2008 Archive

Stem cells: Snagged in the patent thicket

Hilliary Creely ’09 fights for a biotech commons

HillaryFifty yards downstream from a bucking raft, the American River snakes to the right, then kinks back to the left, as it churns through Troublemaker Rapid and roars past Gunsight Rock. Perched on the edge of the raft, Boalt 3L Hilliary Creely digs a paddle into the current, her shoulders glistening with water droplets and late August sunshine. Creely’s raft is taking part in a two-day whitewater trip organized by the Boalt Disability Law Society—a group she’s volunteered with for the past year—which includes several law students with spinal-cord injuries that have rendered them paraplegics or quadriplegics. They’re classmates and colleagues Creely hopes can be helped or cured by breakthroughs in stem-cell therapy.

Navigating river rapids with less-able classmates is emblematic of Creely’s educational and career path, which involves charting a course through what she likes to call “the commons.” It’s a term Creely uses often, confidently, and flexibly: Sometimes she invokes it while discussing human society’s well-being in the broadest sense; sometimes while referring to scientific inquiry or biomedical research; and sometimes in articulating specific hopes and fears for stemcell research.

If anyone at Boalt is entitled to speak confidently of the commons—and specifically about stem cells—it’s Creely. Before law school, she earned a B.S. in biology, then snagged a Ph.D. in molecular and cell biology. During her doctoral studies, she was part of a laboratory team that developed and patented a new way of harnessing a protein to treat neuromuscular diseases. After that—and still before law school—she completed a two-year postdoctoral fellowship in genetics and evolution. She’s now a valued student staffer at the Samuelson Law, Technology & Public Policy Clinic, which specializes in developing legal standards and policy guidelines at the frontiers of science and intellectual property.

Creely’s experience with the patent system—along with her Ph.D. in biology, postdoc, Samuelson Clinic experience, and easy fluency with phrases like “induced pluripotency” and “up-regulating enzymes”—gives her more street cred on biotech issues than some IP attorneys will ever accrue. So when she voices more worry than hope about the pace of stem-cell breakthroughs, we should take notice.

Creely’s hopes, like those of millions eager for cures for themselves or loved ones, soared when human stem cells were first isolated a decade ago. “Pluripotent” stem cells—the simple, undifferentiated cells that can morph into every type of specialized cell in the body—were hailed as the Fountain of Self-Repair and Regeneration. Nudge a stem cell in one direction, it creates kidney cells, Creely explains; nudge it a different way, it yields flesh, or bone, or brain. Liver failing? A British lab is working on ways to grow a new one for you. Heart damaged? Johns Hopkins researchers are testing a stem-cell patch kit. Spinal cord severed? Stem cells have repaired spinal-cord breaks in laboratory mice, raising hopes that people like Creely’s wheelchair-bound friends and classmates might walk again.
[Ed. note: As we go to press, it has been reported that a woman living in Spain underwent a successful transplant of a new windpipe grown from her own stem cells.]

But despite the promise, says Creely, stem-cell breakthroughs are increasingly caught in what she calls a “stranglehold.”

Patent Thicket

Creely isn’t so concerned about the ethical and political controversy that erupted around the use of stem cells from human embryos a decade ago. “That’s gradually being resolved,” she says. “Researchers are finding ways to reverse-engineer cells from human adults.” By reprogramming mature, specialized cells—taking them back into undifferentiated cells—scientists are now creating “induced pluripotent stem cells,” and beginning to prod them in new, desirable directions.

“What worries me far more than the ethical and religious objections,” says Creely, “is the ‘patent thicket’,” by which she means a dense tangle of competing claims, staked out as researchers and institutions scramble to patent each new advance. Unless things change, she fears—unless a culture of openness and sharing replaces the possessive, proprietary impulse—this patent thicket could choke out progress, and extinguish the glittering hopes for stem-cell breakthroughs.

Even before the start of translating stem-cell research into therapies for human patients, thousands of related patent applications have been filed, each contributing to the thicket’s entanglement. And research could already be stagnating, Creely notes, resulting in a decline in innovation. Since 2003, applications for stem-cell patents have dropped by 50 percent in the United States. We could be witnessing the beginning of what she calls a “tragedy of the anticommons.”

Creely’s concern about the anticommons is the flip side of what ecologist Garrett Hardin, in a 1968 essay on human overpopulation, dubbed “the tragedy of the commons.” Hardin argued that individual interests—what he came to call “the selfish gene”—would inevitably trump societal interests and eventually destroy shared resources, be they as humble as a village commons or as big as the biosphere.

Although Hardin’s topic was overpopulation, his reasoning—and his metaphor—have since been applied to numerous other issues, including biomedical research and intellectual property. And that brings us downstream, aboard Creely’s intellectual raft, to stem cells, “the Thomson patents,” and the anticommons: a patch of ground so carved up into small individual plots and guarded by so many owners, that it becomes virtually unusable.

The Thomson Triplets

In the 1990s James Thomson, a veterinary researcher and molecular biologist, began to consider using human embryonic stem cells to explore human development and why it sometimes goes awry. In 1998 his lab at the University of Wisconsin succeeded in extracting and culturing human embryonic stem cells. The university’s technology-transfer organization, the Wisconsin Alumni Research Foundation (WARF), was granted three broad patents—known in biomedical circles as the Thomson patents—protecting the techniques used to culture primate and human embryonic stem cells. The Thomson patents are so broad that any researcher, institution, or biotech company that wants to commercialize an embryonic stem-cell therapy must pay royalties to WARF. At first glance, crying foul seems unfair. Hasn’t WARF devised breakthrough techniques and shouldn’t its members enjoy the rewards of ownership protected by IP law?

But Creely isn’t so sure the patents should have ever been issued to begin with. “The problem with patenting foundational technologies is that it puts a lot of power in the hands of whoever holds the patents,” she says. “There are certain basic laws in biology, and that’s just the way nature works; there’s no work-around solution to some of these foundational techniques.”

Recent advances in the field—especially the discovery of ways to turn mature, specialized cells into induced pluripotent stem cells—might seem to contradict Creely’s assertion. But even some researchers who have succeeded in inducing pluripotency have stressed that for some research, there is simply no substitute for embryonic stem cells. So while thousands of other patents have laid claims to pieces of the stemcell commons during the past decade, Creely considers the three Thomson patents to be “the choke point” in stemcell research—the thickest tangle in the thicket.

She’s not alone. In 2006, the California-based Foundation for Taxpayer and Consumer Rights, along with the New York-based Public Patent Foundation, asked the U.S. Patent and Trademark Office (USPTO) to reexamine and revoke or narrow the Thomson patents. According to the two groups, Thomson’s advances were obvious, based on earlier researchers’ isolation of embryonic stem cells from mice in 1981. They also charged that the patents were overly broad—“like Microsoft patenting computing,” according to John Simpson, the California group’s stem-cell project director—and that they discourage U.S. research on lifesaving stem-cell treatments.

At first patent examiners upheld the challenge, rejecting all three of the Thomson patents. Then, in August 2008—after WARF appealed and elaborated on its case for the unique and original nature of the Thomson lab’s work—the USPTO reversed its position. The decision dealt a blow to Creely’s hopes. “It could have been a good opportunity for the patent office to make a statement,” she says. “A chance for them to say that some insights into biological processes are so foundational, their use shouldn’t be limited by giving a monopoly property right to one individual or organization.”

The Thomson patents expire in 2015; by some reckonings, that’s not so far away. But Creely sees it differently. “If you’re the person living with a spinal-cord injury or a disease that could benefit from a new therapy,” she points out, “seven years can be a lifetime.” What’s more, although expiration of the Thomson patents will remove the patent thicket’s biggest tangle, many additional obstacles—the thousands of more specific patents filed since Thomson’s—will remain for years beyond 2015.

In Creely’s view, advances would be swifter, and the anticommons far less worrisome, if stem-cell researchers adopted the principles of open science.

A Cure for the Selfish Gene?

The profit motive and patent thicket notwithstanding, Creely points out there is precedent for scientific cooperation on behalf of the greater good—the movement broadly known as open science. Within open science are smaller, disciplinespecific submovements. In computing—where the trend first gained momentum—it’s called open source, which began partly as a revolt against Microsoft’s monopolistic grip on operating systems and software. Over the past decade or so, open-source development has spawned a wide range of free software, including Linux, Mozilla Firefox, the Apache HTTP Server (which serves nearly half of all Web sites), and the ubiquitous Internet Protocol. In the nondigital realm of plant biology, major agricultural universities in the United States have joined forces to develop a more open approach to sharing new, improved versions of staple food crops. And when teams of bioengineering students gather at MIT to pit their DNA-modified widgets against one another (see “Playing and Sharing,” page 22.), they agree to play by open-science rules.

Such collaborative efforts resonate strongly with Creely, whose greater-good mindset goes way back. A practicing Quaker—a faith whose members refer to themselves as “friends”—Creely has worked summers as a volunteer fire-fighter and emergency medical technician (EMT). She’s also ladled soup for the homeless, counseled battered women, and taught middle-school math and science for AmeriCorps. “AmeriCorps is very Quakery,” she says, “though I didn’t think about it at the time. The ideals of open science really speak to me. It’s all about community, about the larger society that will benefit.”

As an undergraduate, Creely considered a career in medicine, but her summer as an EMT changed her mind. Instead, she opted for graduate work in molecular and cell biology, followed by a Fulbright postdoctoral fellowship at the Max Planck Institute in Leipzig, Germany. “I knew before going to Leipzig that I wanted to go to law school, but I wanted to learn more about science and live abroad and interact with cuttingedge scientists first.”

Creely’s interest in biotech law was kindled during her Ph.D. work at Brown University. Her lab there “developed a way of using the protein biglycan we hope can treat muscular dystrophy and other neuromuscular disorders—a way to keep the muscle glued to the nerves, basically—and some of the work got patented. That was my first exposure to the way science and law can intersect at intellectual property.”

She wasted no time wading into the IP waters during her first year at Boalt, taking Introduction to Intellectual Property from noted IP scholar Peter Menell—and Copyrights from one of the world’s leading experts, Pamela Samuelson. Creely followed up as a 2L by taking a new seminar on stem-cell law. Boalt’s IP program has long been considered one of the best in the nation, and now California is the world’s epicenter for human embryonic stem-cell research. The state began moving to the forefront in November 2004, when voters approved Proposition 71, a 10-year, $3-billion program to fund embryonic stem-cell research that falls outside the Bush Administration’s funding restrictions. (See “The Law, the Profits, and the Poor,” page 20.)

During her second year of law school, Creely was chosen as a stem cell scholar by the Berkeley Stem Cell Center. The honor includes a fellowship funded by CIRM, whose charter contains a mandate to explore the ethical, legal, and social implications of stem-cell research. Currently 15 UC Berkeley graduate students and researchers hold appointments as stem cell scholars; of those, only two—Creely and 1L Scott Sierra—have received funding to explore legal issues surrounding stem-cell technologies.

And future inquiries like theirs could be in jeopardy. CIRM’s 2009 grants will fund only scientific work, not research on legal issues. “That’s a real loss,” says Lily Mirels, the administrator of the Berkeley Stem Cell Center, “because the law scholars bring such an interesting perspective to the table.” Mirels voices hope that Boalt and the Samuelson Clinic will continue to work at the legal frontiers of stem-cell territory.

So does Creely. “We have a real obligation, especially at this law school and this clinic,” she says, “to make a difference in how things move forward.”

By Jon Jefferson. Jon Jefferson is a writer and documentary producer. He has coauthored—with renowned anthropologist Bill Bass—three crime novels and two nonfiction books on forensic anthropology.