4 November 2003. Most AD investigators would much rather ponder the meaning of a smudge on a 2-D gel than that of a cryptic court decision, but, like it or not, intellectual property law reaches into research labs. On 20 October, a group of technology transfer officers from various universities, pharmaceutical companies, research service providers, and the NIH met in Boston to wrestle with the complex intellectual property issues surrounding the availability and use of research tools in AD and other biomedical fields. The one-day conference was sponsored jointly by the Alzheimer Research Consortium, a new nonprofit corporation formed to promote the development of new research models for AD (see ARF related news story), and Ropes and Gray, a national law firm that provides intellectual property advice to clients.
The meeting grew out of concern among AD researchers that some of the key AD mouse models are either unavailable to many academic labs due to issued patents or the subject of pending litigation, which creates uncertainty as to the availability of these models to biomedical researchers. For example, academic investigators may feel constrained from crossing a patented AD mouse model with other strains, even though such experiments might help uncover additional genes involved in neurodegeneration. Further, investigators and their institutions may be concerned about sharing or providing a mouse model that may be covered by a patent to their colleagues, who might use the model to identify a promising drug for AD. This can impede research progress.
At the conference, J.P. Kim of the NIH Office of Technology Transfer first set a historical context by reviewing principles and guidelines that NIH funding recipients need to follow in their acquisition and use of research resources for NIH-funded research. NIH drew up its (Research Tools Policy) in 1999 as a response to concerns that research resources were becoming increasingly unavailable and scientific publication was being unduly delayed.
Is There an Experimental Use Exemption for Academic Institutions?
On the issue of using patented research tools, universities currently are operating with a sense of legal vulnerability because the recent Madey v. Duke decision has up-ended their longstanding assumption that they enjoy an experimental use exemption from patent restrictions. As Crystal Talley of Ropes and Gray reported, “This case came as a bombshell to many in academia. It eviscerated the experimental use exemption academia had relied on for a century.”
The concept of an experimental use exemption for academia goes back to opinions written in 1813 by Justice Storey that the legislature could not have intended to punish “philosophical experiments” with a patented “machine” so long as that experimentation was not for profit. Since then, case law had similarly exempted noncommercial use from patent restrictions, and the Patent Act passed by Congress in 1952 had left the question alone.
All this changed when academic physicist John Madey sued Duke University for patent infringement because Duke continued to use a laser technology patented to Madey after he left the University. The District Court sided with Duke, but on appeal a federal court ruled that the experimental use exemption did not apply to Duke’s use of the technology for teaching, research, and the expansion of knowledge, which the court deemed a “university’s business.” Ironically, the court cited revenues from the university’s own patent licensing program in its opinion.
Duke subsequently argued that extensive patent checking/licensing for each research project would create a “toll booth” blocking research for the common good, and that a strict implementation of this ruling would disrupt the culture of academic research. Duke failed to sway the court, and the Supreme Court declined to hear the case, closing litigation, and throwing into doubt other universities’ historical use of this exemption.
Proposed solutions to the problem include reinstating the original common law, establishing a Fair Use Doctrine analogous to the one that allows photocopying of copyrighted materials at universities, or enacting legislation to exempt research experimentation from patent infringement, Talley said. Europe and Japan have codified such experimental use exemptions.
Technology transfer officers from universities reported that they encounter few problems with technology transfer between universities, and indicated that their greatest difficulties lie in negotiating access to industry tools. Animal models of AD are an industry tool. Licensing animal models is further complicated by the fact that ownership of cross-bred progeny is often a subject of debate.
AD Amyloid Models Tangled Up
After a brief presentation by Brad Hyman of Massachusetts General Hospital on the science of Alzheimer's transgenic models, Patricia Granahan of Ropes and Gray discussed two of the major APP mutations. One is the PDAPP mouse harboring APP with the V717F London mutation, made in 1995 by Dora Games at Elan Pharmaceuticals. The other is the Tg2576 mouse expressing the original Swedish mutation, made in 1996 by Karen Hsiao Ashe at the University of Minnesota in association with the Mayo Clinic. Workshop presenters reported that a history of high licensing fees, restrictions on cross-breeding, and patent infringement lawsuits have created a general sense of uncertainty about models carrying the Swedish mutation, which has become a barrier to pursuing better therapeutic and diagnostic ideas. (See note below.)
What’s to Be Learned from the Licensing of Other Research Tools?
In the final session of the workshop, speakers J.P. Kim, O. Prem Das of Harvard Medical School, and Lita Nelsen of the Massachusetts Institute of Technology discussed examples of negotiated agreements that have made important biomedical research tools more widely available. One such example is Cre-lox technology, which involves site-specific DNA recombination in eukaryotic cells with the bacteriophage-derived Cre enzyme, and has become standard procedure in creating targeted gene disruptions, or “knockout” models. In 1998, DuPont Pharmaceuticals entered into a Memorandum of Understanding with the NIH that makes the technology freely available for noncommercial biomedical research, and also allows for transfers of materials to for-profit entities. Other examples presented include the oncomouse, one of the first mouse models for cancer caused by oncogene expression, and RNAi, a more recent innovation for targeted manipulation of gene expression.
Other speakers and moderators at the meeting included Alex Fowkes of Pfizer Inc. on the corporate view of technology transfer, William Tew of Johns Hopkins University Medical School, and David Einhorn of The Jackson Laboratory.—Gabrielle Strobel.
Mouse Models of Alzheimer's Research: The Patent Landscape
Developing animal models of AD is a hot area of research as evidenced by the number of US patents and patent applications filed in this area. A quick search of issued US patents and printed applications revealed that there are over 2,900 patents and applications that describe or claim: Alzheimer's disease and (transgen* or "animal model"). The patent landscape is further complicated by the fact that there appear to be multiple patents and applications covering overlapping models of AD. For example, several cover animal models of AD comprising the Swedish mutation, one of the most important mutations of the APP gene, which can be used to create animal models of AD. The patent situation pertaining to animal models of AD is important to those performing AD research, and those trying to develop improved models of AD, since the use of patented models can place researchers at risk of patent infringement.
The animal model comprising the Swedish mutation has been subject to an ongoing patent litigation between Elan Pharmaceuticals and The Mayo Foundation. Mayo has distributed transgenic mice harboring the Swedish mutation (Tg2576). Elan owns certain patents claiming transgenic rodents harboring this mutation, and sued Mayo for patent infringement. Mayo defended on the grounds that the Elan patents were invalid as anticipated by a patent issued to Dr. Michael Mullan describing the Swedish mutation and stating that the mutated APP gene could be used to create transgenic animal models of AD. The case has been heard by a District Court and the Court of Appeals for the Federal Circuit, but the case has not yet been resolved. See Elan Pharma., Inc. v. Mayo Foundation for Medical Education and Research, --- F.3d ----, 68 U.S.P.Q.2d 1373 (Fed.Cir. Oct 2, 2003) (NO. 00-1467). It may take one or more years for the case to be completely resolved. For now, the Elan patents are valid.
In the meantime, Dr. Michael Mullan appears to be seeking to obtain a patent claiming a transgenic mouse expressing the Swedish mutation. The Mullan application claims an earlier priority date than the Elan patents. We still do not know whether the Mullan application will issue as a patent.
There is still uncertainty as to whether there will be one or more valid U.S. patents covering an animal model of AD having the Swedish mutation.—Patricia Granahan and Gloria Fuentes, Ropes and Gray.