Journal of Intellectual Property Rights Vol 5 July 2000 pp 189-196

Patents for Cloning Embryos

P KVasudeva

Panjab University, Chandigarh

Paper unfolds the developments in embryo research in animals and its possible extension into human cloning, with the knowledge and expertise gained so far in that area. Beginning with a detailed description of patenting of biotechnological inven­tions, it focuses on patents for cloning embryos. This includes moral and ethical issues, uses and risk of cloning. At the end, it touches upon patenting genes and gene products, creation of DNA, genetically modified microorganisms, and India's case on biotechnology.

Biotechnology is a fast emerging technology of the millenium and it is difficult to keep pace with the developments taking place in the fiel. However, the patent laws do not refer to 'biotechnology' per se. The Euro­pean Patent Convention refers to 'microbio­logical inventions'. Most of the biotechnological inventions fall within the following broad categories: -

(i) Preparation of chemical substances util­izing organisms. The substances may be new or known but can be prepared by the use of microorganisms.

(ii) The process techniques employed for the production of genetically engineered or­ganisms, probes, vectors, and so on, which fall in the areas of genetic engineering, hy­bridoma technology and cell fusion tissue

culture, gene therapy, and fermentation technology.

(iii) Basic studies dealing with various bio­chemical and physiological processes in liv­ing cells to understand the signals for expression, servetin of secondary metabo­lites and reproduction.

(iv)Studies on the role and structure of mole­cules such as chromosomes DNA, RNA cy­toplasm, specific hormones and their inter and intera-relationships.

However, it is not easy to get patents in biotechnology as the distinction between in­vention and discovery is very thin. The ques­tion as to the extent to which different products of biotechnology may be consid­ered as products of nature, and thus falling within the ambient of discovery, is difficult

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to determine and must be, therefore, de­cided on a case to case basis.

What is Excluded from Patentability ?

The patenting of microorganisms or the pat­enting of biotechnological inventions raises a number of complex issues. According to Article 270f the TRIPS Agreement the only products or processes which countries are permitted to exclude from patentability are: "diagnostic, therapeutic and surgical meth­ods for the treatment of humans or animals; plants and animals other than microorgan­isms; and essentially biological processes for the production of plants and animals other than non-biological processes."

TRIPS Agreement makes it obligatory to provide patents for "microorganism" and "microbiological" processes? Neither micro­organism is defined in the TRIPS Agreement nor does the agreement specify any parame­ter concerning the scope of its protection. However, the term microorganism will be understood in its widest sense tv include any biological material that is self-replicable or replicable via a host organism. Sub-cellular material like genes, gene sequences, plas­mids, replicons etc. will come under the defi­nition of a microorganism.

Some of the patentable microbiological in­ventions are:

(i) Process of producing a new micro­organism.

(ii) The new microorganism as pro­duced by the defined process.

(iii) The new microorganism per se.

(iv) Process of cultivation or otherwise using a known qr new microorgan­ism to (a) a form of multiplied mi­croorganism itself e.g. vaccine or

edible biomass, and (b) a by-prod­uct of microbial growth, e.g. an antibiotic, enzyme, toxin, or an otherwise useful industrial prod­uct.

Patents for Cloning of Embryos

A US company Gerona Corporation based at California has been awarded two British pat­ents that appear to grant it commercial rights to human embryos created by clon­ing. The precedent-setting patents were is­sued on the cloning method that produced the now famous Dolly, the sheep. The com­pany now has exclusive rights to animal em­bryos prepared by transferring the nucleus of a quiescent diploid donor cell into a suit­able recipient cell and including the blasto­cyst stage.

The British Government is almost certain to end the ban on therapeutic cloning of em­bryos' for research that could eventually cure kidney, liver or heart diseases by re­growing a heart muscle or bone marrow, which is not a threat to humanity.

Mom! and EthimJ I!B1es

These new patents have sparked protest from groups concerned about the ethics of biotechnology patents especially those cov­ering human genes or cells. "The British government is the first government in the world that has issued patent protection on a human being at any stage in development," says activistJeremy Rifkin ofthe Foundation on Economic Trends, Washington DC, USA. He cal1s it "profoundly unsetting" and says that he will challenge the patent, argu­ing that British law forbids giving someone property lights to a human when an embryo is only a ball of a few dozen cells.

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The patenting of biological material raises a whole range of not only technical and legal, but also ethical, moral, and social issues. The issues raised are so complex that they have not been resolved satisfactorily even in the industrialized world. The basic reason is that the hio-technical inventions dealing with living matter and scientific advances in genetic manipulation have been so rapid and startling that their consequences have gen­erated wide ranging apprehensions. Instead of making a better mousetrap, the man has started making better mouse. Man has ac­quired the capacity to "play God" through his scientific knowledge and control over life at the cellular level.

Tte European Patent Office said that it made a mistake in recently granting a patent to a process that could include the cloning of humans.The Munich-based office granting Edinburg University a patent on altering cells and human embryos in December 1999,but the decision only came to public attention after the environmental group Greenpeace issued a critical statement in Feburary 2000."It is a mistake ,yes," said Patent Office spokesman Rainer Oster­wad tel' "It could be seen to embrace the cloning of humans . .. What is missing is the disclaimer that it does not refer to humans." Osterwadter said, his office could not imme­diately reverse the decision, but would have to wait for outside parties to file their oppo­sition to the patent. He said it could take years before the review process ends.

Stefan Flothmann of Greenpeace said the group would challenge the decision. "Living organisms and parts of living organisms are not inventions and only inventions can be patented", he said. "It should not be Patent Office that decides this." The mistake oc­curred when patent officials weighing the turgid 235- page application apparently over-

looked a passage-deep inside the descrip­tion-referring to humans. "In the context of this invention, the tenn 'animal cell' is in­tended to embrace all animal cells, espe­cially of mammalian species, including human cells", it said. Flothmann said the process described in the patent referred to the alteration of cells such as those in human eggs and spenn, and to the growing of hu­man organs such as livers and hearts in other animals for later transplant.

Human embryo cells are difficult to work within the USA due to their rare nature, mostly collected from in-vitro fertilization programmes, and opposition from some groups on ethical grounds.

A rare bill that will ban human cloning has been placed in the Japanese Parliament. "It is felt that human cloning could damage human dignity and break down the social structure by muddling family ties", said a spokesman for the Science and Technology Agency ofJapan. The bill will outlaw the act of putting a cloned human embryo-in which a body cell is transplanted into an unfertilized egg from which the nucleus has been removed-back into the wombs of hu­mans or animals. The law will also ban the transplant of hybrid embryos, or human egg cells fertilized with animal spenn, as well as chimera embryos made by combining hu­man and animal embryo cells.

Punishments for those who break the law will be fined unto $ 47210, a prison sentence of up to five years, or both. Some types of basic clone research may be permitted if they are deemed essential and cannot be can;ed out in any other way, but will require review and prior approval by a committee of experts.

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Products of Nature

The question that comes to mind in this context is whether we can patent something that already exists in nature, whether it be an inanimate chemical compound, an en­zyme, a microorganism or higher life form or a gene? Patents are concerned with the economic benefits to the inventor. As re­gards its utility to man, there is no reason, why research into natural products should be treated differently from research in other areas of chemistry. The product of nature problem is also compounded by the fact that most patent laws make a distinction between 'discovery' and 'invention' and exclude mere discovery from the benefit of patent protec­tion. However, natural products are usually inaccessible in nature and have to be spot­ted, dug out and identified. The classic ex­ample of this was the production of vitamin B12 by fermentation and its isolation in bulk as the pure substance. Previously the sub­stance had been available only as crude live extracts which were of no use for therapeu­tic applications. In support of the patent, the U~ court said, "Before the inventors made it available to the world, pure crystalline vi­tamin B12 did not exist." The European Pat­ent Office guidelines refer to free occurrence, To find a substance freely oc­curring in nature is also mere discovery and therefore unpatentable. However, if a sub­stance found in natqre has first to be isolated from its surroundings and a process for ob­taining it is developed that process is patent­able. Moreover, if a substance can be properly characterized either by its struc­ture, by the process by which it is obtained or by other parameters and it is "new" in the absolute sense of having no previously rec­ognized existence, then the substance per se may be patentable." Substances like pro­teins, enzymes, antigens, antibodies and bio-

logically active substances of higher molecu­lar weight which are produced by micro­bilogical cultivation or often by extraction from plant and animal cells and tissue in which they are found in nature may be cov­ered under product claims whenever possi­ble.

The "novelty" of virus has to be taken into account whether it has been isolated for the "first time" or it is "new" because it is a modified form of the wild type: The utility of virus has also to be considered as most usual activity as a vaccine strain and there is no difficulty in principle about obtaining a claim to a vaccine containing virus X as an anti­genic component. The complexities of the new biotechnological techniques including recombinant DNA and cell fusion methods give rise to additional categories of patent­able inventions.

Patents are given for "invention" and not for "discoveries". In the area of biotechnology, the complexity arises from the fact that it is increasingly becoming difficult to determine where "discovery" ends and "invention" be­gins, because the starting point vf any bio­technological invention is pre-existing biological matter provided by nature. Even in the western countries this difficulty is resolved more through judicial pronounce­ments and patent office practices on the facts and the circumstances of each case rather than through clear-cut criteria laid down in law. Simply stated, the doctrine of "man­madness" would appear to have come in vogue in the judicial decisions of USA to distinguish between a "product of nature" and a "product of man". The nature and extent of human intervention have been used as the criteria to decide whether a pat­entable invention has been created or not. In this view, while microorganisms as they are found in nature or in their original natural

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state are not patentable, they can be pat­ented, if by virtue of human intervention they have been isolated, purified, or crystal­lized and the resulting product is valuable and different from what is "found" in nature. This approach relating to naturally occur­ring microorganisms is still evolving, but there is much greater certainty in the west­ern world with regard to genetically modi­fied microorganisms (GMOs). The predominant view is that they are patent­able,· because they are creations of man and they cannot be regarded as "pre- existing" matter. In a report by the British Medical Association December 1992, it has been ex­pressed that living organisms should not be patented (including the results of Human Genome Project) and Europe should not go as far as USA in the matter of patenting such inventions.

Uses of Cloning

Biologist Ian Wilmut and co-author Keith Campbell in a book The Second Creation: The Age of Biological Control , have said that cloning humans, is a long way off, that should give people and their governments time to consider the ethical implications.

Cloning is not about performing a neat sci­entific trick. Combined with genetic engi­neering, it offers humans the ability to modify the animal kingdom to our advan­tage. Wilmut said that the most important sheep in Edinburgh nowadays is not Dolly, but Polly- cloned and genetically trans­formed, and whose milk contains a protein called AATwhich could be useful in treating human lung disease such as cystic fibrosis and emphysema. AAT is otherwise scarce and expensive. There are countless other potential medical uses. If human genes are added to those of a pig, for example, humans in need of new organs may be able to receive

them without the rejection tha t often plagues the process.

Wilmut has defended the two patents granted in Britain on the cloning technology used to make Dolly. 'There is reasonable concern about the idea of patenting process, but the commercial benefits of a patent bring the needed money to bring forward the re­search," he said.

PPL Therapeutics Pic, the British Biophar­maceutical Company that helped to clone Dolly, the sheep has created the world's first cloned pigs. The birth of five cloned piglets­Millie, Christa, Alexis, Carrel, and Doctcom- on 5 March 2000 could herald a new age in animal-ta-human organ trans­plants, or xenotransplantation.

Up to 68,000 people in the United States, 50,000 in European Union and millions in the Third World countries are waiting for liver, kidney, and heart transplants. The list in­creases 15 per cent per year while the list of the donors are dwindling. Scientists believe genetically engineered pigs, which can be bred quickly and whose organs are about the same size as humans, could solve the problem. "It opens the door to making modi­fied pigs whose organs and cells can be successfully transplanted into humans- the only near-term solution to solving the world­wide organ shortage crisis", said the PPL.

Analysts estimate the market for organ transplants could be worth 10 billion a year. Cellular therapies, in which altered cells are transplanted to humans to treat conditions such as diabetes, would add considerably more to that sum."AlI the known technical hurdles have been overcome. It is now a case of combining the various strategies into one male and one female pig, and breeding from these. End to the chronic organ shortage is

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now insight", said PPL Managing Director Ron James in the company statement.

US researchers have introduced cells from pig embryos into the brains of patients suf­fering from Parkinson's disease, with posi­tive results. The treatment which is meant to replace the chemical dopamine in the brain, was fo und to have improved the symptoms of Parkinson 's by 19 to 51 per cent, accord­ing to work published in the journal Neurol­ogy, a publication of the American Academy of Neurology of St. Paul.

Parkinson's is a progressive neurological disorders that debilitates motor skills of suf­ferers and can ultimately be fatal. Pig em­bryo cells that correspond to a similar function in the human brain were extracted and transferred into the region of the Park­inson's sufferer's brains that were failing. The researchers found the cells were able to replenish and become integrated into pa­tients' organ and not rejected as a foreign body.

Risks of Cloning

Wilmut insists the biggest tisk of the cloning breakthroughs is those fears caused by such ideas- and public mistrust of science's her­metic complexity-will some day prompt gov­e rnments and compani e s to restrict research. "My anxiety if anything is that we do not take the opportunities. That we are too hesitant," he said. He further said that the people have lost confidence in science, and tend to take it granted. They think as if all the medical treatments that we have now have been here all the time, and were not the result of research.

"I have never heard a good enough reason to copy a human," says Wilmut. He would also oppose parents trying to "enhance"

the ir offspring throug h gene manipula­tion-giving them improved athletic ability.

Patenting Genes and Gene Products

The DNA sequence constituting a particular gene is an inanimate chemical substance which ought to be patented as a chemical compound. However, if the gene is a natu­rally occuring substance this again raises the compilation of being a 'product of na­ture'. It is known that any biological property is attributable to a particular gene or combi­nation of gene (s), therefore, the gene (s) for sllch a property must exist. To seek and find and identify such genes might therefore, appear as an obviously desirable thing to do in the first instance and it is not an easy task. Unlike bacterial genes which code directly for the polypeptide expression product (via messenger RNA as in the natural process) genes in higher or genesions (eukaryotic) uSllally work in an indirect manner. In eu­karyotic genes, the coding section of the DNA (exons) are separated by non-coding sections of the DNA (introns) . r~ ,. erefore, during transcription of DNA, the primary RNA transcript has to be processed by the cell to cut out unwanted segments deriving from the non-functional parts of the original DNA (introns). The actual m-RNA used for protein synthesis is therefore, not a true RNA copy of the original natural genomic DNA.

When eukaryotic genes are cloned, it is very common to start by isolating the messenger RNA from which the molecular biologist synthesizes a DNA copy of the messenger (complimentary DNA). It is therefore, most frequently the cDNA which is cloned into the microorganism together with the re­quired control regions of DNA which are necessary for expression of the tailored

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"genes". It must be recognized that cDNA, as such does not exist in nature.

Creation of DNA

Scientists have made the world's first syn­thetic DNA, the molecules that form the blueprint for life. The breakthrough means that the first artificial organisms can be "born" within two years and raises the pros­pect of human redesigning whole species, including themselves. The DNA was created at th e Univ e rs ity of T exas where re­searchers have mapped out the exact way it will be configured to create synthetic organ­ism one (SO 1), the microbe destined to be the world's first man-made creature. "We are synthesizing DNA to create the first syn­thetic organism," said Prof. Glen Evans, di­rector of the university's genome science and technology centre. "SOl will have no specific function , but once it is alive we can customise it. We can go back to the com­puter and change a gene and create new life form s by pressing a button," said Prof. Glen.

The researchers are planning to create a series of designer bugs, with super efficient mechanism for infecting target tissues such as cancer tumours-and then killing them. Some would infect the human gut to produce vitamin C. Critics however, have warned that the scientists risk unleashing a microbe master race with increased powers to infect humans and wild life. The researchers' suc­cess lies in having found a way to create long chains of DNA. Such chains are made up of four types of molecule, which join up in two some known as "base pairs." These man­made creatures, which are for the improve­ment of human beings and for curing them holistically, are patentable, because these are synthetic DNA.

Genetically Modified Microorganisms Allowed to be Patented

According to TRlPS Agreement, naturally occurrin g microorganisms, including genes, gene sequences, cell lines, sub-cellu­lar material howsoever derived or trivially modified, are excluded from patentability. But genetically modified microorganisms (GMOs) are allowed to be patented, if hu­man intervention and value addition in their creation is substantial and GMOs involve a novel genetic make up. The prominent view is that the GMOs are patentable, because they are creations of humans and they can­not be regarded as "pre-existing" matter. Judicial rulings and patent office practices in USA and EU are not all in the field ofbiotech­nological inventions. In a December 1992 report, the British Medical Association has expressed the view that living organisms should not be patented (including the result of the Human Genome Project) and EU should not go as far as USA in the matter of patenting such inventions.

India's Case on Biotechnology

Though India has not developed much in the biotechnology, yet it is the technology of the future. It wili have a pervasive role in agricul­ture and industry, food and medicine, envi­ronment and ecology . It is a knowledge-based industry and intellectual, rather than financial, capital will drive it. India has the talent to develop a strong biotechnological base in the country and the approach to the question of intellectual prop­erty protection in this area should be posi­tive, rather than defensive, taking a long term view of the strengths and the contribu­tion biotechnology can make to our eco­nomic development. However, in view of the

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complexities involved in patenting biotech­nological inventions, we need to build up our knowledge and expertise in this area and evolve our own IPR system over a period of time in the light of experience and after the amendment of Patents Act 1970, Biodiver­sitY Bill and Plant Variety Bill introduced in the Parliament which is being considered by the thirty rnember J oint Parliament Commit­tee for their recommendations.

Our approach to patenting of microorgan­isms should be as follows:

Firstly, naturally occurring microorgan­isms, including genes, gene sequences, cell lines, sub-cellular material etc., however de­rived or trivially modified should be ex­cluded from patentability. Secondly, only genetica ll y modifi ed microorganisms (GMOs) should be allowed to be patented, if human intervention and value addition in their creation is substantial and the GMOs involve a genetic make-up. Thirdly, the GMOs should be allowed to be patented, only if the particular claim of trait or use is accepted by us, with the product in which the GMO is incorporated being also allowed patent or plant breeder's rights as per the rules applicable to it. This approach is un­likely to violate the provisions of the TRIPS Agreement. We need to enact our law in this respect by the year 2000.

However, our position in patenting of micro­organisms, recombinant DNA products,

gene patenting, transgenic plants and ani­mals need to be clearly defined through ap­propriate policies and legislation.

References

1 Braga Carlos, Trade- Related Aspects of Intellectual Property Rights: The Uru­guay Round Agreement and its Eco­nomic Implications, World Bank conference paper, 26-27 January 1995, Geneva.

2 Evans Glen, New Life Forms, Depart­ment of Genome Science and Technol­ogy Centre, University of Texas. February 2000.

3 Ganeshan A V, The GATT Uruguay Round: Agreement Opportunities and Challenges ( Rajiv Gandhi Institute for Contemporary Studies, New Delhi) 1993.

4 Genetically Modified Crops :The Ethics and Social Issues{Nuffield Council of Bioethics ,London) 2000.

5 Wilmut Ian &CampbeII Keith, TIle Sec­ond Creation : The Age of Bioiogical Control, Washington,2000.

6 N arayanaswami K, Human Clonp,s, "Alive", New Delhi. December 1998.

7 Swaminathan M S, Genetic Diversity and the Indian Seed Industry (Rajiv Gandhi Institute for Contemporary Studies, New Delhi) August 1993.