Pharmacogenomics studies complicated patterns of genetic variation in people. Patentability of Pharmacogenomics Inventions in Europe

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1 Patentability of Pharmacogenomics Inventions in Europe Wenrong Huang, Dennis Fernandez Pharmacogenomics studies complicated patterns of genetic variation in people and attempts to correlate these patterns to differences in drug absorption, metabolism, elimination, or response. With such information, it is possible to design clinical trials that target patient populations with genotypes that are likely to respond to a drug under investigation. This is expected to reduce clinical development time from the current 10 to 12 years to just 3 to 5 years. Drug companies can also use pharmacogenomic information to identify patients that are likely to suffer adverse effects from the drugs and exclude them from the treatment population, and therefore avoid the drug being withdrawn from the market. Eventually, it is expected that pharmacogenomics will enable the advent of personalized medicine, whereby different patients are prescribed different drugs (based on their individual genetic profiles) that are potentially most efficacious and/or cause the least adverse side effects. Gene variations are the foundation of pharmacogenomics. The most prevalent genetic variations in the human genome are single nucleotide polymorphisms (SNPs), which are single base pair differences that occur in 1% of the human population. The human SNP map shows 1.42 million differences. They are of great value to pharmacogenomics research and development. The worldwide pharmacogenomics market is expected to enjoy tremendous growth in the next few years at an average annual growth rate (AAGR) of 24.5%, and pharmacogenomics is expected to be part of mainstream medicine within 10 years. The SNP identification technologies, genotyping technologies and diagnostics sectors are expected to grow at an AAGR of 14.6%, 26.5% and 28.4%, respectively (Fig.1). The US is estimated to generate the majority of sales revenue with a total of 60%, Europe 25%, and Japan 10% APBN Vol. 10 No

2 Fig. 1. Source: Business Communications Company, Inc. Thus, pharmacogenomics has become a highly competitive field where companies are trying to establish themselves in this rapidly changing technology. Major players include life science R&D companies, who are usually engaged in new technology platform development in the tools, methods, and genome contents used in pharmacogenomics. Pharmaceutical companies, suffering from decreased new drug approvals despite increased R&D spending, view pharmacogenomics as an adjunct technology for optimizing their drug discovery and development process. Virtually all of the giant pharmaceutical companies have agreements with pharmacogenomics companies to boost their drug development strategies. In such a competitive environment, being able to secure the intellectual property in pharmacogenomics research is vital to attracting investment, protecting innovations, and fostering the success of companies with leading technologies. This article will discuss some of the issues related to the patentability of genes and genetic variations in pharmacogenomics studies in Europe. Patentable Invention European patent law prohibits granting patents to inventions the publication or exploitation of which would be contrary to order public or morality. This clause was invoked by the European Patent Office (EPO) against the OncoMouse and stem cells patents. Opponents of gene patents argue that gene patents are also against morality because they allow private ownership of the human genome. In 1998, after balancing ethical and economic considerations, the European Community (EC) enacted the Directive 98/44/EC on the Legal Protection of Biotechnologies (Directive), declaring that isolated genetic materials are patentable subject matter. The directive states that biotechnology is fundamentally important for the EC s industrial development, and that patent protection throughout the EC is essential in order to maintain and encourage investment in the field of biotechnology, which usually bears a considerably high risk. Although the Court of Justice of the EC upheld the legality of the Directive after several member states sought to nullify it, and although the EPO amended the Implementing Regulations of the European Patent Convention (EPC) in conformity with the directive, oppositions for gene patents has not stopped. Some of the most APBN Vol. 10 No

3 controversial gene patents are the hereditary breast cancer genes BRCA 1 and BRCA 2 patents by Myriad Genetics of Salt Lake City, Utah. Many argue that these patents would hinder public access to gene health services. A number of parties including French research organization Institute Curie, the Assistance publique Hôpitaux de Paris, the Institute Gustave Roussy(IGR), the Belgian Society for Human Genetics, and the Associazone Angela Serra per la Ricerca sul Cancro filed an opposition before the EPO challenging the validity of the patents after they were granted. In 2001, the European Parliament passed a resolution requesting the EPO to reconsider the granting of these patents to ensure that all... patent applications in Europe do not violate the principle of non-patentability of humans, their genes or cells in their natural environment. The resolution further cited the consensus by the International Bioethics Committee of Unesco (IBC) stating strong ethical grounds for excluding the human genome from patentability. However, apart from stating that the granting of these patents would impede the availability of low-cost genetic testing based on these genes, the resolution did not give specific ethical grounds for not granting the patents. Nor did the resolution explain why granting patents to gene-related inventions and the resultant higher cost for using the patented genetic testing would be particularly offensive, considering that higher cost for using a patented invention is likely to be the natural result for granting patents, regardless of the type of invention. Since, in passing the Directive, the EC has decided that the economic and social benefits created by the incentives of gene patents outweigh the costs of limited monopoly, the European Parliament s arguments against Myriad s patents seem to be unpersuasive. Although it is now settled law in Europe that isolated genetic materials can be patentable inventions, a new ethical issue is raised by gene and pharmacogenomics claims which are directed at a subgroup of the general population based on their origin or ethnicity. For example, in responding to some of the EPO actions, Myriad limited its BRCA 2 patent to the use of the gene for in vitro diagnosis of a predisposition to breast cancer in Ashkenazi Jewish women, among whom the mutation is more common than in the general population. Critics warn that if such claims are allowed, enforcement of the patent would result in the inquiry into a patient s ethnicity and the potential discrimination against that patient if she falls into the claimed subgroup. With this development and the recent controversial FDA approval of NitroMed s Bidil, which is marketed only to African-American heart failure patients, it remains to be seen whether more companies will follow suit to limit their patent claims to a specific ethnic group and whether such claims will be able to stand. Novelty While the EPO upheld the patentability of human genes, it revoked the BRCA 1 patent for failure to comply with the novelty requirement. Unlike the US patent law, which allows a one-year grace period from the public disclosure of an invention by the inventor to the filing of a patent application, the EPC requires absolute novelty. This means that any public disclosure of the patented invention prior to the filing date will become state of the art, which destroys the novelty of the invention and renders it unpatentable. In the case of the BRCA 1 patent, Myriad discovered that the sequence in the original filing had discrepancies with the actual sequence, and amended the application to include the correct one. However, the correct sequence had been disclosed to the public before the filing of the amendment and thus lost 1020 APBN Vol. 10 No

4 its novelty. Therefore, an inventor who desires patent protection in Europe must be vigilant to any public disclosure, use or sale prior to filing an application. Inventive Step Besides novelty, there are two other patentability requirements recited in Article 52 of the EPC: the inventive step and industrial application requirements. Article 56 of the EPC provides that an inventive step is involved if, having regard to the state of the art, (the invention) is not obvious to a person skilled in the art. Thus, the inventive step requirement is like the no obviousness requirement of the US patent law. However, the analysis of inventive step relies heavily on a technical effect of an invention that could not have been predicted from the closest prior art. The EPO assesses the inventive step using a technical problem-and-solution approach, and requires that the subject matter for a patent application be an invention to solve a particular technical problem, not merely a discovery. The inventive step requirement creates the biggest hurdle for pharmacogenomics patents. Under the inventive step requirement, it has long been established by the EPO that the disclosure of a protein renders obvious the DNA sequence encoding that protein and the same protein in different species. Such a presumption can be rebutted, however, by showing that the DNA sequence is particularly difficult to obtain, that inventive skill is required in obtaining the sequence, or that the DNA has an advantageous and surprising feature that could not be predicted from the disclosed protein. In contrast, the disclosure of a protein generally does not render the sequence of its encoding DNA obvious in the US. The Directive states that a DNA sequence without indication of function does not contain any technical information and is therefore not a patentable invention. Similarly, such DNA sequences will be rejected by the US Patent and Trademark Office (USPTO) under the utility requirement. However, the US utility requirement may be satisfied by homology analysis, which is the linking of a claimed DNA whose function is otherwise unknown to a homologous DNA sequence with known function. However, functions based on homology analysis may cause EPO rejection for lack of inventive step. The EPO states that a DNA fragment (obtained by conventional methods), which is assumed to be part of a certain gene, based on its high homology with a known DNA encoding protein with a known function, is not a patentable invention if there is no showing of unexpected effect. Furthermore, structure no obviousness may not suffice. For instance, the EPO will reject patentability of a receptor for lack of inventive step if it has the same general function as a known receptor and if it is obvious to one skilled in the art to obtain it as a matter of routine screening practice, even though it is so structurally different from the known receptor that there is no reason to doubt that it is a new member of the protein family. This is because work involving mere routine experiments, such as trial-and-error experimentation without employing skills beyond common general knowledge is not considered inventive by the EPO. Thus, a gene variation, such as a SNP of a known DNA, discovered by routine high throughput screening, may be unpatentable if it does not have any unexpected effect. APBN Vol. 10 No

5 Industrial Application Contact Details: Contact Person: Wenrong Huang, Dennis Fernandez Address: Fernandez & Associates, LLP 1047 El Camino Real, Suite 201, Menlo Park, CA URL: Industrial application is intended to cover commercial applications and can be satisfied if an invention can be made or used in any kind of industry. It is believed that the mere commercial manufacture of a claimed DNA would satisfy the requirement. However, in Trilateral Project B3b, the EPO opined that a claimed receptor with no known function does not comply with industrial applicability. Thus the EPO s interpretation for industrial application seems to resemble the US patent law requiring the utility of an invention to be specific, substantial, and credible. However, it is not required that the claimed DNA sequence has a known biological function. If the gene or its mutation is useful in the diagnosis of a certain disease, then it is considered to have an identified function in satisfying the industrial application requirement. For instance, the BRCA genes claimed in the Myriad patents have no known biological function, but are usable in diagnostic kits to screen the susceptibility for breast cancer. Similarly, a gene variation that can be used to predict the responsiveness to a certain drug will satisfy the industrial application requirement. The EPO interpretation also creates much overlap between industrial applicability and the technical function required by inventive step. For genetic variations patents, however, the industrial applicability is a somewhat lower standard than the inventive step standard, which not only requires that a claimed mutant has a particular function, but that the function cannot be obvious in view of known DNAs. Regardless of the grounds for refusal, it is very likely that the EPO will not grant a patent to a new gene variation unless it possesses some function or affect that is unique from the wild type. Although such a policy makes patenting genetic variations more difficult in Europe, it might be beneficial to pharmacogenomic research. The higher standard would prevent companies from receiving upstream patents for gene variations obtained through routine high-throughput screening, and consequently blocking downstream research in the function and effect of such variations on drug response. But an inventor may still receive patent protection for genetic variations if he or she uncovers its function or pharmacogenomic value. However, because pharmacogenomics studies the effect of gene variations on drug response, the discovery of a function or effect of certain gene variations may be highly dependent on the drug being studied. Thus, it is possible that a SNP s function or effect will not be known until the discovery of a drug whose efficacy or side effect is affected by the SNP. At that time, it may be possible to claim the particular use of the SNP in predicting the drug response if its sequence has been known to the public. Conclusion With the intense competition in the emerging field of pharmacogenomics, patent protection is an essential incentive to stimulate innovation and investment. Although the EPO allows gene patents, it seems to impose more stringent patentability requirements than the US patent law. It would be interesting to see whether the differences in patenting requirements between the EPO and USPTO would have a significant impact on the investment and growth landscape of this new industry APBN Vol. 10 No