The subject of 'Life Sciences' has received a surge of interest and rapidly increasing publicity in recent months. The technology advances which have taken place over the years, culminating in the dramatic announcement made earlier this year about the Human Genome Project, have concentrated the research community's focus and attention (and that of the public as a whole) on the proprietary rights which are currently available for 'life science' inventions.
What are 'Life Sciences'?
From the perspective of an intellectual property lawyer, it may generally be observed that the life sciences can be divided into several distinct categories:
pharmaceutical inventions;
biotechnological inventions; and
the patenting of genes, plants and animals.
Patentable Inventions - Substantive Requirements
Before even elaborating on these individual topics, a more preliminary question has to be addressed: under Singapore patent law, what are the requirements which have to be satisfied in order for an invention to be classified as 'patentable'? First, there is the trinity of criteria to consider, ie whether the invention in question:
is novel;
has an inventive step; and
is capable of industrial application: section 13(1), Singapore Patents Act (Cap 221).
In most jurisdictions, there are also basic thresholds to cross before an invention can be considered 'patentable'. For example, any invention which consists of
a discovery, scientific theory or mathematical method;
a literary, dramatic, musical or artistic work or any other aesthetic creation whatsoever;
a scheme, rule or method for performing a mental act, playing a game or doing business, or a program for a computer; or
the presentation of information
shall not be treated as a patentable invention, only to the extent that patent or an application relates to that thing as such (see, for example, section 1(2) of the United Kingdom Patents Act). The relevant sub-section from the Singapore Patents Act (section 13(2)) was repealed with effect from 1 January 1996, thereby providing much latitude for speculation as to whether the above 'inventions' are actually capable of qualifying as patentable subject matter, even if they are patented as such. Although this question awaits judicial determination, it does not preclude a judge from taking the view that notwithstanding the repeal of section 13(2) of the Singapore Patents Act, any of the above still do not qualify as 'inventions'. In life sciences, a distinction will necessarily have to be drawn between a discovery of raw DNA data (as, for example, that generated by the Human Genome Project) and the Expressed Sequence Tag (EST) which has been obtained from the process of isolating messenger RNA from various tissues, and deriving from this a mixture of fragments of c-DNA. The former is arguably a discovery simpliciter (and thus should not be patentable), whereas the latter may be considered patentable, subject to its fulfilment of, inter alia, the trinity of criteria as described above.
Another significant fetter on whether an invention is 'patentable' under the patent legislation is what may be referred to as the so-called 'morality' exclusions. Sections 13(3) and (4) of the Singapore Patents Act provide:
An invention the publication or exploitation of which would be generally expected to encourage offensive immoral or anti-social behaviour is not a patentable invention.
For the purposes of subsection (3), behaviour shall not be regarded as offensive, immoral or anti-social only because it is prohibited by any law in force in Singapore.
There can be much that may be left to the imagination and subjective judgment as to what constitutes an 'immoral invention' for the purposes of sections 13(3) and (4). The 'morality' exclusions, that is, inventions that are not treated as patentable because to do so would encourage exploitation or publication that are contrary to the ordre public are not strangers to intellectual property laws. In other spheres, immoral creations have been refused protection in the past. See, for example, the cases of Re Masterman's Design (The Times, 19 December 1980) (where the Designs Registrar refused an application for the registration of a design in respect of a Scots doll with a kilt which, when lifted, exposed genitalia); Glyn v Weston Feature Films [1910] 1 Ch 261 at pages 269-270 (Elinor Glynn's 'Three Weeks', however opaque its voluptuousness may seem today, was condemned in 1916 as a 'glittering record of adulterous sensuality masquerading as superior virtue'); and Stephens v Avery [1988] 1 Ch 457 (determining the question whether secrets of a personal nature can be protected by the law of confidence, even if they are related to sexual conduct of a lurid nature).
In the absence of prescriptive statutory and even sui generis rules and other criteria which regulate the proprietary parameters of life science inventions, the moral dimension as reflected in section 13 of the Patents Act takes on a significance that surpasses a superficial query as to whether such an invention is contrary to law, for sub-section (4) provides that the mere absence of a legal prohibition is not sufficient to despatch determination of the morality of a particular life science invention, or otherwise. Indigenous cultural considerations may also be relevant: in PLANT GENETIC SYSTEMS/Glutamine synthetase inhibitors T356/93 [1995] EPOR 357, the Technical Board of Appeal of the European Patent Office stated:
The concept of morality is related to the belief that some behaviour is right and acceptable whereas other behaviour is wrong, this belief being founded on the totality of the accepted norms which are deeply rooted in a particular culture. For the purposes of the [European Patent Convention], the culture in question is the culture inherent in European society and civilisation. Accordingly … inventions the exploitation of which is not in conformity with the conventionally-accepted standards of conduct pertaining to this culture are to be excluded from patentability as being contrary to morality.
The difficulty of life science inventions is that the norms of morality remain to be defined in indigenous and cultural terms.
Pharmaceutical Inventions
Substances and compositions that are created for a pharmaceutical use and that satisfy a utility are patentable in all countries that are Trade Related Intellectual Property Rights Agreement (TRIPS) compliant (article 27(1), TRIPS). Such substances that are created for use in a method of treatment or diagnosis are not prevented from acquiring novelty or industrial application in the eyes of the law.
The interaction between pharmacologically active drugs and pro-drugs presents some issues for patent law and the proper definition of the parameters of protection. Pro-drugs are on their own inactive, but can be hydrolysed or otherwise metabolised in the body to form an active drug. If the active drug is invented first, and the pro-drug is subsequently invented that carries some additional advantage, the use and disposal of the pro-drug may run the risk of infringing the original drug patent. For a comprehensive elucidation on the difference between pro-drugs and active metabolites, see Philip Grubb, Patents for Chemicals, Pharmaceuticals and Biotechnology (OUP, 1999) at page 211. In Beecham v Bristol Laboratories [1978] RPC 153, the claim to a semi-synthetic penicillin, ampicillin, was held to have been infringed by the importation and sale of hectacillin, a chemical substance which functioned as a pro-drug, and was converted into the claimed drug upon hydrolysis in the human body. The infringing substance was treated as being the claimed substance (ampicillin) 'temporarily masked' (at pages 200, 203). The pro-drug in this case was seen as a deliberate attempt to capitalise on ampicillin while evading the letter of the ampicillin claim, the court having been persuaded that there was no apparent advantage in using the pro-drug (even though in some cases its administration may reduce harmful side effects).
If patents are similarly filed for active metabolites which are subsequently discovered, but which confer protection for a previously patented (but now expired) drug, it is unlikely that the courts will countenance what effectively amounts to an artificial extension of the patent term. In Merrell Dow v Norton [1996] RPC 76, the plaintiff held the first patent for the drug terfenadine, which subsequently expired. Prior to its expiry, it was discovered that in the liver, terfenadine was metabolised to produce a previously unknown metabolite of terfenadine. The essence of this active metabolite was that it substantially accounted for the effectiveness of terfenadine in the treatment of asthmatic disorders. Through protecting this metabolite, the plaintiff had extended the overall period of protection for the terfendaine drug substantially. The second patent was held to have been anticipated by the first terfenadine patent, which disclosed the use of the substance claimed in order to treat the conditions covered in the second patent, and also the steps in its preparation. It is evident that this would otherwise have constituted an abuse of the patent system. However, owing to the novelty of the active metabolite simpliciter, the House of Lords did not rule out a claim to the metabolite when produced outside the human body.
In the pharmaceutical arena, it is common that a new use made of a compound which already forms part of the prior art may still acquire novelty in its own right. Section 14(7) of the Singapore Patents Act fortifies this principle:
In the case of an invention consisting of a substance or composition for use in a method of treatment of the human or animal body by surgery or therapy or of diagnosis practised on the human body or animal body, the fact that the substance or composition forms part of the state of the art shall not prevent the invention from being taken to be new if the use of the substance or composition in any such method does not form part of the state of the art.
The European Patent Convention (EPC) and the United Kingdom Patents Act contain similar language. In Hoffmann-La Roche/Pyrrolidone derivatives T128/82 (OJ 1984, 164), the Technical Board of Appeal of the European Patent Office has held that claims in the form of '[c]ompounds of formula … for use as a therapeutic substance …' were allowed, and by analogy with pharmaceutical claims, such claims should cover all therapeutic uses of the substances and not only use or the specific indication which was disclosed.
Biotechnological Inventions
In this second category, the discussion shifts to patents for novel productions of useful products by living micro-organisms. A new generation of biotechnological inventions has emerged from two basic techniques of recombinant DNA technology and hybridoma technology. Recombinant DNA technology (also referred to as gene splicing) comprises the extraction of genetic material from an external source and inserting it into a cell in such a way that it causes the production of a desired protein by the cell. With hybridoma technology, different types of immune cells are fused together to form a hybrid cell line producing monoclonal antibodies (see Grubb, op cit, chapter 12).
Microbiological inventions are also not excluded from this second category of patents, and patents for micro-organisms per se are either new organisms which may have been found in nature (for example, by the screening of soil samples) or may have been produced in the laboratory by random mutation or reverse engineering techniques, thereby forming a new compound with improved attributes, such as high yield and/or purity. Article 2(3)(b) of the TRIPS Agreement makes it obligatory for all WTO members to grant patents for micro-organisms (see also section 114 of the Patents Act and the Fourth Schedule of the Patents Rules in Singapore).
In the US, the early cognisance of microbiological patents came with the decision in Diamond v Chakrabarty 206 USPQ 193 (Supreme Court, 1980), where by a five to four majority, the Supreme Court held that a new strain of oil-feeding bacteria produced artificially (by bacterial recombination) was a patentable invention. A scientist working for the General Electric Company, Chakrabarty, had produced a micro-organism strain that had the capacity to decompose crude oil. Chakrabarty engineered the strain by introducing compatible plasmids from three different bacteria into a fourth bacterium, so as to devise a new genetic structure. Chakrabarty applied, on behalf of General Electric, for patents to cover the method of producing the bacterial strain, the carrier material deployed when the strain was put to use in eradicating oil slicks and the strain simpliciter. On appeal, the Supreme Court held that the subject matter met the standard requirements of novelty, inventiveness and industrial utility. The court went on to say that the issue was not whether the organism was living but whether it was a product of nature. In the circumstances, the applicant had done enough to distinguish the subject matter from nature - it was a non-naturally occurring product, the outcome of human ingenuity, with markedly different characteristics from any strain found in nature and with the potential of significant utility.
It is generally acknowledged that the gene splicing patents issued to Cohen and Boyer, two academics working in Stanford University and the University of California respectively (US Patent No 4,237,224, which claims a method of producing a protein by expression of a gene inserted into any unicellular host), foreclose and anticipate (even though the said patent expired in December 1997) many possible application for gene splicing and derivative processes. The advances made in the field of genetic engineering make it extremely challenging to process claims for the products of recombinant DNA technology. The divide separating the obvious from the non-obvious, in the course of an enquiry into whether an invention as claimed lacks the requisite inventive step, is not in practice an easy one to bridge: see Genentech v Wellcome [1989] RPC 147. The English Court of Appeal has recently looked to see if the inventor has produced 'a novel insight or discovery' (see Biogen v Medeva [1995] FSR 4 at page 56), arguably raising the entry bar even more for the determination of inventive step for inventions which involve the use of recombinant DNA technology.
Patent claims for biotechnological inventions, like other patents, are subject to the general rule stipulating the adequacy of disclosure and a general rule against the prohibition of over-broad claiming. The recent House of Lords decision in Biogen v Medeva [1997] RPC 1 is illustrative. The claims in questions were referred to recombinant DNA molecules, which produced a crucial protein for a vaccine against the hepatitis B virus. The virus comprised outer and inner protein cores and DNA genome within the cores. Through recombinant techniques, the DNA molecules were constructed from these cores. Their Lordships held that whilst there was an adequate description of one single method of achieving the recombinant DNA molecule, claiming could not extend to other avenues which were known to produce the same molecule, as there was nothing in the teachings of the patent to point to these alternative methods. The contribution made by the Biogen patent lay in solving the problem of producing the vaccine by recombinant DNA techniques - it was not permissible to claim all ways of doing so.
Patenting of Genes, Plants and Animals
Under this category, the discussion shifts from the patenting of DNA sequences and micro-organisms to the patenting of DNA sequences which are complete human genes or significant fragments thereof, as well as the protection of higher organisms, including plants and animals. Keeping the morality exclusion in mind, the debate introduces wider issues of ethics, social policy and morality into the fray.
The patenting of ESTs has taken an aggressive turn over the last few years. Some 20,000 applications relating to genes simpliciter and ESTs are pending before the United States Patent and Trademark Office (USPTO). Since the first gene-related applications were filed, approximately 6,000 patents have been issued which are drawn to full-length genes from human, plant, bacterial and viral sources. Of these 6,000 patents, over 1,000 patents are specifically drawn to human genes and human gene varieties which distinguish individuals (Margaret Parr, 'Patenting Human Gene-Based Inventions' USPTO TODAY, Vol 1(8), August 2000 at page 23).
Many patent applications before the USPTO have been overreaching in effect, extending protection from DNA fragmentation to individual genes themselves, and in many cases, seeking protection of ESTs without any specified purpose or function. To check this development, which when taken to its extreme can result in nefarious future activities such as 'gene squatting', the USPTO has issued and is finalising guidelines relating to the utility, written description and sufficiency requirements of genomic patent applications. The new utility guidelines require patent applicants to explicitly identify, unless already well established in the claim, a specific, substantial and credible utility for all inventions. A 'real world' utility has to be demonstrated, ie conferring an advantage to mankind. This is arguably not the same as the common law 'utility' requirement which is applicable in Singapore. In Merck v Pharmaforte (28 July 2000), the Court of Appeal applied the common law 'utility' requirement as stated in Alsop's Patent (1907) 24 RPC 733, whether by following the directions of the patentee the result which the patentee professed to produce can in fact be produced. The court did remark that the consideration of whether an invention had a new use or carried further advantages should be subsumed under the query of whether an invention is anticipated by prior art or whether it involved an inventive step (paragraph 20).
The European Union Biotechnology Directive 98/44 came into force on 6 July 1998, and clarifies many issues apropos the patenting of genes, plants and animals. There are several important points to distill from the language of the Directive, which has also been implemented into the European Patent Convention:
The human body, at various stages of its formation and development, and the simple discovery of one of its elements, including the sequence or partial sequence of a gene, cannot constitute a patentable invention.
An element isolated from the human body or otherwise produced by means of a technical process, 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.
The industrial application of a sequence or a partial sequence of a gene must be disclosed in a patent application.
The following patents will not be granted under the Directive or the European Patent Convention:
processes for the cloning of human beings;
processes for modifying the germ line genetic identity of human beings;
uses of human embryos for industrial or commercial purposes; and
processes for modifying the genetic identity of animals which are likely to cause suffering without any substantial medical benefit to man or animal, and also animals resulting from such processes.
Most notably the Biotechnology Directive draws a clear line against the patenting of germ-cell gene therapy. The Directive generally reflects the prevailing approach to life sciences in the West, from which has emerged several ethical and moral norms which will prove influential in the years to come.
The Directive, whilst offering more guidance on what is not patentable in a significant aspect of the life sciences, leaves in place a regime in many patent systems where questions of morality have still to be addressed, in the interests of the ordre public. The question still remains as to whether judges and patent examiners are equipped to carry out the sophisticated exercise of balancing subjective moral values, and jurisprudence from Europe testifies to this difficulty: Harvard Oncomouse [1990] OJ EPO 476, [1992] OJ EPO 589; Plant Genetic Systems [1995] EPOR 357. One should, however, avoid making moral objections of sweeping generality. A good illustration is the European Patent Office's treatment of the Howard Florey/Relaxin patent application [1995] EPOR 541 at page 551, where the European Patent Office allowed a patent for the genetic engineering of DNA from a pregnant woman's body so as to produce the human H-2 relaxin. Oppositions were raised that the process was akin to patenting 'life' itself, and also signalled a return of slavery, the sale of women to industry, and other tangential objections. The patent was allowed, and the patent office characterised DNA not as 'life' but as a substance carrying genetic information that can be used to produce proteins that are medically useful.
Conclusion
The inroads made in Europe and the United States as to what should and should not be patentable in the fast-expanding area of the life sciences leave much food for thought in Singapore. We should ultimately ask ourselves whether we would be justified in adopting similar criteria in regulating the proprietary parameters viz our own indigenous contributions to life sciences, bearing in mind at all times the ethical considerations and sensitivities that permeate this field.
Dr Stanley Lai
Lee & Lee