Chapter 2 - Background to Gene Patent 14
2.1.1 DNA and It’s Roles
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 Id.
16
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.
64 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).
71 Id.
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
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