San Diego

Neuroscientists who use mouse models are closely watching a patent infringement battle between a prominent biotechnology firm and a major US non-profit institution.

Elan Pharmaceuticals, of Ireland, is suing the Minnesota-based Mayo Foundation for Medical Education and Research over mice used to study Alzheimer's disease. The company alleges that Mayo has infringed two patents it holds on transgenic mice with a mutation that causes Alzheimer's.

Mice work: the brain of Elan's one-year-old mouse (far left) shows characteristic plaques of Alzheimer's disease, absent from that of the similar animal (left), which was dosed with Elan's experimental Alzheimer's vaccine. Credit: ELAN CORP

Elan uses its closely guarded mice for work on potential drugs against the neurodegenerative disease. The company alleges that Mayo is infringing its patents by making, using, and selling mice that overexpress an Alzheimer amyloid precursor protein, APP695, from a human genetic mutation. Mayo says it has licences from patent holders for both the mutation and the mice, which it distributes to researchers worldwide. A jury is due to decide the issue in October.

According to documents filed with the US District Court in San Francisco, Mayo is making the counterclaim that the Elan patents were obtained fraudulently from the US Patent and Trademark Office and that they are unenforceable and therefore invalid. Mayo attorney Karen Boyd would not specify the grounds for such allegations.

The battle is spreading unease among US neuroscientists because some are being subpoenaed — along with their laboratory notebooks — to testify in depositions for the civil lawsuit quietly filed by Elan last April.

“It is outrageous,” says Karen Duff, a New York University neuroscientist who has been subpoenaed by Elan. After receiving her doctorate at Imperial College London, Duff once worked at Mayo's research facility in Jacksonville, Florida, and has used the Mayo mouse model to create another transgenic mouse that is considered extremely important for research.

The dispute is seen by neuroscientists as complicating an already difficult research arena, in which the number of animal models for unravelling the biological secrets of the disease is already limited.

“All of this does no one any good,” says John Trojanowski, a physician with a doctorate in neuroscience who directs a National Institute of Aging (NIA) Alzheimer Center at the University of Pennsylvania. “The Alzheimer research field could move considerably faster” without the lawsuit, he argues.

In December 1998, as the Elan–Mayo dispute was heating up, NIA officials held a private two-day workshop of neuroscientists to address problems associated with Alzheimer's research using transgenic rodents. Although Mayo and Elan subsequently held discussions about resolving their dispute out of court, Elan filed its lawsuit a few months later.

Elan attorney Jean Duvall says that no one at the firm's Dublin headquarters will comment except to say “it is Elan's policy to enforce its intellectual property rights”.

The Elan–Mayo lawsuit is so sensitive that Marcelle Morrison-Bogorad, NIA's associate director for neuroscience and neuropsychology, cancelled a scheduled interview on the subject last week — shortly after the joint statement by President Bill Clinton and British Prime Minister Tony Blair on the need for open access to genetic data (see page 324).

“It is critically important that research tools are available to scientists,” Morrison-Bogorad says. “We are looking into the current controversy over research resources for Alzheimer's disease and evaluating its impact on the field, on initiatives in the private sector and on the overall progress of research.”

The Elan–Mayo legal dispute involves a number of patent, licensing and research agreements with both proprietary and academic institutions. The two patents Elan alleges are being infringed are owned jointly by the firm and Eli Lilly & Co.

Elan secured rights to the patents in 1998, after acquiring Athena Neurosciences, a firm that had licensed research findings from academic institutions and companies.

The two Elan patents are for “transgenic … rodents” that harbour an allele for the ‘Swedish mutation’ — named after a large Scandinavian family in which it was identified — that is believed to contribute to Alzheimer's disease by producing a build-up of amyloid plaque in the brain.

Researchers say that Elan transgenic mice are closely held by the firm for its drug development efforts. One researcher alleges that when Elan mice are provided to academic scientists, they are usually neutered females.

Mayo's transgenic mice, provided to more than 50 academic research groups and a dozen pharmaceutical firms, are based on work by a group headed by Karen Hsiao at the University of Minnesota.

Hsiao's group created a mouse that would express amyloid in the brain (see Science 274, 99–103; 1996). After publication, Mayo licensed the discovery from the University of Minnesota, arranged for contract breeding of the mice and began distributing them. Mayo also licensed the sequence of the Swedish mutation from a Kansas firm.

Mayo's mice are considered so valuable that there are reports of breeding trios of males being sold to companies for $850,000. Mayo officials decline to discuss this.

When providing its mice to academic institutions, Mayo requires the signing of a material transfer agreement that gives the non-profit organization an option to buy the rights to any commercial discovery that may come from research with the mice.

This agreement — like those used by biotech firms — is considered by some to be an unusually bold move for a non-profit organization. Even some of Mayo's own researchers have difficulty with this practice.

“My view is there should be no reach-through agreements between non-profit institutes,” says pharmacology professor John Hardy at Mayo's Jacksonville facility, whose laboratories at Imperial College London, South Florida and Mayo have produced leading discoveries and researchers.

Younkin: licensing agreement necessary.

But Steven Younkin, a physician neuroscientist and former director of research at Mayo's Jacksonville facility, defends the agreements as being necessary to cover the organization's enormous cost for the long-term, mouse-producing project. “With a non-profit institution such as Mayo, any money realized from licensing agreements goes back into research,” says Younkin.

If Mayo was primarily interested in making money, he adds, it would have entered an exclusive licensing agreement for the transgenic mice with a single pharmaceutical firm. It deliberately decided not to do this, in order to make the mice available for academic research.

As neuroscientists debate these issues, subpoenas have been spreading through the neuroscience community. Earlier this month, Elan failed in a bid to require Hsiao to produce her laboratory notebooks for a deposition this week.

A number of researchers, including microbiologist David Borchelt, an associate professor of pathology at Johns Hopkins University in Maryland, are debating their options as they face subpoenas. Unable to secure the desired transgenic mice, Borchelt made his own mice.

Elan has now subpoenaed him and his lab notebooks, which he fears may be studied closely by the firm's scientists. Borchelt says he would “go to jail” rather than provide his notebooks.