business. 14
LAURA B.SHRESTHA,CONG.RESEARCH SERV.,RL32792,LIFE EXPECTANCY IN THE UNITED STATES
2-5 (2006) available at http://aging.senate.gov/crs/aging1.pdf (showing that the average American life expectancy has increased by nearly thirty years in the past century and citing medical advances as a reason for these decreased mortality rates); see also Kaiser Public Opinion Spotlight: Views on Prescription Drugs and the Pharmaceutical Industry 1, THE HENRY J.KAISER FAMILY FOUND. (Apr. 2008), http://www.kff.org/spotlight/rxdrugs/upload/Rx_Drugs.pdf (indicating that most American adults take prescription drugs and that a vast majority of Americans believe that prescription drugs improve quality of life).
15
Kyle Jensen & Fiona Murray, Intellectual Property Landscape of the Human Genome, 310SCI.239, 239(2005).
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large portion of those patents related to human health especially cancer related.16 With the increase importance in pharmaceutical development, the recent landmark case on patentability of cancer detecting gene sequence, Association for Molecular
Pathology, et al. v. United State Patent and Trademark Office, et al. (the Myriad
case)17, has bought greater attention from the public and biotechnology industry on
the issue of patentability of human gene sequence.
The patentable subject matter is set forth in 35 U.S.C §101. As the law stated “whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.”18 Attached with this rule are three major exceptions: natural phenomenon, law of nature, and abstract ideas. Those exceptions are excluded from patentable subject matter and all needed to be examined before the Court goes on to reach a conclusion as to the issue of patentable subject matter. Despite numerous preceding court decisions on this issue, prospective inventors are still left with uncertainty the standards used in determining the patentable subject matter. The recent case Association for Molecular Pathology, et
al. v. United State Patent and Trademark Office, et al., may help to determine the
most recent view of the U.S. Courts.
In this law suit, numerous non-profit organizations, research organizations and patients sued defendant Myriad and United States Patent and Trade Office (USPTO) based on the invalidity of breast cancer detecting gene patents, BRCA1 and BRCA2. The defendants’ patents, which encompass composition of matter claims and process claims, were invalidated by the United States District Court, S.D. New York. However, when the case is appealed to the U.S. Court of Appeals for the Federal Circuit, district court’s judgment was partly reversed because the Federal Circuit still holds the same view as expressed in the long practice of USPTO and another leading case, Diamond v.
Chakrabarty, which supports a broad protection of bio-organisms thus "anything
16 Id. at 240. 17
Ass’n of Molecular Pathology v. USPTO, 702 F. Supp. 2d 181 (S.D.N.Y. 2010); Ass’n for Molecular Pathology v. USPTO, 653 F.3d 1329 (Fed. Cir. 2011); Ass’n for Molecular Pathology v. USPTO, 132 S.Ct. 1794 (2012); Ass’n for Molecular Pathology v. USPTO, 689 F.3d 1303 (Fed. Cir. 2012).
18
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under the sun that is made by man" is patentable.19 The case was appealed to the U.S. Supreme Court and certiorari was granted. The case was then vacated and remanded by the Supreme Court to the Federal Court and was given an instruction to reconsider in light of Mayo Collaborative Services v. Prometheus, Inc. case.20 However, in the recent verdict on remand dated Aug 16, 201221, the Federal Circuit still reaffirmed their previous decisions.22 As mentioned above, this judgment by the Federal Circuit may have tremendous impact for the probability that it could bring clarity to the patentability issue regarding human gene sequences. Therefore, this case should be closely analyzed.
1.3 - Research scope, Method, and Structure of the Thesis
1.2.1 Purpose and Scope of the Research
The foundation for the U.S. patent system is based on the Article I, Section 8, Clause 8 of the U.S. Constitution which allowed the Congress to promote the progress of the science and useful arts.23 But, the reality is showing signs that patents are not only assisting but rather partly impeding the progress of science. Since the massive patenting of ESTs (Expressed Sequence Tags) without knowing the actual function of these genes, the issue of patenting genes has become a greater issue because some scientists have argued the difficulty of developing the multiplex gene diagnostic test as it may require hundreds of genes. As more people are reliant on the biotechnology development, this issue must be resolved in order to promote greater progress of science. Via the analysis of the most recent case, Association for Molecular Pathology,
et al. v. United State Patent and Trademark Office, on patentability of gene sequence,
in hoping to determine the patentability of human gene sequence and the standards used to determine the patentable subject matter. Also, examining from a broader view, how will these recent standards set by the Federal Court may affect the future research, patient access and incentive for investment? At last, some possible solutions in
19
Ass’n for Molecular Pathology v. USPTO, 653 F.3d 1329, 1358 (Fed. Cir. 2011). 20
Mayo Collaborative Services v. Prometheus Laboratories, Inc., 132 S. Ct. 1289, 1295 (2012). 21
Ass’n for Molecular Pathology v. USPTO, 132 S.Ct. 1794, 1794 (2012). 22 Ass’n for Molecular Pathology v. USPTO, 689 F.3d 1303, 39 (Fed. Cir. 2012). 23 U.S. Const. art. I, §8 , cl. 8.
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solving the future problems that can be caused by the numberless of previous granted patents.
1.2.2 Research Method and Structure of the Thesis
The Myriad24 case has brought the attention the issue of patentability of human gene sequence. In patent law, patentable subject matter is one vital requirement for receiving a patent protection. Thus, one of the main goals of this thesis is to evaluate the standards used in precedents in determining a patentable subject matter. Standards will be categorized and analyzed via precedent cases that relate to the topic of
patentable subject matter. Confirmed and disputable standards will all be discussed. These standards will be evaluated again in the new Myriad25 case and compared if
there are any changes to these standards.
The first chapter will introduce the motive, purpose of the research, and the research method. Chapter two includes the fundamental background knowledge on human gene sequences. A brief introduction on patent and related terms is also introduced. Chapter three focuses on the U.S judicial decision on the subject matter requirement of gene patents and why this is still an issue today. Different cases related to patentable subject matter are described and further divided into two major
categories: 1) natural product in general and 2) gene in specific. Chapter four provides a detailed follow up on the Association for Molecular Pathology v. U.S. Patent and
Trade Office26 case. Chapter five is the issue assessment of the case and the impact
that the holdings might have on people. Chapter six presents some possible solutions to the problem of gene patents and the conclusion in Chapter seven.
Chapter 2 - Background to Gene Patent
2.1 - Fundamental Knowledge on DNA and Genome Sequencing
2.1.1 DNA and It’s Roles
The total genetic information content of each cell is known as the genome. It
24 Ass’n of Molecular Pathology v. USPTO, 702 F. Supp. 2d 181 (S.D.N.Y. 2010) 25 Ass’n for Molecular Pathology v. USPTO, 689 F.3d 1303 (Fed. Cir. 2012). 26 Id.
15
exists within the long, coiled macromolecules of DNA.27 DNA molecule resembles a ladder with rings and twisted into a spiral.28 One of the major functions of the DNA is that it is a major molecular repository for genetic information.29 The informational message is expressed or processed in two different ways: 1) exact duplication of the DNA that transfers the genetic material to daughter cells during the cell division and 2) expression of the stored information to produce RNA that are used to manufacture proteins that act as the molecular tools that carry out the cell activities.30 For example, the proteins in the human body participate in thousands of chemical reactions that occur in one cell31 and also act as the fundamental building blocks of cellular components.
Nucleic acids are thread like polymers which are made up of linear array of monomers call nucleotides.32 The nucleic acid can range from 80 nucleotides to over 100 million nucleotide pairs in a single eukaryotic chromosome.33 The unit size of a nucleic acid is the base pair (for double-stranded species) or base (for single-stranded species). Each monomer is made up of three parts: organic base containing nitrogen, a carbohydrate and a phosphate.34 The four different kinds of organic bases include adenine (A), cytosine (C), guanine (G), or thymine (T).35 The organic base on one side of the ladder bonds to a corresponding organic base on the opposing side called complementary base pairing.36 Therefore, adenine (A) pair with thymine (T) and cytosine (C) pair with guanine (G) via a chemical bonding called hydrogen bond.37 The sequence of nucleotides in a DNA strand may vary in various ways and this is what makes one organism genetic code unique. Each segment of nucleotide sequence
27
RODNEY BOYER,CONCEPTS IN BIOCHEMISTRY 23-33, 316-46 (3d ed. 2006).
28
ROBERT P.WAGNER,UNDERSTANDING INHERITANCE:AN INTRODUCTION TO CLASSICAL AND
MOLECULAR GENETICS, IN THE HUMAN GENOME PROJECT:DECIPHERING THE BLUEPRINT OF HEREDITY
40-41 (Necia Grant Cooper ed., 1994) [hereinafter THE HUMAN GENOME PROJECT];JAMES D.WATSON ET AL., MOLECULAR BIOLOGY OF THE GENE 73-75 (4th ed. 1987)[hereinafter MOLECULAR BIOLOGY OF THE GENE].
29
BOYER, supra note 27, at 23.
30 Id.
31 Id. at 23-24. 32
MICHAEL BLACKBURN ET AL., NUCLEIC ACIDS IN CHEMISTRY AND BIOLOGY 14-15 (3d ed. 2006).
33 Id. 34
Id. 35
THE HUMAN GENOME PROJECT, supra note 28, at 40-41.
36 Id. 37
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is called a “gene.” The gene is “expressed” when the encoded information is translated into a functional product, protein.38
2.1.2 Protein Synthesis
The gene express through a process known as “protein synthesis.” During the first phase of the synthesis called “transcription,” a gene serves as a template for the synthesis of a single-stranded ribonucleic acid (RNA) called a “messenger RNA” (mRNA).39 The genes of humans contained both the protein coding sequence (called “exons”) and non-coding sequence (called “introns”)40
Second phase of the protein synthesis is called “translation” where the mRNA acts as a template for the production of protein.41 When the protein is synthesized, it can further be processed to produce necessary hormones to catalyze the chemical reactions in the body.
2.1.3 Duplication of DNA
Before the initial of proteins synthesis, the duplication of DNA must first take place. It is a self-directed process and the process of DNA copying is called
replication.42 The process begins with unwinding of a short segment of the two complementary strands. Each strand is then used as a template for production of a new complementary partner strand.43 When DNA is replicated, the new copy of the DNA for the daughter cell must be identical to the parent DNA.44 The complex replication process is not always error free; mistakes such mutations, although very rare, still occur.45 The changes of the base sequence of DNA are called mutations and some are related to the harmful effects in human health, however, some silent
mutations do not affect the function of the protein products. As the result, if the errors
38 Id. 39
Id. at 45; MOLECULAR BIOLOGY OF THE GENE, supra note 28, at 73-75 (Transcription begins when an enzyme, an RNA polymerase, binds to a site on the gene called the “promoter.” The RNA
polymerase unwinds a portion of the double-helical gene, separating the gene into two strands. The RNA polymerase moves along the template strand and transcribes that strand into a single-stranded mRNA molecule.).
40
THE HUMAN GENOME PROJECT, supra note 28, at 45, 64.
41
Id., at 45. 42
BOYER, supra note 27, at 23-33.
43 Id. 44 Id. at 316. 45 Id.
17
are allowed to be transcribed into RNA and translated, protein products are altered and therefore change the biochemical properties in the body which some developed into cancer.46 The replication errors can be categorized into three main types: (1) substitution of one base pair for another (point mutation), (2) insertion of one or more extra base pairs, and (3) deletion of one or more base pairs.47 Among the three types of replication errors, substitution is the most common type of spontaneous
mutagenesis.48 The gene mutagenesis is often difficult to detect without the advanced studies of genes and proper diagnostic equipment. Thus, this shows the importance of studying defective genes.
2.1.4 Study of Defective Genes
Numerous companies engaged in research to identify genes that associate with specific diseases like haemophilia or cystic fibrosis.49 These diseases are caused by defect in a single gene.50 However, there are more diseases that involve a number of different genes and result from interaction with the environment; for example, Alzheimer’s disease is associated with specific genes in the sense that people carry variant of those genes have more changes of developing that disease.51 Finding disease related genes often result from both biotechnology and genetics that involve the studies of large families with a high prevalence of the disease.52 For example, the Mormon Church, for the religious reason, has accumulated the world’s most extensive collection of genealogical data. The access to these data helped Myriad Genetics of Salt Lake City to identify the BRCA genes and their functions which associate with development of breast and ovary cancer.53
2.1.5 Cancer Genes
Mutagenesis in a gene can result with a cancer causing gene. Two general classes
46 Id. 47 Id. at 330. 48 Id. 49
PHILIP W.GRUBB &PETER R.THOMSEN,PATENTS FOR CHEMICALS,PHARMACEUTICALS, AND
BIOTECHNOLOGY:FUNDAMENTALS OF GLOBAL LAW,PRACTICE, AND STRATEGY 301-04(5th ed. 2010). 50
Id. 51 Id. 52 Id. 53 Id.
18
of cancer genes have been identified.54 The first class of genes that involve with the control of cell proliferation and tumor growth such as growth factors,
cyclin-dependent kinase (Cdk) regulators such as cyclins, Cdk inhibitors (CKIs) and the retinoblastoma protein, apoptotic factors, and angiogenesis factors.55 When these genes are mutated or overproduced, they will promote the abnormal accumulation of cells.56 The second class included genes that control the stability of the genome and prevent the mutations in the first class of genes.57 These genes are called
anti-mutators genes that include DNA repair proteins, cell cycle checkpoint regulators, and genes that maintain the fidelity of chromosome segregation.58 Two of the second class genes identified are the breast cancer susceptibility genes 1 and 2 (hereinafter
BRCA1 and BRCA2) which will be discussed in more details later in this thesis.59 The second class genes expressed proteins that can perform all functions during DNA metabolism and DNA repair.60 Conversely, there are some evidences that these proteins also participate in cell cycle checkpoint as they may stop the cell cycle progression in the presence of damaged DNA.61
2.1.6 Importance of BRCA1/2 Gene
Mutations in the BRCA1/2 genes are associated with increase risk in breast and ovarian cancer.62 Woman with BRCA1 and BRCA2 mutations may have up to 85% cumulative risk of breast cancer, and as well as up to 50% cumulative risk of ovarian cancer.63 Among the 10-15% of ovarian cancer cases that are inherited genetically, 80% of women diagnosed under the age of 50 carry mutations in their BRCA1 genes and 20% carry mutations in their BRCA2 genes.64 The women with inherited
54
Kenneth W. Kinzler & Bert Vogelstein, Gatekeepers and Caretakers, 386 NATURE 761, 763 (1997). 55
Yi Wang et al., BASC, a Super Complex of BRCA1-Associated Proteins Involved in the Recognition
and Repair of Aberrant DNA Structures, 14 GENES &DEV. 927 (2000).
56 Id. 57 Id. 58 Id. 59
P.A. Futreal et al., BRCA1 Mutations in Primary Breast and Ovarian Carcinomas, 266 SCIENCE120-22 (1994).
60
THE HUMAN GENOME PROJECT, supra note 28, at 45.
61 Id.
62 Ass’n for Molecular Pathology v. USPTO, 653 F.3d 1329, 1339 (Fed. Cir. 2011). 63 Id.
19
BRCA1 mutations have a 40-52% cumulative risk of ovarian cancer by the time they reach 70 years old.65 For women inherited BRCA2 mutations, the risk is
approximately 15-25%.66 Data shows male carriers with similar mutations have increased risk for breast and prostate cancer as well.67 All these information can help to provide the public with possible prevention for diseases such as lung cancer and ovarian cancer.
2.1.7 DNA Sequencing
DNA sequencing is the technique that allows the physician or scientist to uncover the information regarding the nucleotides within a DNA molecule by
understanding the ordering of the nucleotide sequence. The ordering or the nucleotide can be used to determine existence of mutations that are associated with particular diseases. Genes are mostly discovered by two different methods: genomic DNA sequencing and cDNA sequencing.68
2.1.8 cDNA Sequencing
A cDNA is a sequence synthesized from an expressed gene or messenger RNA (mRNA) via a process called reverse transcription where the mRNA is transcribed69 and this will allow the genes to be identified more efficiently because it contain only the protein coding regions (exons) and therefore it is shorter in length and less time consuming. In contrast, another type of sequencing, the genomic sequencing, deals with both non-coding and coding regions, therefore, maybe involve longer steps. The cDNAs are synthesized in vitro from mRNA. All the mRNAs are collected from various types of tissues of interest.70 The mRNA is used as template and through the action of an enzyme called reverse transcriptase, and cDNA is produced after the reverse transcription take place.71 Hence, one huge difference between genomic
65 Id. 66 Id. 67 Id. 68
JEFFERY P.TOMKINS ET AL.,DNASEQUENCING FOR GENOME ANALYSIS, IN ANALYTICAL
TECHNIQUES IN DNASEQUENCING 158-73 (Brian K. Nunnally ed., 2005).
69 Id. 70
THE HUMAN GENOME PROJECT, supra note 28, at 138; Bernadine Healy, On Gene Patenting, 327
NEW ENG.J.MED. 664, 664 (1992).
20
sequencing and cDNA sequencing is that cDNA sequencing only expresses gene fragments, exons, and not the whole gene.72
2.1.9 Whole-Genome Sequencing
Whole genome sequencing (WGS) is also known as full genome sequencing (FGS). This is the process where the entire genome is sequenced at one time by first obtaining the organism’s chromosomal DNA. This is done with the aid of shotgun sequencing. This is an essential process because it allows the sub-cloning of the DNA sequencing target called library construction where it will be used afterward during comparison between each read or measurement and the library.73 In whole genome sequencing, shotgun sequencing,74 long strand of DNA is broken up randomly into smaller fragments by the specialized instruments or the sonication instrument,75 which are sequenced by using the chain termination method. When multiple overlapping reads for the target DNA are detected by performing several rounds of this fragmentation and sequencing, with the help of the computer program, the full sequence can be obtained. The computer program uses the overlapping ends of different sequencing results and assembles them into a continuous sequence. The number of clones necessary to reconstruct the original target sequence depends on three factors; (1) the average length of sequence obtained from a single shotgun clone, (2) the length of the target sequence, and (3) the desired accuracy of the completed sequence.76
2.2 – Different Categories of Gene Patents
2.2.1 Therapeutic Protein
One of the uses for the gene sequence is to provide a production of high purity
72
Craig D. Rose, Race Is on to Stake Claims to Our DNA: San Diego’s Sequana Among Pioneer
Firms in Fertile New Field, SAN DIEGO UNION-TRIBUNE, Sept. 11, 1994, at A-1, A-4; Healy, supra note 70, at 664.
73
Tomkins et al., supra note 68, at 163. 74
R. Staden, A Strategy of DNA Sequencing Employing Computer Programs, 6 NUCLEIC ACIDS
RESEARCH 2601 (1979).
75 Tomkins et al., supra note 60, at 163-64. 76 Id.
21
proteins via the process of transcription and translation.77 The purified and
biologically functional proteins permitted directed therapy for diseases where other therapy is not allowed.78 Companies like Amgen and Genentech were the first to use the cloning and expression recombinant technologies to produce the human proteins that are used as drugs.79 The products were recombinant version of human growth hormone (hGH), insulin, tissue plasminogen activator (tPA), and erythropoietin.80 These hormones all play crucial roles in maintaining a healthy human body. For example, hGH is important in human growth because it facilitates muscle and skeletal development and insulin can regulate the glucose level in the blood.
2.1.10 Gene Therapy
Human gene sequence is associated to gene therapy as they provide methods which involve genes to treat diseases. As mentioned above, the abnormal protein produced by the defective gene may cause undesirable effect in the human body. Therefore, one example of gene therapy called “gene replacement” allows the change of the defective gene with proper functional gene,81 thus prevent production of abnormal proteins. This can be achieved by modifying the gametes before ova or sperm cells are formed, thus, selecting the only desirable beneficial genes.82 Another type of gene therapy focus on the non-reproductive cells called somatic cell gene therapy.83 There are two main types of somatic gene therapy; ex vivo and in vivo.84 In
ex vivo gene therapy, cells are removed from the body, genetically modified and put
back into body through the cell therapy process.85 The first reported human trial of ex
vivo gene therapy was carried out on a child suffering from rare form of
immunodeficiency caused by the lack of a specific protein.86 During the process, the lymphocytes from the child’s blood were isolated and removed from the body. In the
77
HARVEY LODISH ET AL.,MOLECULAR CELL BIOLOGY 102 (3d ed. 1995).
78 Id. at 256. 79
STUART O.SCHWEITZER,PHARMACEUTICAL ECONOMICS AND POLICY 57-59 (2d ed. 2007).
80 Id. 81
GRUBB &THOMSEN, supra note 49, at 296.
82 Id. 83 Id. 84 Id. 85 Id. 86 Id.
22
in vitro process that takes place in test tubes, the vector containing the normal gene
that aid the production of the specific protein is created by human intervention.87 Then, the vector is inserted back into the patient’s body to allow the production of the specific proteins.88 The second type of gene therapy called in vivo gene therapy where the genes are modified within the human body without removing them from the body.89
The first commercial gene therapy product is called Gendicine and the main function of this product is to deliver the P53 tumor suppressor gene that is used to treat squamous cell carcinoma of the head and neck.90
2.1.11 Diagnostic testing
Diagnostic testing involves the testing of a patient’s DNA sample for the presence of genetic mutation or variation correlated with some clinically significant phenotype, such as genetic disease, a propensity for cancer, or inability to tolerate a particular drug.91 The conventional testing method used to identify a genetic variation in a DNA sample generally involve the making and using of synthetic DNA sequences corresponding to the gene of the interest, for example, the amplification and
sequencing of the patient’s gene or as hybridization probes.92
The current genetic diagnostic testing methods involve making and using a polynucleotide corresponding in sequence to be fragment of interest.93 Many genetic testing methodologies include a step in which the patient’s DNA is extracted and used as a template for the
production of multiple copies of the target sequence, for example, by means of PCR amplification.94 Some testing protocols involve the direct sequencing of the patient’s gene, a process that generally requires the production of copies of fragments of the
87 Id. 88 Id. 89 Id. 90 張珊文等，「頭頸鱗癌基因治療結合放射治療的臨床研究」，中華腫瘤雜誌，第 29 卷第 7 期， 頁 426-428（2007）。 91
Christopher M. Holman, Learning from Litigation: What Can Lawsuits Teach Us About the Role of
Human Gene Patents in Research and Innovation, 18 KAN.J.L.&PUB.POL’Y 215, 238 (2009).
92
MOLECULAR DIAGNOSTICS:FOR THE CLINICAL LABORATORIAN 314(William B. Coleman & Gregory J. Tsongalis eds., 2d ed. 2006).
93 Id. at 317. 94 Id.
23
gene sequence.95 Other testing protocols involve the use of poly nucleotide probes that specially hybridize to know mutations of clinical relevance.96
2.3 - What Is a Patentable Invention?
U.S. Congress was given power by the constitution in Article 1, Section 897 to grants patents that confer a twenty year exclusive right to prevent others from making, using, offering for sale, selling or importing the patented invention in the United States. The congress has set forth U.S. patent law in the Patent Act of 1952. United States Patent and Trademark Office (USPTO) following the Patent Act to grant a patent, the fundamental principle is that the invention must fulfill the requirements of patentable subject matter,98 useful,99 novel,100 non-obvious,101 and adequately enabled and disclosed before patent can be issued.102 Patents come in three types: utility, design and plant.103
35 U.S.C. §101 set forth the inventions that are patentable or the subject matter that qualifies the grant of a patent. The statue stated that “whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefore, subject to the conditions and requirements of this title.”104
Thus, the four statutory categories of patentable inventions are: (1) process (2) machine (3) manufacture and (4) composition of matter. All four previous categories belong to the utility patent and vary in scope protection. The focus of this thesis lies on issues of the Myriad case, hence, only the composition of matter patent and process patent will be further discussed. The followings are the general definitions to the four categories of utility patent. 95 Id. 96 Id. at 316.
97 U.S. Const. art. I, §8 , cl. 8. 98 35 U.S.C. § 101 (2006). 99 Id. 100 35 U.S.C. § 102 (2006). 101 35 U.S.C. § 103 (2006). 102 35 U.S.C. § 112 (2006). 103
USPTO,A GUIDE TO FILING A UTILITY PATENT APPLICATION (2008),
http://www.integrityip.com/Patent_Library/USPTO/PatentFilingGuide.pdf 104 35 U.S.C. § 101 (2006).
24
2.3.1 Process
The words “method” and “process” are used interchangeably, but “process” is more frequently used in cases that involve chemicals, whereas “method” is more commonly used in cases that relates to mechanical and electrical products.105 Process claim compare to product claim, can only protect the process of creation and not the end result. This means other inventors are still free to use a different process that creates the same result. According to Gottschalk v. Benson case, the judge defined method as process, or series of steps or acts, for performing a function or
accomplishing a result106 and according to Muniauction v. Thomson Corp case, a method patent claim is only infringed when a single person or entity practices all claimed steps.107
2.3.2 Machine
A machine is synonymous with an apparatus, and generally has numerous moving parts such as an internal combustion engine.108
2.3.3 Manufacture
Manufacture is usually claimed when the invention does not belong to the other three statutory categories.109 In Chakrabarty, the Supreme Court did explain that main task in that case is to determine if a living organism fell within the statutory categories of “manufacture” or “compositions of matter.“ The Court emphasized the term “manufacture” in 35 U.S.C §101 in accordance with its dictionary definition which means ‘the production of articles for use from raw or prepared materials by giving to these materials new forms, qualities, properties, or combinations, whether by hand-labor or by machinery.’”110
105
ROBERT C.FABER,FABER ON MECHANICS OF PATENT CLAIM DRAFTING (2011).
106
Gottschalk v. Benson, 409 U.S. 63, 70 (1972) (“A process is a mode of treatment of certain materials to produce a given result. It is an act, or a series of acts, performed upon the subject-matter to be transformed and reduced to a different state or thing.”).
107
Muniauction, Inc. v. Thomson Corp., 532 F.3d 1318 (Fed. Cir. 2008). 108
JANICE M.MUELLER.,INTRODUCTION TO PATENT LAW 213 (2d ed. 2006).
109 Id.
25
2.3.4 Composition of Matter
Composition of matter claim is one type of utility patent. Prior to the grant of utility patent, patentable subject matter must first qualify and the scope of patent is then determined. When referring to a gene patent scope, it covers the physical
compositions include the gene itself. As the result, composition of matter claims may thwart the public from using genes that fall within the scope of claims. Hence, composition of matter claims can prevent others from extracting or isolating these genes from the genome by any means. The court in Chakrabarty case gave a general definition for the composition of matter claim: “all compositions of two or more substances and ….all composite articles, whether they be the results of chemical union, or of mechanical mixture, or whether they be gases, fluids, powders or solids.”111
The term “composition of matter” is primarily used in pharmaceutical patents. It can be a chemical compositions and mixtures of substances such as metallic alloys.112 Composition claims are generally very specific. If a composition of matter is claimed, it is the physical structure of the composition that must be novel, not merely its properties.113
2.4- Gene Patent and It’s Different Perspectives
2.4.1 Definition of Gene Patent
The U.S. Patent and Trademark Office (USPTO) grants patents on human gene sequences, that grants patent holders with the exclusive rights to those genetic
sequences, their usage, and their chemical composition. Therefore anyone who makes or uses a patented gene is committing an infringement without permission of the patent holder, no matter whether it is for commercial or noncommercial purposes.
The definition of a gene patent in this thesis will include the different types of patent claims directed to synthetic genetic constructs that includes the genetic
sequence and methods of using those genetic sequences. Synthetic genetic constructs refers to the genetic information in a physical form, including DNA molecules and
111 Id. 112 Id.
26
proteins themselves. Methods of using genes include using the particular genes to treat diseases, or as tools for disease detection or diagnostic.
2.4.2 Incentives to Invest
The important function of the patent system is to provide the incentive to invest in the development and commercialization of biotechnology and gene patent derived inventions because the right of exclusion assures the inventor that within the twenty year patent term, his/her invention will be well protected.114 Establishing
fundamental understanding of scientific process and fostering a viable biotechnology industry require large amount of investments because it demands accumulation of years of research from academic, government and private sectors. The complexity of biological products may present risk not known until late in the clinical investigations or even worse after the product has been marketed and used by a larger population.115 This is one unique characteristic about biotechnology industry. Also, each gene may participate in different roles in the body. Thus, there is a possibility a gene maybe first patented but some unknown functions are not discovered when gene was first
patented.
Nonetheless, there is an underlying theory that “the patent system is not so much needed to stimulate inventive activity; rather, it facilitates investment into costly and risky development processes that are necessary to transform a ‘mere’ invention into a marketable product.”116
One example to oppose this theory is the defendant of the
Myriad case, Myriad Genetics Company, was largely financed by private venture
capital totaling at least 22 million dollars.117 Research funded by private venture capital may rely more on patent than the government or public funded research. In 2007, over $7 million in venture capital was invested in biotechnology startups.118 The solution to secure venture capital for the bio-entrepreneurs was obtaining the
114
Wolrad Prinx zu Waldeck und Pyrmont, Research Tool Patents After Integra v. Merck – Have They
Researched a Safe Harbor? 14MICH.TELECOMM.&TECH.L.REV.367,272(2008). 115
LI WESTERLUND,BIOTECH PATENTS,EQUIVALENCE AND EXCLUSIONS UNDER EUROPEAN AND U.S. PATENT LAW 10 (2002).
116
Id. at 372. 117
Larry A. Roberts, Myriad: How Did Public Policy Weigh In?, INTELL.PROP.STRATEGIST, May
2010, at 1, 5. 118
27
patent protection over their biological product.119 Without patents, the ability to attract the necessary investment would be greatly diminished.120 The private capital investments are often required for small biotechnology companies to survive because these enterprises have very limited or no revenue to conduct the research.121 The continuation of their researches depends on venture capital and public market investors.122 Without the existence of patents, important researches may be delayed or never would have existed. This, in the long run, lead to stagnation in product development because small biotechnology companies play an important role in bridging the gap between basic scientific discoveries and the development of marketable products based on those discoveries.123 As Rebecca Eisenberg stated in her article, patents are purposed to allow “inventors to use their monopoly positions to exact a price that more closely approaches the value that users receive from
inventions.”124
Also, without the protection of patents, biotechnology companies would likely to rely solely on trade secrets.125 This would severely reduce the innovative
advancement for biotechnologies. People who are against the patenting of gene sequence may have failed to appreciate the emerging biotechnologies. Being able to manipulate gene expression in fact has some therapeutic benefits. For example, RNAi, known as RNA interference, the function of this mechanism used in the natural
organisms is to silence the gene activity.126 This discovery allowed the scientists to develop an easy and specific method to manipulate gene expression.127 RNAi has
119
Chrisopher J. Betti, Diagnostic Genetic Technologies Left Stranded on First Base: A Need to
Unwind the Protection Afforded Gene Patents, DUPAGE COUNTY BAR ASS’N BRIEF,22,23(2005). 120
Id. 121
Gene Patents and Other Genomic Inventions: Hearing Before the Subcomm. on Courts and Intellectual Propery of the H. Comm. on the Judiciary, 106th Cong. 74 (2000) (statement of Dennis J. Henner, Ph.D., Senior Vice President, Research, Genetech, Inc.), available at
http://commdocs.house.gov/committees/judiciary/hju66043.000/ju66043_0f.htm. 122
Id. 123
Iain M. Cockburn, The Changing Structure of the Pharmaceutical Industry, 23HEALTH AFF.10,15 (2004).
124
Rebecca S. Eisenberg, Patents and the Progress of Science: Exclusive Rights and Experimental Use, 56 U.CHI.L.REV. 1017, 1046-48 (1989).
125
Michael John, Gulliford, Much Ado About Gene Patents: The Role of Foreseeability, 34SETON
HALL L.REV.711,730(2004). 126
Scott E. Martin & Natasha J. Caplen, Applications of RNA Interference in Mammalian Systems, 8 ANN.REV.GENOMICS HUM.GENETICS 81,82(2007).
28
therapeutic role in treating malignant, infectious and autoimmune disease.128 In January 2008, scientists at the J. Craig Venter Institute published a report describing the first synthetically created bacterial genome.129 This synthetic biology has the potential to create microorganism capable of producing inexpensive medical therapies such as malarial vaccines or environmentally friendly industrial materials. Also, more research is still under way to produce synthetic organisms for use as highly efficient bio-fuels that reduce the environmental cost to produce fuels.
Even though both RNAi and synthetic biology are very diverse technologies, but they share the commonality and that is the both technology require protection of gene patents. Gene patents in these two technologies played an essential role to ensure the useful application will result. Biologics also known as biopharmaceutical drugs currently make up approximately 40% of all preclinical candidates.130 The biologics market is expanding at a faster rate than the conventional drug market.131 The high cost in research and development make the patents absolutely indispensable in providing the necessary incentive to invest.132
Celera, a manufacturer of diagnostic products emphasized “even though the Draft Report suggests that scientists who search for gene-disease associations may not be motivated by the prospect of receiving a patent, they cannot conduct this type of research without considerable capital and resources.133 Celera quoted, “in our experience, meaningful gene disease associations are confirmed only if the initial discoveries are followed by large scale replication and validation studies using multiple sample sets, the costs of which are prohibitive for many research groups. Private investors who provide funding for such research invariable look to patents that
128
Charles X. Li et al., Delivery of RNA Interference,5CELL CYCLE 2103(2006). 129
J.CRAIG VENTER INSTITUTE,FIRST SELF-REPLICATING SYNTHETIC BACTERIAL CELL (2009), http://www.jcvi.org/cms/fileadmin/site/research/projects/first-self-replicating-bact-cell/fact-sheet2.pdf. 130
Stacy Lawrence, Pipelines Turn to Biotech, 25NATURE BIOTECHNOLOGY 1342(2007). 131
Saurabh Aggarwal, What’s Fueling the Biotech Engine?, 25NATURE BIOTECHNOLOGY 1097 (2007).
132
Christopher J. Betti, Diagnostic Genetic Technologies Left Stranded on First Base: A Need to
Unwind the Protection Afforded Gene Patents, DUPAGE COUNTY BAR ASS’N BRIEF, April 2005, 22, at 23.
133
Sec’y’s Advisory Common. on Genetics, Health, & Soc’y, GENE PATENTS AND LICENSING
PRACTICES AND THEIR IMPACT ON PATIENT ACCESS TO GENETIC TESTS 23 (2010),
http://oba.od.nih.gov/oba/sacghs/reports/sacghs_patents_report_2010.pdf [hereinafter SACGHS report].
29
result from such work as a way of protecting their investment.”134
People who reject the patentability of gene patents may argue that even though patents are required to attract investment, but 67% of the patents issued for
discoveries on genetic diagnostics are government or university funded.135 For the scientists and researchers that belong to government or university, desire to advance understanding, hope to improve patient care and career advancement may be their primary motivations.136 For example, International HapMap Project that identified genes that relates to age macular generation and autism where NIH National Institute of General Medical Sciences for providing funding and support for cell line
transformation and storage in the NIGMS Human Genetic Cell Repository at the Coriell Institute.137
They may also argue genetic diagnostic are unlike pharmaceutical patents in which pharmaceutical products must require significant investment before obtaining the approval from FDA. The costs are generally considered minimal. The government and university sponsorship including international collaborations like the Human Genome Project and HapMap Project can result a decrease in research cost.138
However, expensive clinical trials are still needed for the genetic tests. However, even more relaxed standards decrease the price of clinical trials for the genetic testing, it is estimated that is requires approximately half of the $802 million price tag, which is nearly $454 million.139 However even these examples show that Federal Government is the most likely to be the major funder of basic research but there is no definitive data on Federal Government versus private sector investment in basic genetic research.140
Even though the development of genetic tests is lower compare to drugs because of several reasons mentioned above. However, this does not wipe out the possibility that patents are still required to protect the risky investment. The less overall cost of
134 Id.
135 Ass’n of Molecular Pathology v. USPTO, 702 F. Supp. 2d 181, 210 (S.D.N.Y. 2010). 136 SACGHS report, supra note 133, at 32.
137
Int’l HapMap Consortium, A Haplotype Map of the Human Genome, 437 NATURE 1299, 1301 (2005).
138
Andrew S. Robertson, The Role of DNA Patents in Genetic Test Innovation and Access, NORTHWESTERN JOURNAL OF TECHNOLOGY &INTELLECTUAL PROPERTY 12(2011).
139 Id.
30
developing genetics may still remain to be a significant amount for the small
biotechnology company. Whether the issuing of gene patents provides the necessary incentive remain to be further discussed below.
2.4.3 Patient Access
One concern of gene patents is that they may hinder access to medical treatment or tests.141 The gene holder controls any use of its gene. The patent holder can prevent doctors or researchers from testing a patient’s blood. The gene patents have increased the genetic test cost that has diminished the patient access especially when patient’s insurance does not cover the test. One possible reason is that the insurance providers directly bear the burden of increased cost when there is a lack of
competition created by only having a sole provider. Also, with the possible increase in research cost, the increased cost maybe passed on to the patients and insurance
providers. The limited access affects the quality and accuracy of those tests. When exclusive right granted to the patent holder, like Myriad case142, this will likely to result that only one laboratory can perform the diagnostic or research test. This will cause decrease opportunity for patients searching for second opinion test and this may affect patients’ access to better quality testing. The reason is that patients are unable to assess the accuracy of the previous diagnostic test by comparing the test results when the test is only offered by one sole provider. Different providers may provide different test methods of test method or improvement of it. Without competition, there is less incentive to improve the genetic test and thus, the optimal performance may not be achieved.143 The Myriad case involves patenting cancer detecting human gene, BRCA genes144, may have similar effect as well. Many of plaintiffs in that case are patients that were disturbed from access to the diagnostic test. Many patients couldn’t seek for second opinion examination before pursuing mastectomy and hysterectomy. Also, the high cost resulting from the protection of patent is preventing many patients’ from access to the diagnostic test because the some insurance companies are
141
Id. at 15. 142
Ass’n for Molecular Pathology v. USPTO, 653 F.3d 1329, 1339 (Fed. Cir. 2011). 143
Steve Nenowitz, French Challenge to BRCA1 Patent Underlies European Discontent, 94J.NAT’L
CANCER INST.80,80-81 (2002).
31
unwilling to cover such a high expense. Studies from the past few years have shown between 19% and 74% of patients who could benefit from the BRCA testing were not tested.145 Health plans helped to reduce the number of patients who use their own pocket money to pay for the BRCA test.146 For the women whose costs of the tests were covered by their insurance or Myriad programs, only 70% of them already had the BRCA test.147 In contrast, only 22% from patients who pay from their pocket chose to receive the diagnostic test.148 With the protection of patent, the diagnostic test is five times more expensive in the U.S. than in France,149 where the BRCA gene patents were ruled invalid.150 French physicians also alleged that Myriad’s tests only assess 10-20% of the potential mutations in the gene151 and French physicians are able to find mutations that Myriad missed.152 The study practitioners in the U.S. performing genetics tests on a daily basis collectively feel that the cost for patients have increased dramatically due to patent protection and in turn have an adverse effect on the access of patients.153
Athena Diagnostics has used its exclusive rights to various hearing loss genes to stop some laboratories from testing and with Alzheimer disease as well.154 The company holds the exclusive license of the gene and it would not let anyone to perform the test. Doctors were sued across the country where they have to try to determine if their patients have the genetic form of Alzheimer.155 Another example
145
Shannon Kieran et al., The Role of Financial Factors in Acceptance of Clinical BRCA Genetic
Testing, 11 GENETIC TESTING 101, 101 (2007); Complaint at 19, 22-25, Ass’n for Molecular Pathology v. USPTO, 702 F. Supp. 2d 181 (S.D.N.Y. 2010).
146 Id. at 102. 147
Id. 148 Id. 149
Robert Cook-Deega et al., Impact of Gene Patents and Licensing Practices on Access to Genetic
Testing for Inherited Susceptibility to Cancer: Comparing Breast and Ovarian Cancers with Colon Cancers, 12 GENETICS MED. S15, S28 (2010).
150 Id. 151
Declan Butler and Sally Goodman, French Researchers Take a Stand Against the Cancer Gene
Patent, 413NATURE 95,95(2001). 152
Sophie Gad et al., Identification of a Large Rearrangement of the BRCA1 Gene Using Colour Bar
Code on Combed DNA in an American Breast/Ovarian Cancer Family Previously Studied by Direct Sequencing, 38J.MED.GENETICS 288(2001).
153
Mildred K. Cho et al., Effects of Patents and License on the Provision of Clinical Genetic Testing
Services, 5 J.MOLECULAR DIAGNOSTICS3, 5 (2003).
154 SACGHS report, supra note 133, at 33. 155 Id.
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like Miami Children’s Hospital enforced its patent on the Canavan disease gene resulting laboratories stopping testing for patients.156 Canavan disease is a rare genetic disease that occurs frequently in Ashkenazi Jewish that can lead to a
degeneration of the brain, causing the children to lose their vision, suffer with seizures and eventually require tube feeding.157 In this case, the holder of the patent demands a higher than-usually-royalty and tried to control the number of tests permitted.158 This ultimately affected the patients’ access to genetic testing. In comparison, the countries where such gene is not patented, the doctors are able to discover previously unknown mutations by performing the genetic test.159
2.4.4 Research Access
There is a concern that “data sharing is the key to the future of genetic
discoveries and bioinformatics and gene patents impede research aimed at identifying the role of genes in medical conditions”160
Michigan’s law Professors Michael Heller and Rebecca Eisenberg pointed out how patents can deter innovation in biomedical research: “A proliferation of intellectual property rights upstream may be stifling life saving innovations further downstream in the course of research and product
development.”161
The limited monopolies granted by the gene patents and exclusive licensing have created decrease in competition all hinder patient access to gene related diagnostic.
In the case of granting method patents, for example, in one of the U.S 5,693,470 patent claims “a method of determining a predisposition to cancer
comprising: testing a body sample of a human to ascertain the presence of a mutation in a gene identified as hMSH2.162 The patent claims “testing” and this generally refer to, any testing method, including any multiplex testing that “ascertains the presence”
156 Id. 157 Id. 158 Id. 159
Andrea Knox, The Great Gene Grab: Firms Toss Researchers for a Loop, PHILADELPHIA INQUIRER, Feb. 13, 2000, at A1.
160
Ass’n of Molecular Pathology v. USPTO, 702 F. Supp. 2d 181, 208 (S.D.N.Y. 2010). 161
Michael A. Heller and Rebecca S. Eisenberg, Can Patents Deter Innovation? The Anticommons in
Biomedical Research, 280SCI.698,698-701(1998). 162 Id.
