Is There a Line Of Demarcation Between Natural And Invented DNA? The U.

S Supreme Court Decided That Human Genes May Not Be Patented.

By Thomas Dubuisson, LL.M., J.D., LL.B http://www.d-is-freshinteresting.blogspot.nl/ tom.dubuisson@gmail.com - @tdubuisson

One of the most important and complex patent cases has just come to an end.
The U.S Supreme Court, the highest court in the States, recently heard an extremely difficult biotech case: Assoc. for Molecular Pathology v. Myriad Genetics, Inc., No. 12-398, June 13, 2013 (hereafter 'Op.'). It's ruling is expected to have broad implications, not only in the U.S. but worldwide. The central question is: whether human genes could be patented? Put in a simple way: how genes, the basis for hereditary traits in living organisms, could become a companys intellectual property; and who owns the gene? In particular in the field of medicine, modern biotechnology is one of the key technologies of the 21st century, a major source of innovation and a global driver of economic growth. With annual net sales exceeding $90 billion, it's easy to understand the paramount importance of biopharmaceuticals to the pharmaceutical industry today. With all these new technologies, scientists have developed processes to modify the genetic composition of living organisms, better known as "human genetic engineering (HGE)". In other words, it is "a process by which scientists and medical professionals alter the genetic makeup, or DNA, in a living human cell"1. As clearly explained on the World Intellectual Property Organization (WIPO 2 ) website 3 , biotech may also concern "the application of cellular and molecular biology to human needs and the use of cells and biological molecules to solve problems or make useful products (for instance, fix defective genes that cause diseases and other genetic complications). It includes scientific and industrial disciplines directed to understanding and manipulating living or biologically active material at the molecular level. Often it refers to recombinant deoxyribonucleic acid (DNA) techniques and analysis of genetic information".

http://www.redorbit.com/news/science/1112819269/human-genetic-engineering-a-very-briefintroduction/ (last visited on July 18, 2013). 2 The WIPO is the United Nations agency dedicated to the use of intellectual property (patents, copyright, trademarks, designs, etc.) as a means of stimulating innovation and creativity 3 http://www.wipo.int/export/sites/www/about-ip/en/iprm/pdf/ch7.pdf (last visited on July 18, 2013).

Myriad Genetic Laboratories, Inc., a small Utahbased biotechnology company, created a 'monopoly' in the U.S when its co-founder became the first scientist to isolate, sequence and patent two human genes, mutations (BRCA1 and BRCA2) of which can substantially increase the risks of breast and ovarian cancer 4 . Simply put, Myriad has exclusive rights for all clinical use of the BRCA mutations. Even though scientists knew that heredity played a role in establishing a woman's risk of developing breast and ovarian cancer, Myriad identified the exact location of the BRCA1 and BRCA2 genes (on chromosome 17 that has approximately 80 million nucleotides and chromosome 13 that has 114 million). The plaintiff, the Association for Molecular Pathology, sued Myriad, seeking invalidation of the contested claims. The Association "asserted that the claims covered products of nature, laws of nature, natural phenomena, abstract ideas or basic human knowledge, disputing the subject matter's patentability, in light of 35 U.S.C. 101. Further, it argued that the patents hindered scientific research and innovation, prevented competition and threatened patients' rights"5. Moreover, the Association relied on the arguments of scientists who have said that such isolated fragments of DNA do indeed occur through natural processes in the human body. In sum, the main issue is the patentability of isolated DNA sequences in relation to diagnostic and drug screening claims. Before developing the subject into details, it is important to remind ourselves of the genetics basics: "The human genome consists of approximately 22,000 genes packed into 23 pairs of chromosomes. Each human gene is encoded as deoxyribonucleic acid (DNA), which takes the shape of the familiar double helix. Each cross-bar in the DNA helix consists of two chemically joined nucleotides. The possible nucleotides are adenine (A), thymine (T), cytosine (C), and guanine (G), each of which binds naturally with another nucleotide: A pairs with T; C pairs with G. The nucleotide cross-bars are chemically connected t o a s u g a r-phosphate backbone that forms the outside framework of the DNA helix. Sequences of DNA nucleotides contain the information necessary to create strings of amino acids used to build proteins in the body. The nucleotides that code for amino acids are exons, and those that do not are introns. Scientists can extract DNA from cells to isolate specific segments for study. They can also synthetically create exons-only strands of nucleotides known as composite DNA (cDNA). cDNA contains only the exons that occur in DNA, omitting the intervening
4

For a detailed explanation of the facts, see: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3037261/ (last visited on July 18, 2013). 5 http://ipkitten.blogspot.nl/2013/04/patentability-of-dna-sequences-debate.html (last visited on July 18, 2013).

introns" (See Assoc. for Molecular Pathology v. Myriad Genetics, Inc., No. 12-398, June 13, 2013, p. 1-2.) In Europe, under the European Patent Convention (EPC), biological material isolated from its natural environment is considered patentable. This includes inanimate biogically active material such as genes and DNA and RNA sequences and animate matter, such as microorganisms. In other words, as it is explicitly explained in Rule 29 (2) and (3) EPC, if the biotechnological inventions meet the basic criteria of patentability (Articles 54, 56, 57, 83 and 84 EPC), there is no bar to the patentability of genes or DNA sequences: An element isolated from the human body or otherwise produced by means of a technical process, including the sequence or partial sequence of a gene, may constitute a patentable invention, even if the structure of that element is identical to that of a natural element - rule - 2 The industrial application (i.e. the function) of a sequence or a partial sequence of a gene must be disclosed in the patent application - rule 3 In the U.S, the United States Patent and Trademark Office (USPTO) has already granted thousands of patents on DNA sequences (like BRCA mutations) since 1982. Recently, the Court of Appeal for the Federal Circuit (on July 29, 2011) held four important principles: cDNA (complementary DNA) is patentable.

For non-scientists, a cDNA is "a single-stranded DNA that is complementary to a certain sequence of messenger RNA (A type of RNA - molecule - that carries the code or chemical blueprint for a specific protein). It is usually formed in a laboratory by the action of the enzyme reverse transcriptase on a messenger RNA template. Complimentary DNA is a popular tool for molecular hybridization or cloning studies"6. In other words, it is essentially synthetic (designed by humans) and used for medical or agricultural purposes. A Washington Lawyer gave an easier interpretation: "the cDNA has the same genetic information as our natural gene, but it's in a user-friendly form. If you think of a human gene as gold still in a gold mine, then cDNA is the gold after it's been mined and polished". Isolated human DNA is patentable. Method for comparing and analysing human genes is NOT patentable (lacks any transformative step):

"We conclude that Myriads claims to comparing or analyzing two gene sequences fall outside the scope of 101 because they claim only abstract mental processes. See Benson, 409 U.S. at 67 (Phenomena of nature, . . . mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of
6

For more information, see: http://www.answers.com/topic/cdna#ixzz2VX3hH1Tk (last visited on July 18, 2013).

scientific and technological work.). The claims recite, for example, a method for screening a tumor sample, by comparing a first BRCA1 sequence from a tumor sample and a second BRCA1 sequence from a non-tumor sample, wherein a difference in sequence indicates an alteration in the tumor sample. 001 patent claim 1. This claim thus recites nothing more than the abstract mental steps necessary to compare two different nucleotide sequences: look at the first position in a first sequence; determine the nucleotide sequence at that first position; look at the first position in a second sequence; determine the nucleotide sequence at that first position; determine if the nucleotide at the first position in the first sequence and the first position in the second sequence are the same or different, wherein the latter indicates an alternation; and repeat for the next position" (See Appeal from the United States District Court for the Southern District of New York in Case No. 09-CV-4515, Senior Judge Robert W. Sweet. p. 49-50). Method for screening potential cancer therapeutics is patentable.

In this case, both parties appealed to the Supreme Court. The Highest Court reverted back to the Court of Appeal on March 26, 2012 (in other words, to re-hear the entire case again) in view of Prometheus vs. Mayo Decision, 566 U.S. ___ 132 S.Ct. 1289 (where the Court ruled that certain kinds of claims in medical diagnostics patents, including natural phenomena, were not patentable). On Appeal, on August 16, 2012, the Court overturned the District Court Decision, ruling again in a 21 decision in favor of Myriad. Then, a second petition for certiorari was filed with the Supreme Court in September 2012. Oral arguments were heard before the Supreme Court on April 15, 2013 which may be summarized in three questions: - Is the isolation or extraction of natural products patentable? - Are there sufficient incentives for genetic research, if genes are non-patentable? - What are the differences between DNA and cDNA? Which of them can be the subject of a patent? These questions have already been answered by the U.S Court of Appeal for the Federal Circuit in 2011. Based on the comments and questions heard in Court on April 15th, 2013, the Judges of the Supreme Court seemed sceptical about whether these kinds of genes should continue to be patented; and therefore to decide to invalidate the main patents of Myriad and, perhaps, the thousands of patents already issued. On June 13, 2013, the U.S Supreme Court ruled unanimously (9-0 decision written by Justice Clarence Thomas) that human genes cannot be patented, is not eligible subject matter under 35 U.S.C. 101: "Whoever invents or discovers any new and useful (...)

composition of matter, (...) may obtain a patent therefor, subject to the conditions and requirements of this title"; but laws of nature, natural phenomena, and abstract ideasare basic tools of scientific and technological work that lie beyond the domain of patent protection (Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U. S). This decisions appears as a victory for ACLU (the plaintiff) and a split decision for Myriad. Explanations. Justice Thomas wrote: 'Myriad did not create anything (underline added). To be sure, it found an important and useful gene, but separating that gene from its surrounding genetic material is not an act of invention. Groundbreaking, innovative, or even brilliant discovery does not by itself satisfy the 101 inquiry (...).Myriad found the location of the BRCA1 and BRCA2 genes, but that discovery, by itself, does not render the BRCA genes new . . . composition[s] of matter, 101, that are patent eligible'. (See Op. p. 12-13). This passage clearly demonstrates the victory for the American Civil Liberties Union (ACLU). The isolation of the DNA molecule resulting in a physical change in the molecule (as it is chemically removed from its intracellular environment) does not render it patentable. On the other hand, Justice Thomas explained that cDNA molecules are eligible for patent protection. That part is where Myriad focused on: The petitioners argue that 'that cDNA is not patent eligible because [t]he nucleotide sequence of cDNA is dictated by nature, not by the lab technician. Id., at 51. That may be so, but the lab technician unquestionably creates something new when cDNA is made (underline added). cDNA retains the naturally occurring exons of DNA, but it is distinct from the DNA from which it was derived. As a result, cDNA is not a product of nature and is patent eligible under 101 (underline added), except insofar as very short series of DNA may have no intervening introns to remove when creating cDNA. In that situation, a short strand of cDNA may be indistinguishable from natural DNA' (See Op. p. 16-17). Based on the fact that the average American woman has a 12- to 13-percent risk of developing breast cancer (See Op. p.2), this patent lawsuit was not only important for companies (medical innovation), but also for patient care. However, the court's opinion did not settle the question about whether or not it is possible to patent a method or process of working with a gene (a method claim). Moreover, the decision does not involve patents on new applications of knowledge about the BRCA1 and BRCA2 genes, and the patentability of DNA in which the order of the naturally occurring nucleotides has been altered.

protection always strikes a delicate balance between creating incentives that lead to creation, invention, and discovery and imped[ing]the flow of information that might permit, indeed spur, invention. (See Op. p. 2). Regarding the

Patent

facts, it can be concluded that cDNA is patentable because it is not naturally occurring BUT a naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated. In other words, the U.S Supreme Court decided that human genes - a part of the human body - may not be patented and, as a consequence, held 'hostage' by a private company. [UPDATE: Very recently (on July 14, 2013), winning Noble prize Joseph E. Stiglitz wrote a very interesting article about this case and how Intellectual Property (IP) reinforces inequality. For him, it's the American intellectual property regime that contributes needlessly to the gravest form of inequality7; the U.S IP regime is poorly designed and the result is that there is actually less innovation and more inequality8. And added that "genetic researchers have argued that the patent actually prevented the development of better tests, and so interfered with the advancement of science. All knowledge is based on prior knowledge, and by making prior knowledge less available, innovation is impeded (emphasis added). Myriads own discovery like any in science used technologies and ideas that were developed by others. Had that prior knowledge not been publicly available, Myriad could not have done what it did"9. He also encouraged people to use alternatives - as you know the patent system is not the only way - and strongly concluded that "Myriads effort to patent human DNA was one of the worst manifestations of the inequality in access to health, which in turn is one of the worst manifestations of the countrys economic inequality (emphasis added)".]

J o s e p h E . S t i g l i t z , " H o w I n t e l l e c t u a l P r o p e r t y R e i n f o r c e s I n e q u a l i t y", http://opinionator.blogs.nytimes.com/2013/07/14/how-intellectual-property-reinforcesinequality/?gwh=CF9A0808F712E326DEE9B8D985326C68 (last visited on July 18, 2013). 8 Id. 9 Id.