A mouse in sheep's clothing

A MOUSE IN SHEEP'S CLOTHING: THE CHALLENGE TO THE PATENT MORALITY CRITERION POSED BY "DOLLY"

by Amanda Warren Cardiff University

With the debate on cloning still ringing in one's ears, it was not entirely unexpected that PPL Therapeutics and the Roslin Institute have announced that Dolly, the cloned sheep, is the basis of a patent application. The recent public debate has indicated the repugnance with which some view cloning per se, the cloning of humans and/or animals, and the patenting of biotechnology generally. The Rural Advancement Foundation International is already taking steps to ensure that the "cloning patent" will be rejected by the World Intellectual Property Organization (WIPO),[1] making it set to be as hotly contested as the Oncomouse patent remains.

This article addresses the problems of applying a morality criterion through the patent system and looks to both the Oncomouse[2] case and the impending patent application on cloning in order to consider whether the morality of patenting is being addressed on a realistic basis.

The Morality Criterion

The morality criterion is detailed in the UK Patent Act 1977, where it states that "[a] patent shall not be granted...for an invention the publication or exploitation of which would be generally expected to encourage offensive, immoral or anti-social behaviour...",[3] and qualifies in section 1(4) that the "behaviour" is not "offensive, etc." simply because it is deemed illegal in the United Kingdom. It is arguable that the comparable exemption to patentability through the European Patent Convention 1973 (EPC) is wider than that included in the UK legislation.[4] However, since the U.K. legislation was intended to give effect to the EPC provisions,[5] the UK and European legislative instruments will be treated as identical for the purposes of this article.

The European Directive on the Legal Protection of Biotechnological Inventions,[6] which has recently become law, attempts to clarify the morality criterion. Under Article 6(1), patentability requires an assessment of the application's "commercial exploitation" only, and not in addition its publication, as formerly.[7] Furthermore, the "public policy" standard of earlier drafts has reverted to "ordre public",[8] avoiding the difficulties of reinterpretation, and recital 39 indicates that a single ethical thread binds both "morality" and "ordre public" considerations.

However, focusing on this enduring element of "morality", it becomes clear that the imposition of such a standard as a criterion of patentability is a complex measurement to apply. The European Patent Office's (EPO) Guidelines indicate that a "fair test" is whether public consensus would determine that granting a patent would be "abhorrent".[9] Indeed, although the morality criterion has rarely formed a ground for challenging a patent, already two distinct tests have arisen:

(1) to adopt the "public abhorrence" test[10]; or (2) to adopt the "unacceptability" test.[11]

It is apparent that the tests are irreconcilable,[12] since the second test would appear to be more stringent because a patent may not be "abhorrent", but may still be deemed "unacceptable".

In terms of genetically modified animals,[13] the European Directive states that the process for genetically modifying the animal will be unpatentable on the basis of the morality/"ordre public" criterion where the process is "likely to cause [the animal] suffering without any substantial medical benefit to man or animal and also animals resulting from such processes".[14] As with all tests of "substantiality", it remains for case law to define the parameters. However, this will be made more difficult by reason of the surrounding text. The problem lies with the phrase "likely to cause...suffering", since this could be taken as meaning that any pain[15] will instantly require a substantial benefit, or alternatively, that the level of pain incurred by the subject animal is gauged on a sliding scale against a range of substantiality. The ambiguity makes it unclear which of the tests emerging from the case law is being supported by this defined instance of unpatentability.[16] Is it that only pain-free genetic modification is deemed not to contravene public abhorrence, or that a balancing of foreseeable pain-to-benefit must occur in order to be deemed publicly acceptable?

The History of the Morality Tests in Europe

There have been four biotechnology cases which have been challenged on the grounds of morality: the Oncomouse case; Greenpeace v. Plant Systems NV (PGS)[17]; Lubrizol II[18]; and the Hormone Relaxin case.[19] Since all have been thoroughly critiqued within the context of the morality criterion,[20] it is unnecessary to elaborate on the decisions here.

However, it is worth elucidating on the fundamentally predictive nature of the morality criterion. The effect of the morality criterion in the United Kingdom and Europe is that an analysis is conducted of the invention in the public domain, its exploitation. Even given that prior to the TRIPs Agreement this included "publication", the morality criterion focused on the future public access to the patent application: the product or process in manufacture/the market, or the publication of the application. Therefore, "publication or exploitation" cannot be said to extend to sanctioning the method by which the invention was derived,[21] I since this would involve a retrospective morality.

The morality criterion would only address the original method for deriving the invention if it had a bearing on putting that information, or the invention itself, into the public arena. This point can be illustrated by the Hormone Relaxin case, in which the original cell-line founding the patented invention was obtained from routine surgery for an ectopic pregnancy. Since the cell-line was synthesised, there was no need to return to source in order to exploit the invention.[22] The method would only have been at issue, therefore, if putting the information about the source of the invention into the public domain had been immoral, and then it would only concern the information supplied in the application. Therefore, even if the cell-line in this case had been obtained in a dubious fashion about which the patent examiner was aware, provided the information was not part of the application it would not be caught by the morality criterion.

The moral prohibition, even without publication, cannot centre on a retrospective analysis of methods, since to sanction at this point would be redundant and outside the remit of the legislation. Indeed recital 26 of the Biotechnology Directive suggests that consent to the removal of genetic material, while a desirable prelude to patentability, is a matter for national governance.

Nevertheless, the discussion on patent morality indicates that it is not simply the use of disparate tests which is confounding agreement in applying the morality criterion. The central issue which emerges from both case law and critical analysis is whether the patent system is the correct arena for discussions on morality, or whether it should leave the moral quandary to the regulators and employ the morality clause to remove only the most obviously heinous applications of inventions.

New Moral Dilemmas: The Oncomouse Case

In its initial scrutiny by the Examining Division, the issues which were considered to be of ethical importance fell into two broad groups:

(1) environmental: (a) the possibility of escape into the environment; (b) the idea that evolution was being manipulated;

(2) animal welfare: (a) regarding animals as purely a means to an end; (b) the detrimental effects of the tumours on the animals themselves; (c) whether such research could be conducted without the use of animals.

The Examining Division felt that the matter required a fairly straightforward balance between the utility to mankind as against the environmental hazards and the detriment to the transgenic animals. However, it is notable that the initial moral considerations were pared down to the specific circumstances, removing the general objections of principle. Therefore, while the possibility of escape into the environment was considered and determined to be minimal, because the animal models would be confined in secure laboratories and handled only by qualified staff,[23] the objection that transgenic animals in general pose an unethical inter-ference with evolution was entirely ignored by the Division. This reduction to the specific was a pattern followed throughout the decision. In consequence, the disadvantages were outweighed by the perceived benefits which accrued from the possibility that a cure for cancer could result, making the outcome publicly acceptable.

However, an obvious danger of claiming to represent the "public morally acceptable/unacceptable divide" is that the omission from the ratio of objections in principle is seen as a fundamental flaw in the decision-making process. For opponents, morality is not confined to assessing only the exploitation/publication of the invention, which are the practical public aspects addressed by the Oncomouse decisions, but requires an all-encompassing moral agenda that is thoroughly analysed on all levels.

This point is ably demonstrated by an objection levelled at the opposition stage in the Oncomouse case. The contention was that the Examining Division failed to consider the morality of every possible application of the patent which was being claimed.[24] The argument was exemplified by an "oncogiraffe", which would fall within the ambit of "all non-human mammals" claimed by the patent. The alleged impossibility of using a transgenic giraffe as a test model means that animal welfare considerations would shift the balance against patenting. The criticism, therefore, was in failing to consider this moral aspect before holding the patent to be morally acceptable within the meaning of the EPC.

The difficulty with supporting this contention is that it requires a greater moral assessment than the patent system allows. The morality criterion and the requirement for industrial application[25] are inextricably linked, because it is the invention's use, the way in which it is exploited, which must meet the morality criterion. The best indication of the invention's use is the "industrial application" specified in the patent application. However, the criterion of "industrial applicability" states that patentability rests on "capacity/susceptibility".[26] As a result, it can be said that the Oncomouse's moral assessment concerns "all non-human mammalians/rodents which are transgenically altered to incorporate an oncogene[27] for potential use in cancer research."[28] Where an oncogiraffe can be created, it is immaterial that it is not realistically going to be used for medical research; it is only required to be capable of being used for researching cancer treatments. Since it cannot be said that any mammal/rodent is incapable of being an animal research model, it is pedantry to suggest that the moral implications of every animal falling within the patent must be individually considered.[29]

While it is the exploitation which determines the arena for the moral assessment, the possibility of apply-ing a thorough moral analysis at the patenting stage is anomalous. Examination at the patenting stage requires that morality be determined before exploitation has become assured. Therefore it is inevitable that any assessment at such an early stage in the invention's commercial development will entail some considerations which will consequentially prove superfluous, because the exploitation never in fact occurs -- the oncogiraffe being a case in point.[30]

Similarly, where the scope of the patent extends beyond its initially perceived exploitation,[31] making morality substantially a patenting issue will result in the patent system not taking account of moral assessments which will become realities. Since new applications may subsequently be discovered post-patenting, moral consideration of these cannot be regulated by the patent system. However, where morality is the predominant preserve of other regulatory bodies, which only consider proposals for imminent exploitation, superfluity would be minimised and additional uses could be morally examined.

The inference of the recent objection to the Oncomouse case is that the patent system is being expected to regulate morality in its entirety, as if it were the only system of moral regulation. Clearly, this is not the situa-tion that exists. Moreover, patent protection may be granted years before exploitation ever occurs. Since it is indisputable that morality changes temporally and not always more permissively, patenting morality could easily become outmoded by the date of exploitation. This also supports the contention that morality at the patenting stage should be pitched at the social taboo level of "abhorrence", since this is likely to be a more enduring morality which would remain applicable even after a delay between patenting and commercial exploitation.

The Oncomouse case indicates that a major defect in holding the patent system out as being a bastion against moral unacceptability is that, although the rigours of the morality criterion may have been discharged in terms of balancing considerations to this standard, it is not being seen by opponents of biotechnology as having been discharged. A thorough moral assessment is being demanded, but where decision-making must exclude objections in principle, this cannot claim to be a comprehensive moral assessment. This is because morality by its nature is a statement of individually/collectively held attitudes, which necessarily extend beyond the practical.

Furthermore, in combining the moral assessment of a patent's exploitation with the legal protection afforded to the patentee, the patent system is confusing public perception. The consequence is that opposition groups are objecting to "patents on life", and some arguments levelled[32] suggest that this means that it is the life-form which is the subject of the patent. Indeed, it is the inventive concept as it is applied to the life-form which is in fact legally protected. Yet such misunderstanding is perhaps to be expected, because it is the morality of exploiting the "life-form with the invention" which is being examined.

While such misconceptions concerning the morality criterion remain unclarified, it is contended that the patent system will be destined to fail public expectations exponentially as the issues falling to be considered under the morality criterion become increasingly more complex.

New Moral Dilemmas: The Cloning Patent

Since the Roslin Institute's application is currently being considered for patentability, this analysis is primarily conjectural.[33] However, the nature of the application provides an excellent indication of the progressively more complex and diverse issues which fall within the potential scope of the morality criterion. By examining some of these issues, it is possible to illustrate the inherent impossibility of the patent system becoming the "moral watchdog" of society.

The application appears to have been framed to cover the cloning by somatic cell nuclear transfer[34] of "all animals".[35] In including humans, it is clear that the nature of the moral assessment will need to be as diverse as the potential uses.

Potential industrial application: animals

The utility of the Roslin Institute's experiments is to enable the efficient production of transgenic animals as "bioreactors"[36] for the pharmaceutical industry and possibly to produce transgenic animals for the food industry. At present, Mendel's basic laws of inheritance[37] mean that through each successive generation of animals, the genetically altered element is present in fewer individuals. The resultant cost, time and effort to sustain a viable supply can therefore be overcome by simply copying the altered animals.

In addition, the method used to modify an animal genetically could become more efficient. At present, the methods used to produce such animals are relatively inefficient, because they are either limited by the need for germ-line intervention[38] or the delivery system[39] is fairly inaccurate. Cloning by nuclear transfer means that accuracy can be achieved[40] without limiting the number of animals which can be produced. This, of course, would have an impact on the production of transgenic animals, as already mentioned,[41] for use as human-disease models (such as the Oncomouse and knock-out animals) and on the ability to produce transgenic pigs for xenotransplantation in the future.[42]

Similarly, the production of non-modified animals could become more effective: desirable stock animals could become the template for standardised herds or a particularly outstanding animal could be reproduced without the uncertainties of cross-breeding. It also represents an opportunity to replenish the numbers of animals which are becoming extinct, where the species is not able to repopulate itself.[43] Equally, the use of cloned animals in research would enable the reduction in the number of animals required, because their exactness would make results more accurate even with fewer test models.

Advances in cloning by nuclear transfer will make the process more reliable and efficient and provide insights into cellular development. In turn, this could provide the prospect of greater advances in medical technology, such as new treatments for cancer; being able to regenerate damaged or dead tissue; and reversing the ageing process. Dolly already provides a unique opportunity to study these in new ways. This is because the life-cycle of a normal cell is usually terminated[44] when the continual reproduction of the cell has worn down the "fuse" of chromosomal telomeres to a certain minimum point. However, stem cells (such as ova) and cancerous cells produce an enzyme called telomerase, which replaces the telomeres every time the cell replicates, thereby making them "immortal". Dolly is the unique combination of an adult cell, whose telomeres had already been shortened, and a stem cell, which regenerates its telomeres. The outcome of this combination should pro-vide information about how telomerase can be combated in cancer, to make the tumorous cells terminate naturally; and be promoted in damaged tissue and ageing, to prompt rejuvenation.[45]

Dolly also provides a rare chance to study the full impact of mitochondrial DNA. This is because mitochondrial DNA are found in the cytoplasm of the ovum, which in the case of Dolly was inherited from the ovum-donor, making Dolly not quite a true clone in the sense of being an exact duplicate.

It has already been conjectured that one application could be to clone dinosaurs in order to gain information about their evolutionary disparity with modern animals.[46] However, this is an aspect of the scientific advance which is unlikely to be deemed to have sufficient scale to come within the meaning of "industrially applicable" and therefore would not be assessed by the patent system. The morality of such a possibility would consequently fall to be considered by the ethics committee of the particular scientific institution. As such, this potential scientific application illustrates the disparity of making the patent system the main focus of morality when not all scientific applications fall to be considered by it.

It is of note, that one complication of complying with the patenting criteria other than morality is that the research conducted by the Roslin Institute may not be able to support[47] a claim to "all animals", because uncertainty remains that cloning would occur as a result of the differences in embryonic development between species. Experiments with frogs and mice have previously failed,[48] but it is unclear if this failure was the result of differences in the stage at which embryonic advancement occurs, or because of the incompatibility of the cells' life-cycles.[49]

However, the European patent authorities take a less restrictive stance on the issue of support than the English courts. In the Oncomouse case, where the supporting disclosure detailed only mice, the Technical Board decided that the EPC did not require documentary evidence of the potential to produce the entire ambit of the claimed invention: it was enough that the Board could reasonably anticipate that the full range of products could be produced on the basis of what had been disclosed.

Conversely, in Biogen v. Medeva,[50] both the Court of Appeal and the House of Lords decided that detailing a single instance would not always satisfy the legal standard, Lord Justice Hobhouse deciding that it would be judged on the facts of individual cases. Nevertheless, Lord Hoffmann assessed this issue as being dependent on the distinction between a "principle capable of general application", which would not have to detail every claim, and "discrete methods or products",[51] which would require complete disclosure.

Obviously, under the European standard it would probably be sufficient for the Roslin Institute to detail the production of only Dolly.

Potential industrial application: humans

Human cloning comes within the breadth of the present application, and certain uses can be envisaged which, on the moral "unacceptability" test, may be borderline. Infertile couples may well prefer cloning to the alter-native of assisted inception by donor (AID),[52] because it would remove the moral difficulties associated with a donor's rights. With increasing media coverage of the links between particular characteristics and DNA,[53] cloning in this circumstance would remove any qualms about unknown DNA in progeny. After all, cloning by somatic cell nuclear transfer only really requires one woman for procreation to occur.

Human cloning could also enhance the success and safety[54] of IVF: couples who risk transmitting genetic disorders to their offspring may not be able to produce the optimal number of fertilised ova for reimplantation after the screening process has eliminated those with the genetic mutation. Similarly, embryonic cloning could remove the need to superovulate[55] women prior to IVF treatment, especially since superovulation has been associated with ovarian cancer.[56] Certainly in these circumstances, cloning[58] could be seen as the more morally acceptable option in comparison with the relatively recent proposal to treat infertility indirectly by using the immature ova of aborted foetuses and dead women.[58]

Indeed, human cloning by somatic cell nuclear transfer would provide the only possibility for lesbian couples to have a truly genetic child, since the mitochondrial DNA could be inherited from one partner and the nuclear DNA from the other.

However, all such applications of this technology in facilitating procreation would not at present be licensed by the Human Fertilisation and Embryology Authority (HFEA), in consequence of the unacceptably high level of inaccuracy in cloning. Nevertheless, the potential for future benefits has already led Ruth Deech of the HFEA to state that human cloning should not be prohibited indefinitely.[59]

It has also been speculated that cloning could reproduce dead offspring; produce clones for use as spare parts for ailing progeny or as a health initiative; provide children to order[60]; replicate those outstanding or well-loved people of our choosing[61]; and be used to make individuals immortal.[62]

However, it could be asserted that none of these applications meet the criterion of "industrial application", which prohibits the patentability of "a method of treatment of the human...body by surgery or therapy or of diagnosis practised on the human...body...".[63] Nevertheless, under current legislation product protec-tion could be afforded to at least the single cell resulting from the somatic cell nuclear transfer technique by the exception to this prohibition contained in section 4(3) of the Patent Act. This states that "a product consisting of a substance or composition [shall not be prevented from] being treated as capable of industrial application merely because it is invented for use in any such method".

More definitively, the Directive on the Legal Protection of Biotechnological Inventions prevents the patenting of "processes for cloning human beings" as immoral under Article 6(2)(a), as well as "processes for modifying the germ-line genetic identity of human beings".[64] However, Article 5(2) asserts that human biological material, once isolated from the body, is capable of being patented (if it conforms to the main criteria and notwithstanding its being equivalent to naturally occurring DNA). It should therefore be possible to patent the product of the nuclear transfer technique even applied to human cells and irrespective of whether genetic alteration has occurred. This is because it is the technique applied to humans that is being precluded from patentability.

The difficulty with this assessment is that it hinges on the scope of Article 5 of the Directive, which states that "[t]he human body, at the various stages of its formation and development...cannot constitute patentable inventions". If a single human cell is deemed to be a "human body" then, irrespective of its removal from the donor body, it will be caught by the prohibition.

Given that genetic alteration of a germ-line cell[65] could be patentable under current legislation, it is worth examining the difficulties arising from assessing its morality along the lines of the Oncomouse case. Certainly, the objection that doing so risks losing genetic diversity,[66] for example, would doubtless be gauged an "objection in principle" and omitted from consideration, irrespective of its practical implications. The assessment would be constrained by the limiting factors of foreseeable exploitation and would necessarily exclude matters of unforeseeable risk which are so central to the need for caution in pursuing germ-line gene therapy.

Nevertheless, its practical application would probably be regulated by the Gene Therapy Advisory Committee (GTAC).[67] It presently observes an embargo on germ-line gene therapy." Although it allows somatic-cell gene therapy, the genetic alteration of a germ cell could not be more radical than the complete replacement of its nucleus and, therefore, such a patent would be deemed germ-line gene therapy. As such, preventing exploitation would represent a disincentive to patent in the first instance. In this respect, other forms of regulation can be seen as a more effective deterrent to patenting the unacceptable.

Moreover, recreating dead loved-ones or the admired, or securing world domination through self-cloning, is based on the fallacy that cloning produces carbon copies. Environmental, developmental and minor genetic differences[69] make this a fiction and not a fact. Equally, human cloning does not replicate the memory and, therefore, cannot become an instrument for immortality. Finally, the positive eugenic selection of offspring for desired traits is not a realistic possibility at present, given that many desirable characteristics such as intellect remain a combination of genetics and environment and many other characteristics remain unidentified. Therefore these issues require public education rather than patenting.

However, given the present scramble to exclude human cloning for the time being which has already been undertaken,[70] it is extremely unlikely that humans will form part of the range of the patent. However, the Roslin Institute would still likely be able to obtain a European (UK) patent to "all non-human mammals/rodents", notwithstanding the possible difficulty of supporting the claim. Therefore, it is on these applications that the moral assessment must focus.

Public abhorrence v. unacceptability

Having identified the potential exploitation of the cloning patent, it is the moral implications of cloned transgenic animals, cloned non-transgenic animals and human molecular research which must be examined. However, separating the potential industrial application of the patent into three neat groups for moral assessment is clearly insufficient to comply with the "unacceptability" test for animals, which was exemplified by the Oncomouse case.

If each animal to which the invention is to be applied must be morally examined to ensure its compliance with the foreseeable utility, a narrower range than "all non-human mammals/rodents" would be required to be listed. Therefore, the efficient production of transgenic animals for research purposes would comprise a different list of animals from that for the production of transgenic animals for use as "bioreactors". Similarly, although the list for exploitation by animal husbandry would be the same for transgenic and non-transgenic animals, this would rely on all the non-transgenic animals being capable of genetic enhancement. In consequence, each list would be required to be virtually tailor-made to the exploitation intended.

Since it has already been established that morality must focus on the industrial application, any moral assessment would need to be similarly individualised. Specific moral issues will be used to exemplify the fundamental difficulties encountered by this patent application.

The environmental assessment which was conducted in the Oncomouse case would not be dispatched quite so quickly with the cloning patent. Although human molecular research can be agreed not to represent problems of escape into the environment, the same does not hold true of the other applications. The countering argument to concerns regarding transgenic animals interacting with their environment is that they are so rare and expensive to create that they are kept in secure accommodation. Since cloning would mean that herds of transgenic animals would proliferate, this objection would be removed. Instead, it would be commercially inefficient to keep herds in expensive sheds, signalling their release into the environment. The fears encountered over the possibility of the "supersalmon" at Loch Fyne in Scotland[71] escaping and extinguishing their natural counterparts could become only one of the environmental problems posed by transgenic cows.[72]

Similarly with animal welfare considerations the concerns multiply. Cells become mutated during their life-cycle, from both errors in replicating and from environmental factors, which could have a detrimental effect on the animals' well-being. This would add additional intricacy to the examination. Therefore the depth of