Australasian Biotechnology, Vol. 11, No. 5, 2001, pp. 33-35
WHO OWNS YOUR GENES? THE FUTURE OF GENE PATENTS
Code Number: au01059
Freehills Carter Smith Beadle, Sydney, email: Gavin_Recchia@freehills.com.au
Along with the obvious benefits that the completion of the human genome sequence will provide, come a series of controversial and challenging issues to be faced by scientists, ethicists and lawmakers. This article reviews the growing utilisation of intellectual property laws, in particular the patent system, by genomic researchers.
There is no doubt that the recent release of a draft complete sequence of the human genome represents a significant scientific milestone.
It is also but one more stage in a genomic revolution which began little more than five years ago. In that time the complete genetic makeup of more than 40 organisms, ranging from pathogenic bacteria and industrially important micro-organisms to the more complex fruit fly and rice, have been deciphered. Well in excess of 100 other genome sequencing projects are currently in progress .
This explosion of genetic data is a goldmine for researchers but brings with it a raft of complex issues, not the least of which surround the "ownership" of genome information and the ethical and legal implications of such ownership. This article focuses on the issue of gene patenting and looks at the current stances taken by patent offices, particularly those of the US, Europe and Australia, in assessing patent applications for human genes.
Patenting human genes
The patent systems of most countries do not expressly exclude genetic material from patentability. Providing genes and DNA fragments meet the requirements of novelty, inventiveness and industrial applicability (or utility) a patent may be granted. Indeed in a recent survey conducted by the Working Group on Biotechnology of the World Intellectual Property Organization (WIPO), only 6 of 57 responding countries reported that patents could not be obtained in respect of nucleotide or amino acid sequences .
The question of whether patents should be granted for genes and gene sequences is the subject of considerable debate, largely on social, moral and ethical grounds. The most forceful argument adopted by those opposed to gene patenting, particularly in relation to human genes, is that genetic material is part of the human body and to grant private ownership rights to parts of a human body is unethical and immoral . The counter to this essentially holds that DNA is a chemical compound and should be treated in the same way as any other chemical molecule, be it naturally occurring or synthetic. Further, as patents are only granted in respect of genes and sequences isolated from their natural state, it is argued that ethical and moral concerns are largely otiose. The United States Patent and Trademark Office is of the view that the granting of patents for genes does not confer ownership of genes, genetic information, or sequences. Rather it merely provides the inventor with a set of exclusive rights for a limited time in respect of the making, using, selling or importing of the invention for which the patent is granted, namely an isolated, purified chemical entity.
One of the fundamental bases of the patent system is that the granting of exclusive rights rewards ingenuity and inventiveness and stimulates further innovation. In the pharmaceutical industry, for example, it is generally accepted that effective patent protection is necessary to adequately compensate pharmaceutical manufacturers for the enormous costs involved in developing new drugs. Why should similar protection not be available for those who identify genes and proteins, which may potentially have an enormous impact on human health, as the building blocks of the next generation of biopharmaceuticals?
Turning to the requirements which must be satisfied in order to obtain a patent, of most current interest in relation to the patenting of genes is the requirement that the claimed invention have utility, or industrial applicability. To satisfy the utility requirement for patentability, it is generally held that a function must be ascribed to the gene and a use (eg a medical use) for the gene and/or its product must be demonstrated. As patent offices often accept minimal evidence supporting this requirement, companies eager to secure their position in the post-genomics era are rushing to file patent applications for genes and partial gene sequences as soon as they have a hint of a function, however speculative, from homology-based studies. Thus a large number of patents have been issued for genes, the function of which was not first demonstrated by functional experiments in the patent application. A recent US patent issued to Human Genome Sciences (HGS) for the human CCR5 chemokine receptor and its gene  illustrates this type of strategy. While the link between mutations in the CCR5 gene and AIDS is well established, the precise role of CCR5 was unknown at the time of filing the patent application. It was not until after the patent was issued that researchers discovered that CCR5 acts as the entry point for the HIV virus into human cells and is therefore essential for the development of AIDS.
A handful of genomics companies dominate in terms of the number of human gene patent applications filed. Incyte Pharmaceuticals and Hyseq, for example, have each filed more than 5000 US patent applications for full length human gene sequences. Although the number of applications lodged by Celera Genomics is unclear, the company announced that they had filed 6500 provisional applications for human genomic sequences in 1999 . HGS claims to have submitted patent applications relating to about 7500 human genes. Given that current estimates put the total number of genes in the human genome at somewhere between 35,000-45,000, this could in theory give HGS a monopoly over a staggering 20 per cent of the total human genome .
USPTO utility guidelines
In January 2001 the United States Patent and Trade Mark Office (USPTO) released new guidelines relating to the utility of inventions . After a draft of these guidelines was released in December 1999, the USPTO received a large number of submissions criticising the guidelines as they pertain to the eligibility of gene sequences for patent protection, including opposition from the National Institutes of Health (NIH). In rejecting such criticisms the USPTO has said that an isolated and purified gene is patentable subject matter since the DNA sequence does not occur in the isolated form in nature. In this sense an isolated gene is to be treated in the same way as any other chemical compound.
Specifically, NIH argued that, as a single base change in a gene can lead to significant functional changes, it is an untenable position to grant patents for gene sequences where utility is based solely on homology between the claimed sequence and a known gene of known function. The USPTO dismissed such claims on the basis that there is no scientific evidence that homology-based assertions of utility are inherently implausible.
The new guidelines state that at least one 'specific, substantial and credible utility" for the gene must be supplied to satisfy the statutory requirement. However precisely what constitutes 'specific, substantial and credible utility" is not so clear. Despite fierce criticism of the proposed guidelines, the USPTO has maintained its position that patents may be granted on genomic sequences of unknown function provided the sequence is sufficiently similar to a homologous sequence of known biological function. The USPTO does not adopt a per se rule regarding the extent of homology required, and each application will be judged on its merits. A "rigorous correlation" is not required, merely a "reasonable correlation". Again, what constitutes a reasonable correlation is presumably a matter for the Examiner (or indeed the courts) to decide in individual circumstances. The guidelines state that a patent Examiner must accept a homology-based assertion of utility unless the USPTO has sufficient evidence or sound scientific reasoning on which to rebut the assertion.
The European biotechnology directive
In 1998 the European Union (EU) issued a directive on the legal protection of biotechnological inventions . This directive states that
"biological material which is isolated from its natural environment or produced by means of a technical process may be the subject of an invention even if it previously occurred in nature". (Article 3 (2)).
Biological material is defined in Article 2 as being any material containing genetic information and capable of reproducing itself or being reproduced in a biological system.
With reference to human genes, Article 5 states that whereas the 'simple discovery" of an element of the human body, including "the sequence or partial sequence of a gene" does not constitute a patentable invention,
"an element isolated from the human body ... 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".
Thus the gene must be isolated and purified in order to distinguish it from its natural state. However a mere DNA sequence without indication of function is not patentable under the EU Directive. The Directive stipulates that the industrial application of the gene sequence must be disclosed in the patent application, although no specific guidance is provided as to the necessary basis of the assertion (ie homology or experimental) of industrial application. This is currently interpreted as being a similar stance to that taken by the USPTO, although it is not yet entirely clear to what extent the EPO will adopt the US position in relation to homology-based utility descriptions.
The EU biotechnology directive has generated considerable controversy. The Netherlands has filed an objection with the European Court of Justice on the grounds that the directive violates basic human rights to the freedom of the human body from private ownership. There has also been considerable disquiet in France given that its national laws expressly prohibit a patent being obtained for the complete or partial structure of a gene. Nevertheless, since its inception the directive has been largely implemented by the European Patent Office in its evaluation of patent applications. All EU member states are obliged to adopt the directive, but to date only Germany, Great Britain, Denmark, Finland and Ireland have done so.
The German government last year promised that, in implementing legislation in accordance with the EU Biotechnology Directive, patents for genes would be interpreted in a narrow way so as to encourage rather than stifle research. Ministerial comments accompanying the bill state that patent offices should "restrict a patent to those parts of a gene substantial for the function described in the application."  The German Government is seeking to influence the interpretation placed on gene patents by the courts, however as such ministerial comments are not binding, they may have little impact.
How will Australia react?
The most recent information from the Australian Patent Office (APO), released in November 1998, indicates that
"genes ... existing in, and reproducible from, micro-organisms or like biological material" are patentable. 
This includes genes (including human genes)
"which have for the first time been identified and copied from their natural source and manufactured synthetically as unique materials with a definite industrial use".
The current view of the APO is evident in its decision in Kiren-Amgen Inc. v Board of Regents of University of Washington  . In that case it was held that a claim to a "purified and isolated" DNA sequence is valid as the sequence is not a naturally occurring entity, but rather an "artificially created state of affairs".
To date, patent applications claiming synthetic genes and DNA sequences, mutant forms and fragments of gene sequences, vectors containing the gene of interest, gene probes, anti-sense DNA and regulatory sequences have been accepted in Australia  .
The APO has not yet defined its position on this issue to the extent of that of the USPTO, but with the rapidly growing number of patents for human gene sequences being filed overseas, it will soon become clear how rigorously the APO will enforce utility requirements.
However, even though the APO may grant such patents, it does not necessarily follow that the courts will adopt the same position. There has not yet been a decision of an Australian court regarding the patentability of genetic material. The question of non-obviousness (inventive step) is likely to be the most hotly contested issue, and some gene patents may struggle to survive on this ground.
Several practical issues remain to be resolved in relation to the patenting of isolated genes. Among these, utility is foremost. When is it appropriate for a patent to be granted in respect of a gene? We have seen from the foregoing discussion that the USPTO regards 'sufficient" homology with a sequence of known function to be a reasonable assertion of utility. However the practicality of such an approach must be questioned if the homology-derived prediction of function is ultimately found to be incorrect, thereby potentially rendering the patent invalid. A more reasonable position may be for a patent office to require an assertion of utility founded on experimental evidence of function of the gene (and encoded product) in question. The adoption of such a stance would undoubtedly be vigorously opposed by the major players in the field of gene patenting.
A related difficulty surrounds the effect of "downstream inventions", that is, subsequent discoveries of new functions for protected genetic sequences. In particular, a major concern is what implications an existing patent will have on further research and development relating to the downstream invention. This issue is currently a topic of much debate and has been specifically referred to the WIPO Working Group on Biotechnology for investigation . A further concern being addressed by this Working Group surrounds the growing gulf between developing and developed nations with respect to intellectual property laws and the effect these may have on access and rights to genetic resources.
Genomics companies will undoubtedly continue to file patent applications for gene sequences soon after they are isolated in the hope that at least some of them will be found to encode potentially useful drug targets. Some of these applications are likely to be rejected on the basis of a lack of utility, a fact accepted by many of these firms as part of their overall intellectual property strategy. It is a commercially viable option for these companies to secure at least provisional protection for as many potentially valuable genes and gene products as possible prior to investigating their potential further. A number of issued gene patents may also be ruled invalid, either on similar grounds or on the basis of lack of an enabling disclosure, if ultimately tested in the courts.
Copyright 2001 - AusBiotech