New rules for natural products research
Dwindling natural resources have spurred tighter regulations for biodiversity prospecting.

Previously published in Nature Biotechnology

Vol. 17, September 1999, pp. 921-922

As recently as a decade ago, the legalities of obtaining samples of plants, microbes, and animals were straightforward. In many instances, a researcher could simply arrive at a field site, collect samples, and take them home. There was no applicable law. The researcher might obtain informal permission from a local community or landholder, as much for being on the land as for collecting. At most, the researcher might be required to obtain a permit similar to a fishing or hunting license to collect from national lands. Recent changes in the legal environment have made it much more complicated to obtain biological samples. In effect, access to nature's greenhouse has become regulated. In addition to habitats and species being wiped out at an alarming rate, the new regulations have compounded the difficulty of finding and identifying new biological materials.

Sources of the new rules

The new rules for biodiversity prospecting and natural products research derive from three sources: international treaties, national laws, and professional self-regulation. The 1993 Convention on Biological Diversity (CBD) established sovereign national rights over biological resources and committed member countries to conserve them, develop them sustainably, and share the benefits resulting from their use. Sustainable use of biological resources means finding new drugs, crops, and industrial products, while conserving the resources for future studies. The 1994 General Agreement on Tariffs and Trade (GATT) set minimum standards for protecting patents, trade secrets, trademarks, and copyright. These standards will be in place for most countries by the year 2000, with the least developed countries, notably African countries, given five more years to comply. The effect of the GATT Trade-Related Aspects of Intellectual Property Rights (TRIPS) agreement is to increase dramatically the international value of intellectual property. Some people view the sovereign rights created by the CBD as an ecological counterpoint to the technological intellectual property rights that we in the US are familiar with, which are expanding due to the GATT-TRIPS agreement. Thus, the combined influence of TRIPS and the CBD is leading us to a new intellectual property regime.

Through national biodiversity-related laws and regulations, countries have begun to exercise their sovereign rights over biological resources as established in the CBD. In effect, many of these laws create a new category of poaching, in which biological materials are collected or exported without obtaining permission (informed consent) and without satisfying certain conditions such as benefit sharing. Meanwhile, many institutions and professional organizations have decided to implement natural products research policies for their members, and these policies have quasi-legal or contractual status. Examples include botanical gardens (Kew Gardens in London and the Missouri Botanical Gardens in St. Louis), biotechnology companies (Shaman, S. San Francisco, CA; Monsanto, St. Louis, MO), and professional groups (the Declaration of Belém of the International Society of Ethnobiology, based in Athens, GA).

The basic bargain underlying passage of the CBD was that sovereign rights would be tempered by providing access to genetic resources in exchange for a share of the benefits, including access to biotechnology. To satisfy the three goals of the CBD (conservation, development, and benefit sharing), the principle of sovereign rights is best applied through what has become known as Access and Benefit Sharing Agreements (ABAs). Under the CBD, prior informed consent is the standard for ensuring a fair and equitable ABA. The source country providing access to genetic resources must know in advance what will be done with the resource, and what benefits will be shared. Without such an under-standing between the collector and the supplier, there can be no fair agreement on benefit sharing. (Benefits may include support for research and conservation, contributions of equipment and materials, assistance to indigenous and local communities, up-front fees, milestone payments, and royalties.)

Consequences of breaking the rules

There is a very simple reason for people who collect biological samples to follow the new rules on informed consent and benefit sharing: the consequences of following the old "take-and-run" approach are extremely serious. First, patents on natural product inventions are subject to attack unless all public knowledge about the species in question and its use are fully disclosed. Organizations in the bioresource-rich but economically poor countries of the developing world have demonstrated a willingness to attack natural product patents on the basis of traditional knowledge, motivated by principles of justice rather than the economic forces usually underlying patent disputes.

For example, a 1995 patent, "Use of turmeric in wound healing,"1 was canceled in 1998 after a reexamination proceeding instituted by India's Council of Scientific and Industrial Research. The new evidence established that use of turmeric to promote wound healing had been known for generations in India. Likewise, a 1986 plant patent 2 claims an ostensibly new, distinct variety of Banisteriopsis caapi, known in the Amazon as ayahuasca. However, new evidence establishes that the claimed plant is actually the wild uncultivated type, and is neither new or distinctive. COICA, an organization of indigenous people, and the Amazon Coalition have requested reexamination of the ayahuasca patent, seeking to eliminate what is perceived as an immoral expropriation of their traditional and biological heritage. More such challenges can be anticipated.

Where a plant sample is collected illegally and then a new drug compound or valuable gene is isolated from the sample, patented, and commercialized, the patent could be held unenforceable as the result of "tainted research." The tainted research doctrine is illustrated in the case Regents of the University of California v. Eli Lilly & Co.3 In developing cDNA encoding human insulin, some researchers violated NIH regulations that embargoed the use of uncertified plasmids in mammalian recombinant DNA research. They then lied in their patent application, stating that they had used a certified plasmid.

The lower court held the patent unenforceable for fraud, the illegitimate fruit of a for-bidden tree. However, the appeals court reversed, holding that it would not have affected examination of the patent if the truth had been told. In other words, the misrepresentation in the patent was not "material." This case teaches that if an invention is based on tainted research material, such as a plant sample smuggled out of a country in violation of its laws, and the inventor lies about it in a patent, a case of fraud might be made. However, the inventor must have gained some advantage by the misrepresentation, such as being the first to make the invention.

It is already common practice (if not required) for natural product patents to identify the country from which biological material was obtained. In 1997, the European Parliament went further by adopting a measure that would have required a patent applicant to indicate the geographical place of origin of biological material, and to provide evidence that the material had been used in accordance with access and export restrictions in force in the place of origin (e.g., entering an ABA). Ultimately, the European Commission rejected that proposal on the grounds that it exceeded the requirements of the CBD. However, if such a proposal were ever adopted in any country, then an absence of source country approval would doom a patent. Likewise, a misrepresentation would become considered material, and would jeopardize the patent.

A second consequence of breaking the rules is that if a researcher removes biological material illegally from a source country, and then profits from the material, the source country or affected person could recover all or some of the profits, in a US court, based on a theory of misappropriation and related doctrines. Thus, there is a real legal risk for someone who fails to reach agreement on an ABA before taking a sample home. The conditions a court might impose for a successful product could be much more onerous than one that could be negotiated at the outset, when success is still a highly unlikely outcome. This risk is highest in a country that requires an ABA.

Third, clean title to biological material now means that it was obtained legitimately, and with prior informed consent from whomever had initial control over it. If there is no clean title, the value of the material is seriously reduced. The collector of an illegitimate sample will not be able to pass it on, in turn, to collaborators, partners, or third par-ties in the normal course of conduct for researchers. Absent assurances that the material was collected in compliance with all applicable laws and regulations including benefit sharing, a savvy recipient of biological material will not accept material.

Moreover, if the supplier certifies that a sample was properly obtained, and it was not, then the recipient could assert a contractual claim for damages back against the collector. To assure a clean, cloud-free chain of title for materials collected since 1993 (the CBD's effective date), compliance with the new rules needs to be established. Material collected before 1993 is "grandfathered" under the CBD, such that sovereign rights and the obligation of prior informed consent do not apply. Nonetheless, claims to such pre-CBD material are being asserted by source countries, too, on political, if not legal grounds, so it could be advantageous to show that pre-CBD material was collected with prior informed consent and benefit sharing. The centers of the Consultative Group on International Agriculture Research have adopted a trust agreement whereby their extensive pre-CBD collections are held in trust for the benefit of the world.

Fourth, as a practical matter, if a collector does not agree to provide an equitable share of benefits, in advance, to the source of biological samples, the collector may well be denied access to the samples. Simply put, the possibilities for fieldwork will dry up. Fifth, someone who is branded as a "biopirate" will suffer from the bad reputation. Likewise, someone who gains a reputation for evading access restrictions, or for being hard to deal with, may find it increasingly difficult to find doors open for further research. There is an intense gossip-mill active on the Internet, and self-anointed watchdog groups like Rural Advancement Foundation International and the Center for Law in the Public Interest are quick to spread the names of companies and institutions they believe are violating the standards for collection.

Corporations have recognized that adherence to principles of sustainable development, including the use of ABAs for natural product research, brings significant benefits to the company. Why are companies following the new rules? By doing so, they can (1) improve the reliability and quality of the material supplied to them; (2) benefit from access to traditional knowledge about plants and insects; (3) establish goodwill that can pay off in present or future markets for the their products; and (4) distinguish them-selves from less green competitors, thus obtaining a competitive advantage. On the other hand, a company that is associated with biopiracy may end up with weak patents, be exposed to equitable claims for profit sharing, lose sources of supply, and face the prospect of consumer and government boycotts, barriers to importation of biotechnology products, loss of market share, and financial penalties.

Finally, the ultimate legal sanction- criminal penalties, including jail-may apply. It is not uncommon for hunters to be jailed for poaching or trespassing, and there is at least one instance of a researcher who was temporarily detained in Australia for unauthorized collecting of plant materials. Collection of biological materials without a benefit-sharing agreement is likely to find its way into the list of criminal violations in some countries, so that biopiracy could result in a jail sentence.

Conclusions

In summary, given all these risks, many organizations have concluded that it is wise to enter into an access and benefit-sharing agreement for every collection. Additional tips for collectors and recipients of biological materials include these: Cultivate long-term relationships with suppliers; make friends with local regulators and find out what the local rules are; find out what you can offer (it may be worth more to the provider than to you); allow plenty of time to obtain permits; plan big, long-term projects instead of small, one-time deals; be proactive and enter into an ABA even if no law is in place; try to obtain materials with-out restrictions; scrutinize the records of intermediaries (botanical gardens, brokers, institutions) to be sure the material was properly obtained; and be sure to disclose all relevant information to regulators, collaborators, and patent offices.

Just as it is becoming harder to obtain natural materials, it is becoming easier to obtain synthetic samples from combinatorial chemistry and genomics. Research in natural product supply, high-throughput screening, and new extraction methods must compete with genomics, biosynthesis, and combinatorial chemistry. But will the demand for new natural materials disappear? No. As E.O. Wilson points out, "Organisms are superb chemists. . .collectively better than all the world's chemists at synthesizing organic molecules of practical use (p. 285)."4

The true risk to natural product research is not that the greenhouse door will be shut, thus reducing supply, or that demand for natural products will cease. It is that supply will drop because species are disappearing faster than we can study them. As Wilson says, "Useful products cannot be harvested from extinct species (p. 282)."5 The most fundamental risk to natural products research is continued loss of biodiversity. If the new rules for biodiversity prospecting succeed in reducing biodiversity loss, while allowing research to continue, then any inconvenience they bring will be justified.

1. US Patent No. 5,401,504.
2. US Plant Patent No. 5,751.
3. 39 USPQ2d 1225 (S.D.Ind. 1995), reversed in pertinent part, 119 F.3d 1559, 1570 (Fed. Cir. 1997).
4. Wilson, E.O. The biodiversity of life. (Harvard University Press, Cambridge, MA; 1992).
5. Id.