Eye for an Eye
If you begin to go blind one day, this is how it will likely happen: Abnormal blood vessels will start to grow beneath your retina. As they grow, multiply, and swell, your vision will become distorted, but probably not enough to cause concern. Eventually, however, some of the vessels will start to leak and a pool of blood will form, damaging the retina and impairing your central vision. An ophthalmologist will tell you that, like thousands of people every year, you are losing your sight to something called wet age-related macular degeneration.
Two years ago, the treatment options for this condition were limited, at best. Today, your ophthalmologist can strap you down, point a low-intensity laser at the center of your eye, and clean up those rogue blood vessels without damaging the retina. It’s a new treatment method, developed right here in Boston, that uses a light-sensitive drug therapy called Visudyne.
It’s no surprise that in the place where more government-funded medical research is conducted than in any other city in the country — where medical breakthroughs are not just anticipated, but expected — the approval of Visudyne to treat age-related macular degeneration registered barely a ripple. What is surprising is the largely hidden drama unfolding behind it.
Two interconnected hospitals, Mass General and the Mass. Eye and Ear Infirmary, which for more than a century have shared not only the same Beacon Hill neighborhood but many of the same doctors and researchers, are squaring off in court over who deserves the most credit — and therefore the biggest financial payoff — for coming up with this particular application of Visudyne. In a five-page document that was filed quietly in U.S. District Court, Mass. Eye and Ear argues with Mass General over who really invented the procedure used to treat macular degeneration, which is the number-one cause of blindness in older people. It’s a secretive and lucrative battle, with at least part of Visudyne’s $250 million in annual sales on the table at a time when cash-strapped hospitals are frantic for new sources of revenue. It’s also an example of how the enormous and increasing role of money in academic medical research has created a climate of competition, secrecy, and even suspicion in place of the traditional cooperation and collegiality that helped create this city’s dominance of the healthcare field in the first place.
For more than 100 years, Mass General Hospital and the Mass. Eye and Ear Infirmary have been like siblings. Academics and clinicians amiably commingle in the buildings, work together in research groups, use one another’s resources, hold titles at both institutions, and teach side by side at Harvard Medical School. That’s what makes a court battle so out of character, and it’s no doubt why both hospitals have worked hard to keep their dispute out of the newspapers.
Representatives of both institutions insist there is no rift. They won’t discuss the suit, and even a former Mass General employee reached in Germany referred questions to the hospital’s attorneys.
Behind the scenes, however, many make clear that, regardless of who is right or wrong about the credit for this particular success, the same openness that makes doing collaborative science so successful is what makes doing business so difficult. From the point of view of the medical researcher — investigator, in the lingo of the medical world — openness about ongoing research has always been a murky issue. One Mass. Eye and Ear investigator, speaking anonymously, summed up the problem by saying she would gladly share her research with “anyone here” but wouldn’t tell a “competitor” anything, for fear of having her ideas stolen, which she says had happened in the past. Asked if she considers Mass General an ally or a competitor, she fumbled her answer. It depends on the circumstances, she eventually responded.
Intellectual property disputes have become especially common in the medical community, and eye research is particularly touchy. “Ophthalmology is lawsuit-happy,” says Jerry Helzner, associate editor of Ophthalmology Management magazine. One reason is that the eye is perhaps the only place where scientists can easily and clearly see blood vessels as they react to drugs, lasers, or other treatments. That makes it an ideal testing ground for research that might lead to more new drugs or medical techniques.
Photodynamic therapy falls into that category. Right now its primary consumer application is the one that is the subject of the dispute between Mass General and Mass. Eye and Ear: correcting macular degeneration. But the technique can also be applied to other diseases, including skin and ovarian cancer.
Back in the late 1980s, investigators at Mass General were looking into various applications of photodynamic therapy. Funding their work was a Vancouver company called QLT, which owns the rights to a specific photodynamic drug called BPD. These facts are certain. What happened next is at issue in the lawsuits and countersuits that have been filed over the course of this battle.
According to papers filed in court by QLT, researcher Tayyaba Hasan of Mass General, along with a colleague named Ursula Schmidt-Erfurth, was looking into eye treatment using photodynamic therapy. After successfully testing the therapy on rabbits, the team was ready to progress to primate trials. All they needed were some primates — and there was a menagerie of primates kept for experimental surgery next door at Mass. Eye and Ear. A doctor named Evangelos Gragoudas from Mass. Eye and Ear was invited to join the Mass General study. Soon after, a colleague named Joan Miller also joined in.
Mass. Eye and Ear disputes this version of events. It says Miller and Gragoudas had decided independently to research the use of photodynamic therapy for treating macular degeneration. What they needed was a supply of BPD, and they approached Mass General about sharing its store. In cordial and collegial fashion, Mass General got some BPD for Miller, who used it to treat macular degeneration in primates.
The accounts converge again in the fall of 1992, when all sides agree that Julia Levy, chief executive officer of QLT, flew from her Vancouver headquarters to Boston to check in with Hasan and the other Mass General researchers her company was funding.
At Mass General’s Wellman Laboratories, Levy (who quit as CEO last month) was introduced to Miller. Impressed with Miller’s progress — according to Mass. Eye and Ear — she agreed to provide BPD and funding directly to Miller and Gragoudas. But what Levy didn’t realize at the time, according to one lawyer involved in the litigation, is what many people don’t know — that Mass. Eye and Ear and Mass General are separate institutions, distinct hospitals that happen to share some common space. It’s an understandable confusion: Wellman Labs, where Miller was working when she met Levy, is at Mass General but is connected to Mass. Eye and Ear by corridors that make the buildings appear seamless. Both institutions are Harvard Medical School teaching hospitals. Miller, like many at Mass. Eye and Ear, even holds a title at Mass General — clinical associate in surgery — in addition to her Mass. Eye and Ear commission.
According to the lawyer, none of the researchers worried about drawing boundaries or documenting conversations or attributing every idea. They were just doing what researchers do: in this case, trying to save people from going blind.
The primate trials continued over the next two years, with QLT providing more of the drug, and by 1994 the resulting treatment method was ready to submit for a patent. Mass. Eye and Ear agreed to let QLT take care of the paperwork and pay the filing fees. But when one of the resulting patents came out in August of 1998, it listed not only Mass. Eye and Ear’s Miller and Gragoudas but also Mass General’s Hasan and Schmidt-Erfurth — and QLT’s Levy — as coinventors. The patent cited Mass General’s parent, General Hospital Corporation, and QLT as coassignees along with Mass. Eye and Ear.
QLT already had a deal to pay Mass General a percentage of QLT’s share of eventual sales and says it offered the same deal to Mass. Eye and Ear. But Mass. Eye and Ear officials balked. QLT claimed it had every right to proceed without Mass. Eye and Ear involved at all. Which is exactly what it did.
Not much else changed: Hasan and Miller were still coauthoring papers as late as 1999. But then, in April 2000, the U.S. Food and Drug Administration approved Visudyne for doctors to use on patients. That’s when money entered the picture. Lots of money. “This isn’t some little kind of drug — it’s a bigtime drug,” says Helzner of Ophthalmology Management. “The growth of the drug is pretty staggering.”
Within two weeks of the FDA’s approval, Mass. Eye and Ear filed suit against QLT, and QLT countersued. Then things got even nastier. Last May, Mass. Eye and Ear secured a separate patent on specific steps of the general procedure — and immediately sued QLT for violating that brand-new patent. QLT again countersued, claiming that both it and Mass General should be added to this latest patent.
All of these suits are pending. Trials could begin as early as this spring.
Through it all, Mass General and Mass. Eye and Ear have tried to appear publicly neutral. But court papers make it clear that Mass General won’t stand for being left out after making the initial deal with QLT and providing lab space and materials.
Mass. Eye and Ear (abbreviated MEEI in court documents) doesn’t appear to be in a particularly sharing mood, judging by its April 2000 complaint. “This is an action to establish plaintiff MEEI’s exclusive rights as the owner to certain inventions it developed,” the document says. Mass General was just a conduit for Miller of Mass. Eye and Ear to get the drug she needed to test her work, it says. And QLT, along with Mass General researchers, were focusing only on broader applications of the procedure, not macular degeneration, according to the lawsuit.
Not so, says Mass General (abbreviated as MGH in court documents). “Tayyaba Hasan at MGH will vigorously defend the notion that she and Dr. Schmidt-Erfurth did the conceptual work, and that MEEI was brought in because MGH didn’t have the primates [to test on],” says a QLT attorney.
One thing is sure: Within a matter of months, all the scientists who had worked in that open, collaborative atmosphere will be testifying under oath against one another.
In the fall, Mass General finally jumped fully into the fray and filed a document in the patent lawsuit, proclaiming itself opposed to Mass. Eye and Ear’s position. Mass General says it is protecting its scientists’ integrity, but the hospital also increasingly relies on its revenue from patentable research done for corporations and can’t afford to let that money get away. Mass General’s take from U.S. sales of Visudyne for treating macular degeneration is roughly $1 million a year and could increase dramatically. According to the lawsuit, the same procedure has applications for treating diabetic retinopathy, angiomas, and tumors. Future developments along these lines could belong in part to the holder of that first patent. If Mass General ends up with no ownership, it may have no claim on any of the potentially vast rewards to come.
As for Mass. Eye and Ear, if the courts rule by next spring that it’s owed triple damages, that could mean a $12 million check just for starters — more than 75 percent of its entire annual research budget.
Administrators at Mass General know exactly where they stand on this issue: Protection of the hospital’s intellectual property is crucial to its financial security. The hospital, the largest nongovernmental employer in Boston, puts its researchers through annual training on this point. Michael Hamblin, a researcher at Mass General, says he receives pressure from the people in the hospital’s patent office to send them everything with potential patent implications. “Previously, you sort of filed when you knew you’d discovered something,” he says. “Now you file just in case you do discover something.”
What makes all of this ironic is the fact that, in 1997, a Mass General investigator decried the growing trend of research secrecy. According to a study the hospital presented in cooperation with the University of Minnesota, a worrisome percentage of academic researchers — especially those in research relationships with the industry — admit they have delayed publication or refused to share their research, often in order to protect its proprietary value. Another survey, which appeared in the Journal of the American Medical Association, found that nearly one in five scientists delayed publication of research findings to protect proprietary information.
Mass General takes its contracts with for-profit companies so seriously, in fact, that three years ago it created the Partners Office of Corporate-Sponsored Research and Licensing to handle all of these contracts for Mass General, Brigham and Women’s Hospital, and other members of Partners HealthCare.
As for Mass. Eye and Ear, no investigator interviewed knew of such an intellectual property policy.
That seems likely to change as it goes to court with its friend of 100 years.