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Inventor Disputes DNA Sequencer Patent
syntap writes: "USA Today is reporting on a story on an argument between a research company and the California Institute of Technology over who 'owns' a particular DNA sequencing technology, and they want it placed in the public domain. 'The suit also claims that millions of federal dollars were used to create the device, which would give researchers backed by the government the rights to buy and use the sequencer without paying royalties. It demands that Caltech and Applera refund millions of dollars to federal agencies for royalties they paid on sequencers used in public research.'"
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Was government cheated on DNA decoder?
By Peter Eisler, USA TODAY
The scribblings of Henry Huang helped start the great race to map the human genome, and they may help settle allegations that the U.S. government got robbed on the way to the finish. The biologist and his research notes lie at the heart of a legal battle over who gets the credit -- and the profits -- for inventing the device that deciphered life's genetic blueprint. The device promises huge advances in treating everything from cancer to birth defects. Federal investigators, lawyers, scientists and academics all have wanted to learn what Huang knew about the technology and when he knew it.
Read more below
Graphic
* How the gene sequencer works
After years of ducking the fray, the quiet biology professor at Washington University in St. Louis is ready to talk. In an interview with USA TODAY, he answered the question everyone is asking: "I am the inventor."
Huang, 52, now figures as a key witness in a civil lawsuit charging some of the biggest names in genetic research with defrauding the government and federally funded scientific institutions of tens of millions of dollars. The scientist himself is not a party to the lawsuit, which was sealed by court order when it was filed two years ago. He would not share in any monetary awards.
The case centers on a device known as a four-color automated DNA sequencer. It is the machine that enabled scientists last year to chart the DNA codes making up the human genome, which steers all physical development, be it eye and hair color or predisposition to disease or disability.
Patent and development rights for the sequencer belong to one of the nation's top research universities, the California Institute of Technology, and a heralded biotech company in Norwalk, Conn., Applera Corp. The suit, filed by MJ Research, a biomedical instrumentation firm in Waltham, Mass., aims to kill those rights.
The suit alleges that patents on the sequencer are invalid because they fail to credit fundamental aspects of its invention to Huang, who has no ties to MJ Research. The complaint asks that the technology be put in the public domain, which could break the lock that Applera and Caltech have on the lucrative sequencer market.
The suit also claims that millions of federal dollars were used to create the device, which would give researchers backed by the government the rights to buy and use the sequencer without paying royalties. It demands that Caltech and Applera refund millions of dollars to federal agencies for royalties they paid on sequencers used in public research.
The case is a window on the competing interests and legal jockeying that have become common in the new world of cutting-edge science. The costs and technological demands of genetic research are enormous, as are the potential profits. Disputes over who owns the rights to particular discoveries, especially as the government finances more genetic exploration, are becoming routine.
Sequencer is 'crucial'
In the scramble to capitalize on the deciphering of the human genome, the sequencer is the common denominator. It was used by both the federally funded Human Genome Project and its private competitor, an Applera subsidiary in Rockville, Md., called Celera Genomics, in last year's race to map the genome. Now, scientists worldwide are using it to isolate DNA sequences on that map that may bring treatments for HIV, Parkinson's disease and other ills.
"That instrument is absolutely crucial" to the future of genetic research, says Robert Cook-Deegan, a biomedical expert at the National Academy of Sciences and author of The Gene Wars: Science, Politics, and the Human Genome.
The suit raises a thicket of questions about who gets to use the machine and how much they pay -- models currently sell for up to $300,000 each. And it plays to growing concerns in Congress about oversight of federal research grants. As a result, Cook-Deegan says, the case "could be highly disruptive" for both the defendants and the government.
Caltech and Applera, which have made hundreds of millions of dollars on the sequencer, are mounting an aggressive defense. They argue that patenting and licensing of the device were proper. The government is staying on the sidelines.
The Justice Department filed secret notice in federal court last month that it would decline an option to take over the litigation on behalf of the plaintiffs. That ends a 3-year federal investigation of the underlying charges. But the government also decided not to seek a dismissal, and it retained the right to step in at any time and share in any damages the case might yield.
After the federal filing, the judge lifted the seal that kept the suit secret, which opened the door for the case to proceed to a trial that could be years away. USA TODAY reviewed more than 1,000 pages of contracts, grant proposals, scientists' notebooks and other material related to the case.
It's all about Henry Huang.
Tangle of charges
Huang began work on the DNA sequencer in 1979 as a post-doctoral project in the Caltech lab of Leroy Hood, a world leader in genomic research. Huang was 29, an immigrant from Hong Kong who came to the United States a decade earlier to pursue his studies. Like scores of young researchers, he was drawn to Hood's lab by its landmark work in immunology and developing high-tech instruments to open scientific frontiers.
Huang worked for three years on his ideas for the sequencer, even producing an early prototype. But he abandoned the project -- and Hood's lab -- in 1982 to take a teaching offer at Washington University. The project then was taken up by several lab colleagues who soon took their ideas to a nascent biotechnology company, Applied Biosystems, which forged an agreement with Caltech to develop commercial products from the sequencer work done at Hood's lab.
The sequencer built by Applied Biosystems, of Foster City, Calif., cornered the market. The latest versions, some as big as a small refrigerator, remain dominant, despite the introduction of rival technologies by other companies. Applied Biosystems, like Celera, now is part of Applera.
Today's controversy is rooted in those early years at Caltech. The dispute runs on two fronts, and Huang is center stage on both:
* Patents for the sequencer are held by Hood and several of the scientists who took over work on the device after Huang left the Caltech lab. Huang is not listed on the patents, despite notebooks and other records suggesting that he conceived fundamental elements of the device. Huang had no gripes until investigators showed him the original patent submissions, which convinced him that his ideas were key. Now, he simply wants his name added to the patents.
But plaintiffs in the lawsuit say Huang's willingness to testify that his ideas were crucial to the invention could have broader consequences: In rare cases, courts have invalidated patents entirely after finding that patent-holders intentionally hid essential contributions by someone else.
* Federal funding of the sequencer's invention is a central issue. If government money that went to Hood's lab financed basic aspects of the machine's development, the law entitles the government and certain institutions working on its behalf to buy the technology without paying the royalties usually included in the purchase price.
Huang's sequencer work was funded by a federal grant, one of many routes by which millions of federal dollars reached Hood's laboratory at Caltech. The lawsuit claims that neither the government nor the many contractors and institutions working on its behalf received the required discount, which would amount to hundreds of millions of dollars.
Allegations denied
Officials from Caltech and Applied Biosystems say the federal grants to Hood's lab only went towards refining the sequencer after it already was working -- a legal distinction that would leave the government with no special rights to use the technology. And they say Huang's federally funded work was too preliminary, and misguided, to credit him with playing a key role in the invention.
"People's memories and history are very, very different from one another," says Hood, who left Caltech several years ago to co-found the Institute for Systems Biology, a non-profit research institute in Seattle that applies genomic research to disease prevention.
Hood dismisses the lawsuit's allegations as off-base and declines to discuss Huang's role in the sequencer's development.
"There are a number of technical issues dealing with the chemistry, dealing with making it work, that have an impact on whether to name (Huang) as an inventor," says James Asperger, an attorney for Caltech. "We believe that his work did not rise to the level at which he should be named as an inventor."
Asperger says Caltech has no qualms about having Huang's name added to the patents if it is proven that his work was instrumental in the sequencer's invention. Such a change would not affect how the technology is sold or licensed as long as the patents aren't wholly invalidated, the lawyer says. "It's inconceivable that he would have been intentionally left off the patent," he says.
Asperger, like officials at Applied Biosystems, also says the federal grant that funded Huang's work on the device is not covered by laws giving the government royalty-free rights to technology it pays to develop. Besides, they say, the government got bulk-purchase discounts on the sequencers that far exceeded the amount it would have saved by not paying royalties.
Officials at both Caltech and Applied Biosystems point to the government's refusal to take over the lawsuit as evidence that there's no basis for its claims that the government got fleeced. "They've concluded, in essence, that there isn't sufficient merit to justify them pursuing the case," Asperger says.
But the government, in explaining its decision to stay out of the case for now, says the action should not be seen as reflecting on its merits.
What's more, previous accounts of the sequencer's invention by the various patent holders conflict with each other on key issues, including how and when the machine was invented and who paid for the work. They also are inconsistent with notebooks and other accounts written during and since the sequencer's creation.
Huang's project was the first serious attempt in Hood's lab to automate the laborious job of sequencing DNA, the two-stranded molecules that steer cellular development in all creatures.
Huang set out to build a device that could decode -- or sequence -- the patterns of the four nucleotides that make up DNA molecules. The number and pattern of the nucleotides, which are coded A,T,G and C, represent the genome in any given species, or the blueprint for physical development. The human genome comprises about 3.1 billion letters of code.
When Huang began his work, sequencing was done manually, by "tagging" the DNA with radioactive elements. That required scientists to identify each tagged compound by eye. The radiation made it risky, and it was too slow to hold hope for decoding the human genome's billions of nucleotides.
By the end of 1981, Huang's lab notes show, he had the idea of tagging the nucleotides in a DNA fragment with chemical dyes, a different dye for an A, T, G or C. He figured the colors could be read by an optical scanner linked to computers that would discern the pattern and determine the compounds' order.
He built a prototype and ordered dyes, according to lab records and accounts from people in the lab. His initial tests had limited success: Huang never was able to differentiate the dyed DNA fragments. Soon after, he left Caltech for Washington University.
About the same time, a young biophysicist named Lloyd Smith joined Hood's lab and picked up Huang's work. Smith, citing the possibility that he might have to testify, declined to discuss any circumstances surrounding the sequencer's development. But in a 1991 letter to Cook-Deegan, who sought Smith's recollections for a chapter on the sequencer's birth in The Gene Wars, Smith provided an account that suggests Huang paved the way.
Smith recalled that he quickly realized that Huang was using the wrong dyes -- absorptive rather than fluorescent.
"I pulled the plug on the project shortly thereafter," Smith wrote, adding that "back-of-the-envelope calculations" showed that Huang's approach "was hopeless."
However, Smith remained curious about the possibilities, according to his account, and continued to investigate the concept of tagging DNA molecules with dye for automated sequencing.
"The idea of using fluorescence, which is critical, was entirely mine," Smith wrote.
Smith pioneered the chemistry of attaching fluorescent dyes to the DNA molecules, and became the core of the Caltech group that developed the first working sequencer. Others included biochemist Michael Hunkapiller, a top assistant to Hood, and his brother Tim, a computer scientist.
The Hunkapillers argue that they, not Huang, conceived the idea of attaching four different colored dyes to the DNA nucleotides, but Smith disputes that in his account, which credits that idea -- and the birth of the project -- to Huang. "Henry Huang is the silent member of the group, who really set the wheels in motion with his ambitious but unfeasible early approach," Smith wrote.
Huang says his ideas for the sequencer were more developed than Smith's story suggests.
Smith knew relatively little about sequencing DNA, as he conceded in his letter to Cook-Deegan. And Huang says his work provided all the seed ideas for the sequencer: fragmenting DNA, labeling the pieces with four dyes, running the fragments through a single "lane" of tubing to isolate them, identifying the nucleotides with an optical scanner, and using a computer to decode the patterns.
Huang says that he started with absorptive dyes because the chemistry was easier, but that he also considered the possibility of needing fluorescents -- an idea documented in his notebooks -- because they were known to be more sensitive.
Before leaving the lab, he adds, he discussed his ideas with Smith. "Whether you used absorption or fluorescence was a minor thing in the grand scheme of things," Huang says.
'My ideas were clearly key'
Huang says he had never worried about credit until about a year ago, when investigators showed him the first invention disclosure filed by the Caltech group in its push to patent the technology.
The disclosure, signed by Smith and the Hunkapiller brothers, says they conceived the sequencer idea on Oct. 1, 1982 -- just five weeks after Huang departed.
"If I'd known about that disclosure before, I would have been a lot more vocal and clearly annoyed," Huang says. Until then, he adds, he had believed that the Caltech group spent years expanding his ideas before seeking patents.
"If it took them only five weeks, my ideas were clearly key," he says.
Huang's old notebooks detail much of his work. He even has receipts for the dyes he ordered to test his color-tagging theory.
As it was, Smith, the Hunkapillers and Hood went on to obtain initial patents on the sequencer in 1992. The issuance of the patents was delayed at the developers' request until the device was ready for market.
The scientists, all of whom ultimately worked for Applied Biosystems, ceded their patent rights to Caltech. Caltech, in turn, gave Applied Biosystems an exclusive license to refine and commercialize the invention. Applied Biosystems has made hundreds of millions of dollars on the sequencers, with various models selling from $50,000 to $300,000, and continues to dominate the market.
Michael Hunkapiller, now president of Applied Biosystems, says he is surprised by Huang's claim of inventorship and asserts that the professor's claims go far beyond what he knew Huang to be doing back in the days when they both worked in Hood's Caltech lab.
In an account that differs from those of both Huang and Lloyd Smith, Hunkapiller says he and his brother were the first to figure out a workable way to use four dyes to decode DNA fragments pushed through a single "lane" of tubing.
"There were a lot of elements that had been thought of before, but that doesn't mean they were relevant with respect to the patent," he says, adding that the important thing is making those ideas work.
Hunkapiller says he's confident that Huang's work had no direct role in the invention, but notes that there could be evidence in Huang's notebooks that was not shared within the lab. "There's no reason not to have him on (the patents) if he's legitimately an inventor, but inventorship is a matter of fact," Hunkapiller says.
Without Huang's testimony, the fight over the rights to the sequencer comes down to the question of whether federal funds helped pay for its invention, a question bogged down by complex and untested legal issues.
Hood's lab received a series of federal grants beginning in the early 1980s that totaled at least $30 million, the lawsuit claims. And it alleges that much of that money was based on applications that said a portion of the federal money would be used to develop an automated DNA sequencer.
But Caltech officials say none of the grant money went towards work on the sequencer until the device had been "reduced to practice," a legal term meaning that there was a working version.
The university even has secured an affidavit from John Wooley, who administered some of the early National Science Foundation grants to Hood's lab, in which Wooley testifies that he saw a working version of the machine before the grant money began to flow.
The university's argument is significant because one of the laws at issue, called the Bayh-Dole Act, gives the government rights to royalty-free use of a technology only in cases where federal funding is used to invent that technology or get it to work. If the money only goes towards refining a device that already is working, the law does not apply.
"There are many areas of Bayh-Dole that are subject to interpretation," says Frank Fulton, an analyst with Congress' General Accounting Office, which has issued two reports on the law's implementation.
One problem is that the government never has gone to trial to enforce its rights to a discount on a product covered by the Bayh-Dole Act -- not once in the law's 20-year history. "Generally, the law has not been litigated," Fulton says, "and some areas may not be clarified until there is case law."
Little interest in profit
Ultimately, the suit's strongest charges may be those involving Huang, who is sure to be a chief witness if the case goes to trial. And he is, in many ways, ambivalent about the case.
Huang says he believes that his name should be added to the patents so he's properly credited for his role in the invention. But he refuses to attribute any ill will to the listed inventors, noting that they did a lot of work to make the sequencer viable.
He also shows little interest in profit. He has made no effort to go after Caltech or Applied Biosystems. He became a figure in the lawsuit only after he was sought out by the plaintiffs, who have been locked in a series of bitter legal disputes with Applera for years.
Huang isn't even sure he supports the suit's goal of having Caltech and Applied Biosystems stripped of patent and licensing rights to the sequencer. Such an outcome, he says, might be a boon to foreign competitors seeking to break the market dominance of the Applied Biosystems sequencer.
Huang worries that the interests of keeping the United States competitive in the world of genetic research could far outweigh the benefits of recovering any money the government may be due in discounts on the sequencers.
But, like many in the world of genetic research, Huang believes that giving the government greater rights to the invention -- one potential outcome of the lawsuit -- could give publicly funded researchers easier and cheaper access to the device. That could speed efforts to develop genetic cures for deadly diseases.
"Free market forces are nice," Huang says, "but they must be aligned to national interests and, if not, to humanity's interests."
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I just heard some sad news on talk radio - Horror/Sci Fi writer Stephen King was found dead in his Maine home this morning. There weren't any more details. I'm sure everyone in the Slashdot community will miss him - even if you didn't enjoy his work, there's no denying his contributions to popular culture. Truly an American icon. He will be missed :(
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MJ Research, who filed the lawsuit, is a manufacturer of "affordable" lab equipment - including thermocyclers for PCR amplificaton of DNA - which might have been a previous patent issue for them (since they don't explicitly mention PCR in the description). Judging from their product line, they'd like to crack the sequencing market. As an aside, they have offices "all over the world", including Lake Tahoe (Incline Village, NV) - I wonder if that's a condo?
Huang says that he started with absorptive dyes because the chemistry was easier, but that he also considered the possibility of needing fluorescents -- an idea documented in his notebooks -- because they were known to be more sensitive.
...
The disclosure, signed by Smith and the Hunkapiller brothers, says they conceived the sequencer idea on Oct. 1, 1982 -- just five weeks after Huang departed.
So, the idea of using dyes (instead of radioactivity) was his. He also came up with the idea of using fluorescent dyes because of their increased sensitivity. He also came up with the idea of running the fragments through a single 'lane' of tubing to isolate them. And using an optical scanner to identify them. And using a computer to decode the results.
Sounds to me like he had an awful lot to do with it. Whether or not that means the other part of the article (that the government should get them royalty-free) isn't as clear, but it sounds to me like Henry Huang was certainly an inventor of the process.
Every single person who works (in any capacity, mind you) at Caltech (a.k.a. the Institute) signs a piece of paper that makes any hardware you patent or software you write, using Intitute funds or facilities, intellectual property of the Institute. I believe you can be the patent holder or author but the Institute gets the royalties or whatever.
This has been upheld in court, ad nauseum.
Another sysadmin I know has written a useful program, that he cannot release under GPL for fear of the legal brigade.
I find it kind of funny that a key argument here is about the gov. being ripped off by researchers. I work at the Hood lab as a student. I've noticed that the researchers were rather concerned by the University of Washington's poor handling of Intellectual property. (one of the reasons they left to form a private non-profit) I've heard of many small examples but the best one is that of one researcher who developed a cell line that the UW sold the rights to a company for dirt cheap and didnt reserve any rights for itself to continue to work on it. So that reseacher is working illegally on something that he developed. I'd guess similar things happen a lot of other public research centers. Maybe public research centers need better IP lawyers?
The patent was filed in 1990 and issued in 1992 (number 5,171,534). According to the article, the invention was made in 1982, and Hood's lab was showing the devices and describing the process to visitors in the mid-to-late 1980's. That makes me wonder whether the patent is even valid: if you disclose your invention before filing, the patent is generally not valid.