Maria FreireConsidering that she has just taken her place in one of the hottest of NIH's hot seats, Maria Freire is remarkably calm, collected, and personable. The new head of NIH's perennially beleaguered Office of Technology Transfer (OTT) assumed the position in February and since then, has been systematically taking inventory, setting priorities, and making contacts with NIH's technology development coordinators and the scientific directors who supervise the research that OTT patents, licenses, and markets. Her arrival comes just as NIH is becoming a highly visible player on the biomedical tech-transfer scene, with its decision to drop controversial patent claims to hundreds of cDNAs isolated by former NIH researcher Craig Venter, its successful negotiations over the BRCA1 gene patent, and its success in winning a very broad patent on ex vivo gene therapy licensed to Genetic Therapy Inc., the Gaithersburg, Md., firm that was NIH's partner in a Cooperative Research and Development Agreement (CRADA) for the method.
"We have a legal mandate to transfer technology at NIH, so it's not a question of should we do it but, rather, how do we do it appropriately -- how can we lower the barriers to technology transfer for scientists and get the technology to the bedside?" Freire asks.
A chorus of inventors at NIH would have some swift and grumpy answers for her. And basic scientists who are unlikely ever to use OTT's services have their own qualms about the effects that tech transfer may have on the research community.
Says one intramural inventor, "Tech transfer at NIH is in miserable shape." Her complaints include frustrations getting through to the correct person via OTT's mazelike voice-mail system -- or getting a call, fax, or letter answered promptly after she does get through. "I have had a major licensing problem. A license expired three years ago and still has not been renegotiated, even though four companies have tried to license it," says this inventor, who asked not to be named. "I do not know whether it is a problem of shortage of people, disorganization, or lack of motivation, but my personal experience has been that the service is nonexistent at OTT."
Other problems plaguing OTT, along with the biotech industry as a whole, range from conceptual issues surrounding the patentability of DNA sequences to delays at the U.S. Patent Office, which has seen an explosion in biotech patent applications in the past decade. For some basic scientists, the issues are less concrete, but no less heartfelt. They see NIH as the last refuge for pure basic research and note that with the increasing emphasis on commercial development of discoveries in molecular biology have come new problems dealing with access to genes, reagents, and other tools. They complain of an apparent chill on the free, uncensored exchange of ideas that occurred among scientists in an earlier era.
Freire is acutely aware of these concerns as well as a passle of other problems that must be addressed simultaneously -- like improving her office's morale and hiring replacements for the 13 program staff members who have left OTT in the past 18 months for positions in industry, trade groups, law firms, and academic tech-transfer offices. "Staffing is a key" to solving OTT's problems, Freire contends, explaining that "at the moment we are just trying to get out from a terrible rate of attrition" that coincided with last year's HHS-wide hiring freeze. The intense scrutiny of an HHS Inspector General's review of OTT generated a list of 88 corrective administrative actions for the office, creating mountains of extra work and undermining OTT's morale.
"To their credit, these people [who are leaving OTT] are getting good jobs, and when they leave here, their caseload goes from handling 120 cases to 10 cases" at a time, Freire says. "NIH has a reputation as a wonderful training ground. If they can make it here, they'll make it anywhere." In addition to the large number of cases each tech-transfer officer handles, Freire notes, "we handle some of the most difficult cases in the industry." But she remains undaunted by such challenges, saying, "I find this incredibly exciting. I'm sure we will make mistakes -- and learn from them -- because we are trailblazing."
Freire, who holds a doctorate in biophysics from the University of Virginia in Charlottesville and who came to NIH from a position in charge of the tech-transfer office for the University of Maryland's Baltimore and Baltimore County campuses, says solving OTT's problems will not be painless. Her starting point has been examining NIH's tech-transfer process and whether the expectations of scientist-inventors and others are realistic. The next question, Freire says, is, "What are we doing wrong and right, internally, given the process?"
"If it's things like phones and meeting Patent Office deadlines, we just have to fix them," Freire says. But other issues are only barely within OTT's influence. "In terms of the time it takes -- three years, on average -- to get a patent, that is process-driven by the times required by the Patent Office, the FDA, etc.," Freire says. "In the field of biotechnology, we are challenging everybody. The Patent Office ... is learning what questions to ask. ... That's another role of NIH -- to push the envelope and suggest ways to handle these issues." Jack Spiegel, acting director of OTT's Division of Technology Development and Transfer, says the Public Health Service currently receives 250 to 300 reports of new inventions per year -- mostly from NIH. Patent applications are submitted on about 150 inventions per year and typically cost $10,000 to $15,000 each to prepare, file, and steer through the application and approval process -- if there are no significant challenges or questions raised.
Freire sees educating NIH researchers and working closely with the various institutes' scientific directors and technology-development coordinators as the keys to improving tech transfer. A major effort is underway to make "leaner and meaner" the institutes' portfolios of potentially patentable inventions. This means improving the balance between patenting and licensing. It will also mean asking scientific directors more and more often to relay the ego-shattering news that NIH won't be seeking a patent on every scientist's precious brainchild.
Freire says that NIH's would-be inventors must understand that only a tiny fraction of their clever concepts will become products. "Just consider the attrition rate from beginning to end for getting a product to market at a large pharmaceutical company -- where product development is what they do for a living," Freire suggests. "If they churn out 60 projects a year, of that -- if they're lucky -- they will have one to two drugs in 10 years." As the scientific and biomedical research environment evolves, patent portfolios must also change, she says, "and the odds are small that something will make it all the way to market, even when it's not highly exploratory research" like much of the work coming out of NIH.
Freire's forthright approach appears to be winning over the scientific directors. After NICHD Scientific Director Arthur Levine and tech-transfer staffs from both NICHD and OTT spent a long day reviewing NICHD's extensive tech-transfer portfolio, Levine concluded that "Freire's background in fundamental science, the experience she gained at the University of Maryland, and her knowledge both of patent law and of the science marketplace combine to give her an exceptional sense of clarity, focus, and sensibility, which promise -- for the first time -- a truly effective and efficient OTT."
Freire also wants NIH scientists to understand that they are a key source of information on where to market rights to an invention. "At MIT, for example, 54% of the licenses come from researchers' contacts. And it's about 60% to 70% at the University of Maryland and Johns Hopkins," Freire says.
As OTT proceeds with these efforts, other critical tech-transfer issues are starting to sort themselves out favorably. In late February, after two years of active negotiation between OTT and major universities, NIH became the first signatory on a Universal Biological Materials Transfer Agreement (UBMTA), which is now being sent out for the universities to sign. UBMTA is expected to simplify and speed the sharing of research materials between scientists at signatory institutions. Also in February, access to gene sequences opened up dramatically when Merck & Co., in Whitehouse Station, N.J., and Washington University in St. Louis announced the release of 15,000 human expressed-sequence tags (ESTs) to the public domain. The ESTs should be a boon for researchers seeking to map, identify, or find homologies for sequences they have found. The company's "Merck Gene Index" project will place 300,000 gene sequences in GenBank's EST division over the next 18 months.
On the basis of an extensive study by OTT's Deputy Director Barbara McGarey, NIH Director Harold Varmus persuaded HHS to strike the so-called reasonable-pricing clause from CRADAs and Exclusive License Agreements. McGarey found that the clause has blocked companies from entering into CRADAs because the firms fear that the government will dictate prices that prevent earning a profit on products emerging from the collaborations. She was unable to turn up a single instance in which the clause had served its purpose of keeping down prices on products flowing from NIH scientists' ideas.
Although some scientists may continue to debate the appropriate role for tech transfer at NIH, Freire says that for OTT there is no "either-or" question of supporting basic or applied research -- both must be maintained -- and the bottom line is clear: getting NIH's scientific discoveries turned into products that improve public health. "It's important that we don't lose the ivory tower," Freire says. "If we lose our basic research and our trailblazing, we lose the future." But she also points out that if there are no rewards for commercial developers or if the tech-transfer process is too frustrating and cumbersome, "You can lose products and, ultimately, better therapies for patients."
Deputy Director for Intramural Research Michael Gottesman's office assumed operational responsibility for OTT after Freire took the reins, allowing Sandy Chamblee, NIH's acting deputy director for science policy and technology transfer, to tackle some of the broader tech-transfer issues. Gottesman believes intramural science as a whole will profit from the changes at OTT, saying that Freire "knows the industry and the science. Her judgment and instincts are sound."
Reflecting on her first months at NIH, Freire says, "I feel like a kid in a candy store. This is awesome technology we are seeing. I'm really impressed with our portfolio -- and I've seen some of the best. This is so rich, we have a moral obligation to find a partner to bring the technology out."