While heralded as a technological breakthrough for investigating gene function, the Cre-loxP system is at the centre of a clash between academic and industrial interests. Prior to implementing the technique in their laboratory setting, users are obliged to obtain a licence from DuPont, which holds the patent on the use of the Cre-loxP system to modify DNA in eukaryotic cells. The conditions of the licencing agreement invoked a maelstrom within the academic research community, with many claiming the terms too restrictive for basic scientific investigation. The National Institutes of Health (NIH) became a prominent opponent to the policy and the Jackson Laboratory, the largest mouse mutant archiving and distributing facility in the United States of America, also declined to sign the agreement. Finally, after almost a year of negotiations, the NIH and DuPont have indicated that they expect to resolve the matter in the imminent future, with a revised version of the licencing conditions that both sides find acceptable. Last month, the Jackson Laboratory signed a licencing agreement with DuPont and will immediately commence distribution of Cre-loxP mice, on request, to researchers holding licences to use the technology. With the tempest subsiding, one wonders about the source of the contention and whether the harmonious outcome signifies a new level of understanding between the public and private research sectors on the exchange of research tools.

The technique in question takes advantage of the natural editing capabilities of the bacteriophage Cre recombinase enzyme, which splices out intervening DNA stretches between two loxP sites and reseals the ends. The use of the system to manipulate DNA in mammalian cells was developed by Brian Sauer, while an employee of DuPont. A powerful adaptation of the technique is the creation of `conditional' mouse mutants, where strains expressing Cre in specific tissues are crossed with those carrying a targeted gene flanked by loxP sites, thus allowing the analysis of gene function in particular cell types. Although anxious to use the technology, many researchers have objected to the DuPont licence on several grounds. Academics are unaccustomed to needing `permission' to use a technique and, because they do not receive any materials from DuPont, it does not necessarily occur to some that using the technology is an infringement. Furthermore, DuPont's approach is more aggressive than many researchers have encountered — in some instances, directly contacting academic users to remind them that a licence is mandatory. In addition, the vague nature of certain clauses of the licence are unsettling, as it is unclear whether DuPont could have claims on future discoveries made by the user. The licencing agreement indicates that an academic is free to use the Cre-loxP system with no payment obligations for nonprofit research purposes, but if researchers choose to use it for commercial purposes, they need to negotiate a new licence from DuPont. “The terms of agreement are very ambiguous” notes Rebecca Eisenberg, of University of Michigan Law School, “DuPont defines commercial purposes very broadly and in a way that seems to embrace future discoveries not involving the ongoing use of the Cre-loxP system.”

DuPont believes that much of the controversy has arisen from miscommunication and claims that resolution with the NIH will result not from revision of the licence but primarily from clarification of the terminology in the licencing conditions. The company feels that many criticisms of their policy are unfair, given that “substantial number of years and money were spent on developing this technology and DuPont has, in turn, generously licenced it out to the academic community for free”. The company, however, expects to be compensated for use of the technology for commercial purposes or for the benefit of a commercial organization. This will come in the form of licence fees from for-profit institutions and from transfer fees for Cre-loxP materials moving from academia to the for-profit sector. DuPont states that “no royalties are expected to be associated with downstream products under such licences, unless the product or its use or manufacture fall within the scope of the patent”. This implies that they would seek to profit from any commercial products containing Cre-loxP, but not those developed based on knowledge of gene function discovered through the use of the technology, provided that the discovery was made outside of a relationship with a commercial organization.

DuPont acknowledges that they were not “sensitive” to the need of academic researchers for flexible transfer of materials to and from colleagues. Under the initial terms of the agreement, researchers were prohibited from transferring materials derived from the Cre-loxP system to other licenced research holders without first obtaining approval from DuPont. The licence has now been revised such that academics can directly exchange Cre-loxP -derived materials with a licenced recipient through a standard university material transfer agreement (MTA), without the need for prior permission from DuPont. It should be noted, however, that MTAs themselves can often involve cumbersome negotiations between academic technology transfer offices, leading to delays in accessing research tools.

Over 170 academic institutes, according to DuPont, have signed the agreement, indicating that many do not view the licence as unreasonable. Max Cowan, the chief scientific officer of the Howard Hughes Medical Institute — which was among the first to sign the agreement — believes that “the constraints put upon our scientists by the agreement are no more burdensome than many material transfer agreements that we've entered into with other for-profit corporations”. The dispute over the use of Cre-loxP is perhaps inflamed by comparison with the accessibility of a similar recombination system, which uses yeast Flp recombinase to slice out the intervening DNA between two FRT sites1. The Salk Institute holds the patent on the technology, but academic researchers can use it without a licence. The intense focus on the DuPont licence may be because it serves as an indicator of the conditions under which academic researchers will be able to access future technologies developed within or exclusively licenced to commercial groups. Notably, the mouse cloning technique developed at the University of Hawaii, by Ryuzo Yanagimachi and colleagues2, has been exclusively licenced to ProBio America Inc., which will manage the technology. On the issue of whether academics will need a licence, Laith Reynolds, chief executive officer of ProBio, indicates that “a number of areas are yet to be addressed and resolved, but we intend to take a very open-handed approach.”

The controversy of the DuPont licence is symptomatic of more general concerns that the conditions under which research tools can be accessed may be impeding the pace and direction of research. In response to the issue, Harold Varmus, the Director of the NIH, appointed a Working Group on Research Tools, chaired by Rebecca Eisenberg, to investigate the nature and extent of the problem. The group's report (http://www.nih.gov./news/researchtools/index.htm), released in June, reveals that both the public and private sectors experience frustration in gaining access to research tools, that these barriers are impeding the progress of discovery — and that the problem is getting worse. The lack of standardized agreements under which research tools can be used exacerbates the matter, but is due to the fact that the value of each research tool can be difficult to assess, that research tools may vary in their value and that the providers and users, not surprisingly, may have different views on the value. The `reach-through' aspects of licencing agreements are frequently contentious, where the provider of the tool seeks either ownership, licence rights or royalties on future discoveries made by the recipient. Researchers are often anxious about making a commitment before any downstream discovery is identified and its true value assessed. There are fears that any prior agreements may shackle the development of the discovery by undermining funding from other private sources or diminishing its attractiveness for future commercialization by another company. This latter point underscores broader concerns that the `stacking' of licences, through the use of various patented research tools in the stages leading to a discovery, may deter commercial groups from undertaking the commercialization of the discovery3.

It could be argued that academics cannot have it both ways — on the one hand, having free access to research tools developed in the commercial sector and, on the other, exemption from contractual commitment should they profit financially from something that incorporates, or is directly generated by, a marketed technology. Commercial groups like DuPont that develop `enabling' technologies upstream of a marketable end-product, face the challenge of how to recover the costs invested in developing these techniques. As highlighted by the NIH Working Group's report, some commercial firms would argue that because academic users are unlikely to discover anything of commercial value, the industry should be entitled to a profit on the rare occasion when a commercially viable discovery is made in order to recoup the costs of all other unprofitable transfers. One wonders, though, whether those rare events are worth the effort and aggravation, or whether industry shouldn't generously overlook those rare chances of financial return in light of the fact that it profits tremendously from leads and strategies developed in the public sector.

It would be unfortunate if the controversy surrounding the DuPont licence for the Cre-loxP system were to dissuade other commercial groups from making their research tools widely accessible to the academic community. Rather, it is hoped that the episode will motivate commercial groups to carefully consider the terms under which they make research tools accessible to academic science. The commercial sector gains from the widespread use of patented research techniques in academia, such as the identification of novel and potentially lucrative applications of the technology as well as the opportunity for fruitful collaboration.

“You'll be hearing from my lawyer, pal!”

With the commercial value of biomedical research an increasing realization, the line between science and business has blurred. As academics become more savvy in their negotiations with industry and, reciprocally, as industry adapts to the needs of academic research, both stand to gain a common objective — state-of-the-art research tools.