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GENETIC PATENTS and THE FUTURE OF THE PHARMACEUTICAL INDUSTRY Introduction As has been the case for other

subject matter protected by intellectual property, the rationale behind granting patents for biotechnological inventions is to foster scientific progress and create incentives for the development of new drugs and treatment methods. The pharmacological inventions of the 20th century, either in the form of novel chemical compounds or the synthesis of substances readily available in the human body, are long past their glory days when the profits peaked. Such decline may be connected with the introduction of generic drugs due to the expiration of patent rights and the increasing ease in the production of alternative chemical compounds possessing equivalent biological functions. 1 Today, the clinical practices classified under "personalised medicine" are a model which seem to be a truly promising source of revenue for the life sciences industry. The discipline of Pharmacogenomics is the major contributor to this model. Pharmacogenomics is founded on the fact that the individual genetic variation of a patient has a direct relation with both her susceptibility to disease and her response to a drug. Therefore, understanding the genetic makeup of a patient is the key to creating personalized drugs with greater precision, efficacy and safety. Accordingly, personalised medicine utilizes tailor-made drugs and therapies that are adapted to each patient's own genetic makeup. The BRCA gene mutations The variation among different genotypes metabolic responses to a certain drug is a result of the fact that mechanisms which control drug-metabolizing enzymes, and other functional molecules, operate at the genetic level.2 Moreover, receptor proteins that regulate drug efficacy may differ according to genetic variations. Accordingly, the personalised medicine model begins with an analysis of the genetic profile of a patient before the administration of any drug or treatment. 3

there will be five more years of pain, as big brands lose patent protection, with

revenue losses from small molecule blockbuster drugs whose patents will expire in the next 24 months exceeding $60 billion. Bkz. D. Christopher Ohly and Sailesh K. Patel, There is no Orange Book: the coming wave of biological therapeutics, Journal of Intellectual Property Law & Practice, 2011, Vol. 6, No. 7 Farmakogenetik, Dr. A. Gkhan AKKAN, C.T.F. Farmakoloji ve Klinik Farmakoloji AnabilimDal,

Alessio Squassina, Mirko Manchia, Vangelis G Manolopoulos, Mehmet Artac, Christina Lappa-Manakou, Sophia Karkabouna, Konstantinos Mitropoulos, Maria Del Zompo, George P Patrinos, Realities and Expectations of Pharmacogenomics and Personalized Medicine: Impact of Translating Genetic Knowledge into Clinical Practice, Pharmacogenomics. 2010;11(8):1149-1167.

To give a current example, in May 2013 actress Angelina Jolie underwent preventive mastectomy surgery because she carried the BRCA gene mutations which made her susceptible to breast and ovarian cancer. Since 2006, BRCA1 and BRCA2 gene mutations have been the subject of legal controversy concerning the patentability of genetic sequences before U.S. Courts. Patents on BRCA1 and BRCA2 gene sequences owned by Myriad Genetics Inc. were challenged by a U.S. citizen named Genae Girard. Genae Girard, together with co-plaintiffs (including the Association for Molecular Pathology, researchers, doctors, breast cancer patients, and the American Civil Liberties Union ACLU-) initiated the legal proceedings upon her insurance companys refusal to pay 3000 U.S. Dollars for the genetic test, which she had to undergo before deciding for preventive surgery, as in Angelina Jolies case. Since the high cost of the test was due to the monopoly exercised by Myriad over its patents on BRCA gene mutations, the case aimed to invalidate Myriad patents and thus abolish the monopoly, allowing patients to receive the test at a competitive price. BRCA gene patents Myriad Genetics Inc. owns both product and method patents on BRCA1 and BRCA2 gene sequences. The product patents on the nucleotide strings that constitute the BRCA gene sequences confer Myriad with an exclusive right to conduct genetic tests for the detection of these BRCA mutations. Method patents cover the use of genetic test results for determining the effectiveness of the drugs used for treatment and thus administering the optimum dosage. The lawsuit went through a three-step progression, with the court of first instance (District Court) deciding in favour of the Plaintiffs and declaring all of the contested claims invalid. The Court stated that "DNA's existence in an 'isolated' form alters neither this fundamental quality of DNA as it exists in the body nor the information it encodes. Therefore, the patents at issue directed to 'isolated DNA' containing sequences found in nature are unsustainable as a matter of law and are deemed unpatentable under 35 U.S.C. 101." The District Court did not recognize genetic sequences as inventions, but as the physical embodiment of information already available in the human body. The decision was appealed by Myriad and the case was then heard by the United States Court of Appeals for the Federal Circuit. The Federal Circuit mostly overturned the decision of the District Court by stating that both isolated DNA sequences and the methods for screening cancer therapeutics were patenteligible. According to the majority of the Justices, isolated DNA was chemically distinct from the natural state of a gene in the body.4 Judge Bryson,5 who wrote the dissenting opinion, voted against the patentability of all isolated DNA

Pathology_v._Myriad_Genetics 5 Judge Bryson agreed with the majority with respect to the method claims and the patentability of longer sequences of cDNA.

sequences as well as very short cDNA sequences. The Federal Circuit only affirmed the District Courts ruling by agreeing that Myriad's method claims for comparing DNA sequences were patent-ineligible. During the appeal phase, the U.S. Department of Justice provided a legal brief, which contradicted the longstanding policy of the United States Patent and Trademark Office (USPTO) and argued that human genes without further modification would not constitute patent-eligible subject matter. The U.S. Supreme Court on the patentability of genetic sequences On 13 June 2013, the U.S. Supreme Court delivered the final judgment with unanimous opinion6,7 and asserted a distinction between naturally existent DNA sequences (genomic DNA gDNA-) and cDNA (Complementary DNA), which does not exist naturally. According to this distinction, the isolation of a nucleotide string as it exists within the genome is not a patentable invention. With regard to naturally occurring gDNA segments, Myriads principal contribution was nothing more than uncovering the precise location and nucleotide series of BRCA1 and BRCA2 genes. The Court held that no matter how ground breaking the discovery was, it was not an effort eligible for patent protection since it lacked the requisite inventive step. But conversely, cDNA may be patented as it is produced from the naturally occurring DNA segment by eliminating certain parts of the nucleotide string, which do not hold information (intron), also known as junk DNA. 8 cDNA contains only the nucleotides (exon) that are used by the ribosomes to code one of 20 amino acids. cDNA is an exons-only molecule (omitting the intervening introns), which is not naturally occurring. It is the part of a DNA segment that may be utilised in the laboratory to conduct genetic tests and medical research.

The Supreme Court did not conduct an assessment regarding the method patents. The Court also did not assess the issue of whether or not the method/technology used for the isolation of BRCA gene mutations constituted an invention on the date of patent application. Inventions based on the manipulation of naturally existent nucleotides were also left outside scope of the review made by the Supreme Court. The Court stated that altered programming of genetic code was a different field of legal research. 7 For a summary of the protracted legal battle that started in 2009, and relevant documents, see 8 DNA which does not hold any information that matches with the amino acid string in a protein. In many eukaryotes (organisms which are not bacteria or archaebacteria prokaryotes-), a large part of the genome consists of noncoding DNA and only 5% of the human genome contains protein coding series. Certain noncoding DNA regulate the activity in the coding segments of the genome. Until recently, the functions of noncoding DNA were unknown, and thus it was referred to as junk DNA.

Conclusion A preliminary assessment of the Judgments practical consequences reveals that the companies whose business models are based on gene patents did not take the result to be catastrophic. Firstly, Myriads patents on cDNA were left untouched by the Supreme Court and the invalidated gDNA patents would have expired by 2015-2016 in any case. Right now the most important asset of companies similar to Myriad are the proprietary databases which were built up over the life of their patent-based testing monopolies. Such a database contains clinical test data on DNA sequences that are associated with certain treating effects and thus provides its holder with a very sharp competitive advantage in the analysis of the genetic test results. This is even more the case where a rare variant of a mutation is in question. In line with this, Myriad has recently announced that the expansion of its European business9 would not rely on DNA patents but on databases consisting of the relations between the variant mutations and the clinical data. The decision reflects a certain compromise and balance among the industry actors. Discovery of genetic sequences in their natural form as found in the genome is not considered to be patent-eligible. As a result, research on the relevant genes yielding new products and services will be permissible. On the other hand, patent protection of cDNA provides the necessary economic incentive for continuing research and development in the area of genetics.10

Assist. Prof. Dr. Emre Bayamlolu Law School

The emphasis on Europe is due to the sui generis protection granted to nonoriginal data and information collections in the EU as per the 1996 Database Directive. 10 Rachel Feltman, A Supreme Court loss on human gene patents is just what Myriadand the biotech industryneed,