Will US patent 6,200,806 obstruct stem-cell research? Steve Farrar reports.
On August 9 2001, George Bush, the president of the United States, spoke to the nation. It was his first live televised speech since January. He wanted to tell his countrymen about "one of the most profound (issues) of our time" - human embryonic stem cells.
An especially exciting area of biomedical research, which held out the promise of a therapeutic revolution, had also proved to be an ethical nightmare. For extracting hES cells involves the destruction of living human embryos.
Bush struck a legalistic compromise to "resolve" a moral dilemma. Public money could be spent on this work, but the permitted cell lines would be exceedingly limited.
Only those derived before the day of Bush's speech from embryos that had already been destroyed were allowed in federally funded laboratories.
Scientists grateful to get public support for the first time, winced when they considered the implications. Just 64 existing cell lines were eligible. All were grown on mouse feeder cells, making them unsuitable for use in human patients. And many, if not most, could yet prove unviable.
Understandably, attention has focused on the impact that those restrictions will have on the future of the science. Many fear that research will be held up and distorted. Some have even predicted that US scientists will seek to pursue their work abroad.
However, it may be that an earlier ruling laid down during a previous administration could prove more telling in the long run.
Well after Bush's decision has been superseded, US patent 6,200,806 - "Primate Embryonic Stem Cells" will still be there.
When James Thomson, a developmental biologist at the University of Wisconsin, announced on November 6 1998 that he had derived hES lines for the first time, the limelight was shared by a Californian biotech outfit called Geron Corporation.
Regulations had prevented Thomson using public funds for research involving tissues from human embryos. He had to turn to private money. Geron was only too pleased to provide it.
Since then, the company has championed the research and its potential applications.
Embryonic stem cells have the ability to become any of the variety of different cells found in the body. They have the potential to produce transplant tissue and therapies using cells derived from the sufferers themselves. They could revolutionise the treatment of many diseases and conditions, from Alzheimer's to muscular dystrophy, herald new diagnostics and provide scientists with powerful tools to study human development. Thomson's breakthrough opened the way.
The day of Bush's speech, Geron issued a press release welcoming the decision. A week later, it gave notice that a lawsuit had been filed against it by the Wisconsin Alumni Research Foundation, holders of patent 6,200,806.
At the heart of the dispute lies one of the most potentially lucrative pieces of intellectual property in biomedicine. The patent covers the method of isolating hES cells that Thomson pioneered as well as the cells themselves. Its claims are very broad in scope. David Earp, Geron's vice-president of intellectual property, said: "It is on human ES cells period. It is not limited to a particular cell line."
Carl Gulbrandsen, managing director of Warf, that holds the patent, added a note of caution. "I think we will see tremendous discoveries, but there is really no certainty that what we have patented will ultimately result in commercial gain," he said. Certainly, he said he did not want to see Warf's patents stand in the way of research.
But the foundation is not completely in control. It signed over to Geron commercialisation rights for six carefully selected cell types that can be derived from hES cells - including heart muscle, neurons and liver - in the deal that put the corporation's dollars into Thomson's laboratory.
Geron wants to exercise an option to expand those rights to other types of cell. Warf wants to bring in new partners to share the responsibilities and riches.
The outcome of their legal fight will have profound implications for the future of hES cell research.
Cutting-edge firm with sharp commercial sense
* Geron started out in 1992 as a bright biotechnology firm working on telomerase, an enzyme that extends the lifespan of normal cells and is intimately involved with cancer.
Yet the corporation has proved far more ambitious. After learning of James Thomson's work deriving ES cell lines from rhesus monkeys, Geron offered the crucial backing necessary for him to take the next step to humans.
Alongside stem cells and telomerase, the corporation has since added cloning technology. In May 1999, it bought the company spun off by the Roslin Institute in Edinburgh to exploit the science that produced Dolly the sheep.
With it came the exclusive commercial rights to the technology.
The company sees the three strands coming together in many powerful ways.
David Earp, a British-born alumnus of Leeds and Cambridge universities who joined Geron in June 1999, was bullish. "Geron saw the potential when others didn't," he said.
It was not simply a matter of acquiring licences and filing patents, he said. The corporation was doing its own cutting-edge research and has many products in the pipeline.
Geron experts were the first to clone the human telomerase gene; they are testing a treatment for Parkinson's disease in animals and before the end of the year a clinical trial on a new cancer vaccine will begin. Three weeks ago, the corporation announced that it had been able to grow hES cells without using mouse feeder cells, paving the way to their therapeutic use.
But the Wisconsin Alumni Research Foundation is not convinced that Geron can develop hES cells alone. MD Carl Gulbrandsen said he hoped Geron would make a good commercial return on the money it had invested in the science.
But he added: "They are a small company and this is a big area. It is not realistic that a small company can deve-lop this technology to the extent that it requires."
So when Geron exercised its option to add additional hES cell types to its licence, Warf objected.
"You always have these tensions between commercial entities and university licensing bodies," Mr Gulbrandsen said. Warf are old hands at the game. The non-profit body was set up to commercialise research at the University of Wisconsin-Madison and pump the proceeds back.
Since striking a deal with a breakfast cereal company in 19 to enhance its products with vitamin D, its success has been spectacular. The blood anti-coagulant Warfarin is another achievement. Today, Warf has more than 1,000 US patents and gives the university about £24 million a year.
When the disagreement between Warf and Geron remained unresolved after several months, the foundation decided that a legal ruling was needed.
Geron stated it was optimistic the matter would be resolved "in the near future". Warf says it hopes the litigation will be concluded quickly and amicably. Scientists fear it could take years.
In the US, the result of the case will have a wider significance.
Mark Frankel, director of the scientific freedom, responsibility and law programme at the American Association for the Advancement of Science, said whether or not Geron ends up with a quasi-monopoly on hES cells would depend on how aggressively the corporation asserted its rights and what limits the courts placed on them. The immediate result was a great deal of uncertainty within the scientific community.
"It is not the kind of environment to encourage people to invest their time, effort and resources in working with these cells without knowing precisely what their rights will be. They may end up being a lab for Geron without knowing it," he said.
Dr Earp said Geron was encouraging academic researchers to work on hES cells. But he added that the corporation had spent a lot of money to protect its investment and if anyone wan-ted to commercialise research covered by its patent licence they would have to strike a deal.
Warf insisted the dispute would not affect the distribution of hES cell lines to collaborators.
In Europe, a separate ruling could make all the difference.
Warf may have the US patent in the bag, but obtaining one in Europe is not proving so straightforward. Mr Gulbrandsen admitted that it seemed the European Patent Office "has to a certain extent put patents of this type on hold."
Some scientists believe it may never been granted.
Richard Gardner, who chaired the recent Royal Society working group on cloning, said he did not believe the patent contained anything original or highly innovative.
"I think it's both premature and rather inappropriate and not helpful to progress in biomedical research. It's an American obsession with patenting everything that moves," he said.
Peter Andrews, professor of biomedical science at Sheffield University, has signed an agreement with Warf to grow the Wisconsin cell lines in Britain and is still trying to derive his own.
"There is an awful lot of basic science to do. Turning these things into a usable product is perhaps ten to 30 years away," he said. Indeed, Warf's patent may have expired by then. "Getting too worked up about commercial advantage now is putting the cart before the horse."
Nevertheless, Professor Andrews has already filed his own patents on directing the way hES cells develop into specific specialist cell types.