WARF Learns! Will Stem Cells?

The Wisconsin Alumni Research Foundation will patent researcher James Thomson's new method of deriving stem cells from non-embryonic sources that was announced last week. But an official from the University of Wisconsin tech transfer office told the New York Times yesterday that it will look the other way and not charge non-profit researchers who use the new technology.

“They can do it in their own lab,” said Carl E. Gulbrandsen, the managing director of WARF. “They don’t have to tell me about it, and I don’t really have to know.”

The University of Wisconsin's technology transfer arm came under a firestorm of criticism when it began charging non-profit researchers $5,000 for access to the cell lines derived using Thomson's original embryonic method. Their value was greatly enhanced when President Bush restricted federal funding for embryonic stem cell research to previously derived lines like those owned by WARF. The university clearly didn't want a repeat of that episode.

We now have a natural experiment proving that the brain cells of technology transfer offices can be transformed into neurons capable of intelligent responses. It remains to be seen if researchers can do the same thing with skin-derived stem cells.

Eyes on Prizes

It's always hard to know what to make of the endless talkfests on global health that take place in Geneva. Last week, a subcommittee of the World Health Organization discussed ways of increasing the amount of research and development that goes toward cures for the neglected diseases of the developing world: tuberculosis, malaria, leishmaniasis, Chagas disease and the like.

News accounts Saturday suggested that these "talks" are progressing slowly, although the indefatiguable Jamie Love of Knowledge Ecology International was characteristically upbeat in this Reuters reports. The Intellectual Property Watch newsletter is also keeping close tabs on the talks, which will resume next spring.

Knowledge Ecology, Doctors Without Borders and a feisty coalition of non-governmental groups (NGOs) are pushing the WHO to endorse a prize system for developing new drugs. Under a prize system, donor countries and health care payers could put up large one-time payments for any major breakthrough against a neglected disease. By making the reward for industry (or non-profit) R&D a one-time payment, rather than the ongoing surtax of high prices on the price of the drugs or vaccines, the IP could be transferred by the prizemaker (and therefore new owner) to generic manufacturers, who would then provide the technology to poor countries on much cheaper cost-plus basis.

Relying on the WHO to experiment with such a system will take forever since the glacial pace of the talks is directly related to the fierce opposition of the global pharmaceutical industry. That's why anyone interested in this approach should pay close attention to the machinations of the X Prize Foundation, launched a few years ago by Internet billionaires like Larry Page, a co-founder of Google, Inc.

Most of the news from that group was generated when it offered prizes for commercial space travel and the 100-miles-per-gallon car. But last month, with the encouragement of the Clinton Foundation, they ponied up $300 million in prize money for innovations in public health and education.

They promised a first round of targets (presumably with the prize dollar amounts attached) next spring. Following this story -- what they deem prize-worthy, who goes after it, and whether the goals are achieved -- should provide an early test of the viability of using a prize system to encourage medical innovation.

Geron: Where's the Stem Cell Beef?

The blog on the Wired Magazine website had a great post earlier this week on Geron's failure to take any of its vaunted stem cell therapies into clinical trials. Geron, you'll recall, funded University of Wisconsin researcher's James Thomson's seminal work on isolating embryonic stem cells, and licensed its most promising uses. That patent, held by the Wisconsin Alumni Research Foundation (WARF), was recently challenged by the Patent and Trademark Office, a challenge backed by several consumer groups. The Wired blog post provides ample evidence as to why it would be a good thing if WARF and Geron lose their battle to hold onto exclusive rights to embryonic stem cells' most promising uses.

WARF Stem Cell Patent Under Fire

The Wisconsin Alumni Research Foundation financial claims on rival stem cell researchers took another hit earlier this week when some of the nation's leading stem cell scientists filed petitions supporting the Patent and Trademark Office's decision to rescind James Thomson's seminal patent on embryonic stem cells. The California-based Foundation for Taxpayer and Consumer Rights and Public Patent Foundation organized the scientists to file comments supporting the PTO's action.

For background on the scientific significance of breaking down the patent barriers in the emerging stem cell field, see my article in PLoS Medicine here.

The most interesting brief came from Douglas Melton of Harvard University, one of the nation's leading stem cell scientists. He wrote:

I very much believe that Dr. Thomson deserves the scientific and public recognition he has received. However, he deserves that recognition because he undertook the arduous and timely task of getting fresh and high quality human embryos to use as starting material in his work, and sufficient funding for such research, not because he did anything that was inventive. It was access to those resources, which were, and to this day still are, very difficult to obtain, that enabled Dr. Thomson to achieve his accomplishment. His perseverance and commitment deserve recognition and accolades. But I believe that had any other stem cell scientist been given the same starting material and financial support, they could have made the same accomplishment, because the science required to isolate and maintain human embryonic stem cells was obvious.

As every patent attorney knows, a new invention must meet the test of being "not obvious." Melton points out in his comment that anyone with adequate funding could have used readily available technologies to isolate embryonic stem cells. It was only Thomson's access to funding from Geron Corp. that allowed him to claim the mantle of being first. But being first isn't what defines an invention. That requires doing something no one else has ever thought of. The WARF patent, Melton said, fails that test.

Not Obvious

The Supreme Court yesterday made it tougher to get patents on inventions that are obvious. All the news reports I have seen focused on information technology and the impact this may have on software developers and business use patents like one click shopping. Precious little was said about the pharmaceutical and biotechnology industries.

It is not like they were not interested. Here's one quote from the New York Times report.

“And we could see thousands of cases asking the Patent Office to re-examine patents it has already granted,” said Mr. Kreeger, who was one of the lawyers who had prepared a brief filed by the Biotechnology Industry Organization in support of the patent. “It doesn’t take a lot of resources to ask for a re-examination.” To be eligible for a patent, an invention must be novel, useful and not “obvious” to a person of “ordinary skill” in the field.

So here are my questions. Isn't it obvious and therefore non-patentable when a company separates out the enantiomer from a racemate mixture when there are no real side effects to eliminate, such as happened when AstraZeneca patented Nexium to be the follow-on drug to Prilosec. Isn't it obvious and non-patentable when a company first patents the molecule and then patents the use of that molecule, as has happened with numerous "surround" patents in medicine -- I believe there are several involving Amgen's Epogen.

Perhaps a patent attorney could enlighten readers on the implications of this ruling for medicine.

A Victory for Open Science

Stem cell research, though promising as an approach to treating diseases ranging from Type I diabetes to Parkinson's disease, has a long way to go before something shows up on the Food and Drug Administration's doorstep claiming to be a cure for a disease. Most of the advances breathlessly reported in the daily press are basic science insights or suggestive animal experiments. No one has conducted the successful animal safety test that would allow researchers to inject an experimental therapy derived from stem cells in humans.

That's why yesterday's announcement by the Patent and Trademark Office that it was voiding three seminal patents in the field previously awarded to James Thompson of the University of Wisconsin is good news for patients. Thompson was the first to isolate human embryonic stem cells, and in that discovery's wake, his university claimed all subsequent uses of the technology.

While, as this New York Times report points out, the university promises to litigate the decision, the PTO decision marks a welcome turning point in the battle against the unnecessary and unproductive privatization of mankind's quest to understand the natural universe.

Since passage of the Bayh-Dole Act in 1980, scientists receiving government funding have been encouraged to patent their discoveries if they were commercially viable. The patent fever set off by the law extended to virtually any research conducted at universities, whether publicly or privately financed. Because of U.S. government restrictions on funding embryonic stem cell research, Thompson's research was funded by Geron Corp., which ultimately received an exclusive license to the most promising uses of Thompson's discovery.

But that didn't stop the Wisconsin Alumni Research Foundation, which manages patents for the university, from charging private firms $100,000 and academic and non-profit institutions $5,000 every time they wanted to use the Thompson stem cell lines. This aggressive posture set the tone for the entire field, and encouraged other researchers to patent their discoveries.

This profusion of patent applications, what economists call a patent thicket, will inevitably retard the pace of research as researchers scramble to secure the necessary licenses and material transfer agreements. A British survey several years ago identified nearly 18,000 patents and patent applications in the stem cell field.

There are ways for researchers to collaborate in this aggressive intellectual property environment. In an article that appeared in PLoS Medicine a year ago, I proposed a patent pool for the stem cell field as a possible path through the patent thicket.

But another way to cut down the underbrush is by eliminating those patents that are most appropriately considered scientific discoveries about the workings of the natural universe. For something to receive a patent, it has to be a previously unknown invention that reflects the hand of man. Discovering human embryonic stem cells, which have been around since man first walked the earth, is more like Isaac Newton discovering gravity than the Wright Brothers building the first airplane.

The Public Patent Foundation and the California Foundation for Taxpayer and Consumer Rights, which challenged the Thompson patents, have provided a valuable service for the entire science community. Unfortunately, the PTO ruling relied on the traditional tenets of patent law. The examiners, upon reexamination, claimed the patent was obvious based on previous papers that had appeared in the literature. Obviousness and previous publication are cause for rejecting a patent application.

WARF's top officer immediately restaked their claim on those grounds. “It is inconceivable to us that Dr. Thomson’s discovery, which Science magazine heralded as one of the greatest scientific discoveries in history, would be found to not be worthy of a patent,” said Carl E. Gulbrandsen, the managing director of WARF.

In a bygone era, "one of the greatest scientific discoveries in history" would have gladly been shared with all mankind, not seen as a building block of academic alchemy that would turn basic science into gold. Basic science that may ultimately lead to useful products should be free and open to all who would build those useful products. Its inventors should not be allowed to become toll collectors on the road to innovation. Hopefully, the PTO decision yesterday is the first step on the road back to a reasonable standard for establishing where basic science ends and commercial invention begins.

Prizes, Not Profits

The Nobel Prize-winning economist Joseph Stiglitz in the current British Medical Journal has endorsed proposals to finance drug innovation through a prize fund. This approach has been championed for several years by the Consumer Project on Technology, which is run by Jamie Love.

Earlier this year, Love won one of the coveted MacArthur Foundation "genius" grants. His dogged determination to get the idea of the prize into the public domain is proof of the age-old concept that genius is one-tenth inspiration and nine-tenths perspiration. As we get set to power down for the Xmas holidays, it's fitting that I salute Love's latest endorsement. I've always operated as if only the power of an idea mattered in the so-called marketplace of ideas. But as in most markets, ideas need grease to gain traction and his obviously has.

Way to go Jamie.

For those not familiar with the concept, a prize fund would be established by government (or a consortium of governments) to reward innovations in medicine based on their usefulness. So a vaccine for malaria would take a bigger share of the fund than the fifth or sixth statin drug, which would probably get very little. The intellectual property would then be turned over to generic manufacturers to provide health care systems around the world with the lowest possibly priced medicines, so the maximum number of people would get to use them.

As Stiglitz put it, the prize fund "holds the promise that in the future more money will be spent on research than on advertising and marketing of drugs, and that research concentrates on diseases that matter."

Gas Pedal Case May Limit Abusive Rx Patents

The European Patent Office on Tuesday voided a patent on AstraZeneca’s Nexium, the best-selling acid indigestion pill. This is good news for European consumers, since the drug is nothing more than the mirror image molecule of Prilosec, which went off patent a few years ago.

While the EPO's reasoning won’t be released until early next year, observers say the decision hinged on the drug’s lack of originality, known as “obviousness” in the patent trade. A similar case was recently argued before the U.S. Supreme Court. Patent lawyer Robert Goozner explains why KSR vs. Teleflex, which involved an adjustable gas pedal, could wind up benefiting U.S. drug consumers:

The dispute over U.S. Patent 6,237,565 held by Teleflex involved an adjustable gas pedal that combined two elements, an electronic throttle control with an adjustable pedal system. Both inventions were well-known to automotive engineers.

Since most patents are modifications or combinations of previous inventions, the first question facing the patent examiners was whether the new invention was novel or obvious. If the latter, it can’t be patented.

The current test for determining obviousness is the teaching-suggestion-motivation or TSM test. Under TSM, if one of the known “prior art” patents or publications explicitly teaches, suggests or motivates someone to modify a known technology or combine with other known technology to produce a new invention, then that new invention can't be patented. However, the patent examiner must point out a specific passage in the published patent that actually does the teaching, suggesting or motivating, i.e., the logical road map to produce the obvious and therefore unpatentable invention. The result? The test can almost never be met and trivial inventions like painting a face on the side of a bag wind up getting patent protection (In re Dembiczak).

This low standard of patentability has been exploited by the pharmaceutical industry to reap enormous profits. When a patent for a drug is about to expire, many pharmaceutical firms frequently get another bite at the exclusivity apple by obtaining a patent for a minor variation of the compound coming off patent, an enantiomer (a compound having the same formula and structure, but with mirror image symmetry), for instance, or a prodrug (a compound that produces a known drug when metabolized by the human body). Nexium is the enantiomer of Prilosec.

During oral arguments in November, conservatives on the Supreme Court bench oozed contempt for the TSM test. “It is misleading to say that the whole world is embraced within these three nouns, teaching, suggestion, or motivation, and then you define teaching, suggestion, or motivation to mean anything that renders it nonobvious. This is gobbledygook," Justice Scalia said.

When Teleflex’s counsel Tom Goldstein retorted by noting that “every single major patent bar association in the country has filed [Amicus Briefs] on our side,” Chief Justice Roberts snapped: “That just indicates that this is profitable for the patent bar.” Justice Scalia piled on. “It produces more patents, which is what the patent bar gets paid for, to acquire patents, not to get patent applications denied but to get them granted. And the more you narrow the obviousness standard to these three imponderable nouns, the more likely it is that the patent will be granted,” he said.

The Supreme Court appears eager to raise the obviousness bar for obtaining a patent. If it closes this patent loophole, it could eventually lead to lower prices at the pharmacy. – Robert Goozner

Stem Cell Patents on Trial

With the Senate about to vote on opening the federal research spigots for stem cell research, the California-based Foundation for Taxpayer and Consumer Rights has petitioned the Patent and Trademark Office to void James Thomson's keystone patents on the technology, the Wall Street Journal reports this morning. You can read what I've written on this subject in PLoS Medicine, here and here.

The folks at WARF should have seen this coming. They've been making unreasonable royalty claims for using their stem cell lines, which is discouraging academic researchers and small firms from pursuing certain lines of research. It also would up the ante for researchers funded by the California Institute for Regenerative Medicine, which will be spending $3 billion of taxpayer money on stem cell research. Supporting patent lawyers at another state's university is probably not what the taxpayers had in mind when they approved Prop 71 in California.

This is a classic case of how the rush to patent every basic science insight can hamstring medical research, especially when a field is in its early stages like stem cells. Bravo to John Simpson at the Foundation for taking on this fight.

Info to the People!

Here's the latest statement on public access to research findings developed on the taxpayer nickel. Alas, it is from Great Britain. courtesy of the British Medical Journal:

Publicly funded research must be made accessible and free of charge to the public, recommended a statement published this week by research councils in the United Kingdom.

The statement said that information derived from publicly funded research must be made available at no charge for public use as widely, rapidly, and effectively as is practical.

It also advised that published research findings must be subject to rigorous quality assurance, through effective peer review mechanisms, and that mechanisms for publication and access to research results must be efficient and cost effective. Finally, the outputs from current and future research must be preserved and remain accessible for future generations.

The recommendations were developed by the executive group of Research Councils UK, which represents the eight research councils in the country, including the Medical Research Council.

Contrast that with the policy of the National Institutes of Health, which a) only asks that taxpayer-funded research be made publicly available one year after published in a journal and b) such open access publishing is voluntary.

WARF Pushes Stem Cell Patent Claims

The latest dust-up over stem cell patents took place earlier this month in California when the Wisconsin Alumni Research Foundation's chief counsel told a conference she expects California to pay royalties to her agency. WARF owns the original patent filed by James Thomson of the University of Wisconsin on deriving human embryonic stem cells, and believes anyone who uses any variation of the technology must obtain a license.

There is a research exemption (in which case WARF only charges $5,000 per use), but, according to the California Stem Cell Report, WARF had a change of heart regarding California because the state's Institute for Regenerative Medicine (CIRM is the body set up by Prop 71, which established California's $3 billion stem cell research fund) recently approved rules that "give the state roughly 25 percent royalties on inventions developed by CIRM-funded research at non-profit institutions."

However, attorney Lawrence Ebert, who publishes a widely read blog on intellectual property issues, warns:

"The folks at WARF ought to be careful. CIRM is a state agency. Accusations of patent infringement against states play out a bit differently than the garden variety suit against a garden variety defendant."