Patenting human genes
This essay was written by David Owen and was first published in the 1995 Mill Hill Essays.
Genes have been known to be the basis of heredity for more than one hundred and twenty years, in particular through the research of Charles Darwin and Gregor Mendel. Each studied genetics through careful observation of the appearance of successive generations of a variety of species, and began to understand the way in which defined characteristics were passed to following generations.
Each individual’s genetic make up is inherited from his or her parents, and determines their individual nature, for example whether they are male or female, their colouring and so on, but also their predisposition to some illnesses or diseases. This intimate involvement of individual genes in good or poor health has stimulated great research interest in genetics among biomedical researchers. It is known that a change in a single gene can lead to illnesses such as cystic fibrosis, some cancers and some diseases of the heart and circulation, whereas other diseases follow from a more complex, and presently poorly understood, interaction between genes.
In the interval since the classic work of Darwin and Mendel, research has moved to allow substantial, and rapidly increasing, understanding of genetics at a molecular level. Thus, the chemistry of genes ( their composition as nucleic acids ), their structure ( the double helix of DNA ), the way in which genes lead to the production of specific proteins, and factors which control the activity of genes within individual cell types is understood in general terms, and has been studied in detail for selected genes.
The precise DNA structure and the biological trait or characteristic associated with individual genes, such as gender, colouring, development of body shape, or role in disease, is known for a limited number of genes, but in 1995 the structure and function of the majority of individual genes remains unknown.
In order to redress this lack of knowledge the scientific community has embarked on the “Human Genome Project”. This is the largest of many current adventures in biomedical research. Its purpose is to identify the exact chemical structure ( termed sequence ) of each of the twenty three pairs of DNA molecules, called chromosomes, which contain all the genetic information (the genome), and to deduce the correct location of each of the genes along the chromosome (termed mapping). Thus the HGP should lead to a knowledge of the precise DNA structure of each gene, coupled with its position along its chromosome. This in turn will aid the search for the function of each gene, although better methods for doing this remain a major challenge for research workers. For those genes which have a known function in a defined disease, the knowledge from the HGP will underpin improved approaches to therapy, designed to tackle the cause of that disease rather than the more usual use of drugs to alleviate the symptoms. The HGP research work is being conducted in laboratories across the world, funded by many national research agencies, by research charities, and increasingly within industrial laboratories supported by private funding.
How will this knowledge of gene sequences lead to improvements on present drug treatments? The purpose of the therapy should be to treat the cause of a disease. Regrettably it remains the case that many therapies deal only with symptoms, and therapies which strike at the cause of disease are limited. An exception to this is the effective use of antibiotics to kill infecting organisms. The antibiotics are targeted specifically at the invading microbe, and when this cause of disease has been eliminated the symptoms disappear.
However, many drugs widely used to treat common disorders such as arthritis, inflammation, high blood pressure and asthma act only to reverse the symptoms, which usually reappear when the treatment is stopped. These drugs can be highly effective in symptom control and improve the quality of many patient’s lives. Anti-arthritic drugs can significantly reduce the pain of rheumatism, reduce swelling, and increase mobility, but they do not usually halt the progression of the disease. Many drugs lower blood pressure and reduce the risks associated with it, such as stroke, but sustained lowering is only possible with continued administration of the drugs.
Increased knowledge of genes, their sequences and their functions will lead to improved drugs. Knowledge of the gene function and the protein produced from that gene will allow more precise targetting of drug therapies. This offers the prospect of more effective drugs with fewer side effects, and also the identification of new targets for drug discovery to allow treatment of diseases currently lacking therapies. These novel therapies might be based on administration of the protein produced by the gene of interest, or a synthetic non-protein compound which mimics the effect of the protein. An alternative strategy would be to give drugs which inhibit the effects of the protein by preventing its formation, or reversing the effects of the proteins actions.
Knowledge of gene sequence and function will also permit absolutely new approaches to therapy. These will include the discovery and development of compounds which bind specifically to individual genes and thereby prevent the gene functioning. This has been called anti-sense therapy. Alternatively, the gene itself might be used as a drug. This requires that a functioning gene can be inserted into the nucleus of identified cells so that it will produce its protein, thereby eliciting the desired therapeutic response. Gene therapy studies have just started in highly selected areas. The earliest studies were intended to use a gene which would replace a key enzyme needed for immunity to infection. The first studies have proved successful and a small number of children have been able to leave the controlled environment of barrier nursing previously needed to protect them from infection. Recently, gene therapy studies have started to treat cystic fibrosis and results are awaited with great interest. Studies are in the planning stage to use gene therapy to treat among others, cancers, heart disease and serious infections.
The conclusion must be that gene sequencing and mapping will improve human therapeutics. The rate of progress will be determined at least as much by availability of investment as by the intellect of the researchers. Therein lies the dilemma outlined in this essay. As the importance of gene sequencing and mapping becomes better established, so the value of that information becomes clearer. The pharmaceutical industry has always sought, and needed patents to protect its investment in novel therapies. It therefore follows naturally, to some, that patents should also be filed on inventions made during gene sequencing and mapping. Others feel that gene sequences represent fundamental knowledge that should not be controlled by any single group of people or company, but should be generally known to all interested research workers. Those espousing this argument do not dispute the importance of patents to justify pharmaceutical company investment, but believe that a commercially competitive position should only be obtained from patents based on inventiveness in the subsequent use of gene sequencing and mapping information.
If we ask the question, “where are the interests of society best served?”, we must first understand why the patent system has developed. This system developed centuries ago to encourage inventiveness that serves the interests of society through the provision of time-limited commercial advantage for patent holders. The consequent incentive encourages investment of money and intellect to solve problems where the inventions will be of broad benefit to society. The granting of a patent, by National Patent Offices, constitutes a contract between the inventor (or employer of the inventor) and the State. In return, the inventor discloses the invention to the public eighteen months after the invention was first filed. This publication is deemed to be preferable to the alternative of research secrecy, and ensures that others do not waste their intellect and investment repeating an earlier invention. It also provides a new and publicly available knowledge base for further invention.
The process of patenting has largely served society well over centuries. Certainly there have been many inventions made, some of great benefit, others which fail, and yet more that fulfil the notion of the eccentric inventor. National and International Patent Offices determine whether an invention qualifies for the grant of a patent. These Offices are State institutions intended to act in the interests of society, balancing the likely rewards to inventors with the contribution of their invention.
This balancing of rewards and contribution has been crucial to attracting private investment into pharmaceutical research. Private investment in the discovery and development of effective drugs has been underpinned by the patent process, and would diminish sharply, if not totally, without a strong patenting process. Drug discovery and development is very costly; the most recently cited figure is about two hundred and thirty million pounds sterling for each new drug developed. It usually takes between eight and twelve years from starting research to first marketing, and is highly risky. The failure rate is huge as drugs fail to meet the aspirations of their inventors, and do not satisfy national requirements for evidence of effectiveness and safety. The successes however can be immensely valuable. Without a fully functional patent system to protect companies who do achieve success in this risky business, there would have been little past investment in drug research, and many modern therapies would not have been developed. Clearly, while many illnesses and diseases remain inadequately treated, it must be beneficial to encourage investment in the discovery and development of improved drugs. The availability of the patent system to protect successful inventions is essential.
There are defined technical requirements for a successful patent application. The patent officers assess applications against a number of fundamental technical criteria. Firstly, the novelty of the invention, is it really new? This can be investigated by consulting records. Secondly, the inventiveness, was the invention obvious? This is judged by reference to the so-called “individual skilled in the art”. In other words, if an invention is made in, say, molecular biology, was the invention the product of true inventiveness of an individual or group of researchers or would it have been obvious to any molecular biologist? Next, does the invention have industrial use and is it of practical value? Finally, is the invention adequately described in the patent application? Has the inventor conducted experiments to demonstrate the practical features of the invention, and is there adequate description to permit the “individual skilled in the art” to repeat those experiments?
Let us examine whether knowledge of gene sequences meets these technical criteria. Knowledge of the sequence of a freshly identified gene is invariably new, and therefore meets the criterion of novelty. The inventiveness criterion will depend entirely on the manner in which the knowledge has been obtained. In general, large scale sequencing activity, yielding information on large numbers of new genes has been based on well-defined methods. It can be readily argued that applying known techniques to sequencing will inevitably lead to gene sequence information, and is therefore not an inventive step but something obvious to an individual skilled in the art. This conclusion is complicated by inventive improvements to the methodology used for sequencing. This latter could, and should lead to a successful patent application on the new methodology, but not on the genes sequenced. The inventiveness criterion is therefore not generally met, since a great deal of the work to sequence human genes has been rendered routine by the inventiveness of past researchers. The industrial usefulness criterion is clearly met. This is demonstrated by the growing industrial investment in sequencing work. Finally, the adequacy of the description of each invention will vary from application to application so no general point can be made.
It would seem from the above that the overall conclusion ought to be that patents should not be granted on human genes obtained by the use of established techniques known to give sequence information. If this is the case, and patents can not be obtained, what are the alternatives? Clearly, one alternative is to publish the information making it available to everyone. This course is favoured by many workers within the HGP. Alternatively, those who undertake sequencing can choose to keep the information to themselves, and deny access to others. This choice of secrecy does not prevent others repeating the sequencing studies, to derive their own information, which they might also choose to retain to themselves, or might choose to make public.
The normal progress of a patented invention is that once a successful application has been obtained, the patent holder is able to determine whether to restrict research and development work in the defined area to themselves, or to come to an arrangement with others who might then also be allowed to “work the invention”. Normally, when companies hold the patent, they retain this right to themselves.
So what would be the consequences of successful patent applications of gene sequences? Knowledge of human gene sequences can be used in a very wide range of methods to discover new drugs. However, when a single company, however large and well resourced with both money and research talent, hold the patent rights to a large number of genes, only a limited range of uses of the information will be practical. The scale of available resources cannot, in these circumstances, match the full range of research opportunities.
Ideally, fundamental information such as gene sequence and mapping data should be free for use by all, but we must remember that much of this information would not be available without investment which expects to profit from that investment.
Perhaps then it would be better if the patent protection essential to justify the large and risky investment needed to discover and develop new therapies were based on the inventive use of fundamental gene sequence information, rather than control of the data. This approach would permit multiple attempts to use the information, with each effective approach amenable to subsequent protection through patenting the inventions arising from it.
The importance of the patent process to aiding investment in useful and novel therapies cannot be overstated. The traditional use of patenting to protect single therapeutic entities has been essential to justify the huge research and development budgets in the pharmaceutical industry. The need for patent protection of inventions derived from the new genetics is equally profound. The promise of improved therapy is well founded, but will only be possible with large scale investment to convert science into products. Thus, appropriate patenting is a crucial element of improved health care from the HGP.
In contrast, successful patent application based solely on gene sequences will result in the control of huge quantities of information in very few hands, and this information cannot, in these circumstances, be applied optimally, or on an adequate scale.
o we return to the question “where are the interests of society best served?”. The past few years have seen a growth of attention to this question, and where the balance lies. Many groups and organisations have studied the topic. Although there has not been complete agreement from these studies, a dominant position has evolved. Formal groups including eminent scientists of many nationalities, politicians, and industrialists, have come to the conclusion that patents should not be granted on gene sequence data alone, but should be allowed for inventions based on the function of specific genes, and also on described understanding of how to modify the function of the gene to achieve useful new therapy.
If applied, these conclusions would provide patent protection to those parties who had successfully invested money or intellect in specific genes, but would prevent any party taking undue control of a whole swathe of gene sequence information through the use of established methodology. This balance should serve the public interest through the provision of incentive to multiple sources of money and research intellect likely to maximise the range of improved therapies.