With New Patent, Mayo Clinic Owns a Cure for the Sniffles Center's Sweeping Rights for Treatment
That Isn't Yet Proven Angers Others
By PETER LANDERS
Staff Reporter of THE WALL STREET JOURNAL
ROCHESTER, Minn. -- Jens Ponikau of the Mayo Clinic says he has made a breakthrough in treating one of America's most common diseases. Now Mayo has made a breakthrough of its own: It locked up the rights to that discovery.
The disease is chronic inflammation of the sinuses, which leaves some 32 million Americans with a persistent stuffy nose. Dr. Ponikau, a 37-year-old German citizen, believes the condition is caused by an immune response to common fungi in the air. In his nine-year quest to prove his ideas, colleagues have called him crazy. Even his father, an ear, nose and throat doctor in Hof, Germany, suggested that Dr. Ponikau drop his research and return to the family clinic.
The Mayo Clinic is adding a modern twist to this age-old tale of a maverick scientist challenging established medicine. Tuesday, the nonprofit clinic captured an unusually broad patent that could give it a chokehold over a new generation of treatments for chronic sinus inflammation, or sinusitis.
The patent, in effect, blocks others from selling an antifungal agent to treat the condition without Mayo's approval. That adds to a similarly broad patent Mayo received in 2001 for treatment of chronic asthma, a disease that Dr. Ponikau says has the same cause. Mayo filed both patents, which received little public notice, in October 1998.
Broad patents such as Mayo's, called "method patents," are rare for a basic reason: Researchers very rarely claim to have discovered the root causes of a disease. In most cases, researchers seek to patent only specific treatments. Approval by the patent office doesn't mean that a product is considered safe or effective -- just that the rights to that product are protected.
The new patent may add to the growing debate about nonprofits' role as handmaidens to the drug companies, doing the high-risk basic research that shareholders won't pay for. Some critics fear nonprofits will grow so enamored of that role that they will neglect research without commercial potential. Meanwhile, the patent is also likely to add to the already fierce criticism of Dr. Ponikau and Mayo by some doctors, who accuse the clinic of blocking future innovation by stifling research. "That is ethically wrong," says Berrylin J. Ferguson, a sinus specialist at the University of Pittsburgh.
Dr. Ponikau and Mayo executives disagree. They say they sought the broadest possible patents because they wanted to be sure that they could attract a pharmaceutical company to license the patents and bring the advances to patients. As is typical at research institutions, the clinic owns the patents obtained by employees such as Dr. Ponikau, although he is eligible for a portion of future royalties.
"Nobody will put the resources behind this if you don't have a patent," says Dr. Ponikau. "This whole thing will die if we don't do this." Mayo will soon enter negotiations to license its patents, and officials say they're looking for a drug company that can sell an antifungal spray world-wide.
The Food and Drug Administration has yet to approve any drugs for chronic sinusitis, although it is common for doctors to prescribe inhaled steroids or antihistamines. America's 17 million asthmatics do have several FDA-approved drugs, but these merely relieve the symptoms of the disease and many have severe side effects, such as glaucoma and weight gain. Asthma kills more than 4,000 people each year in the U.S.
Dr. Ponikau says his quest to solve the sinusitis mystery goes back to an assignment he received in 1994 during a six-month stint at Mayo. Eugene Kern, a veteran ear, nose and throat expert at Mayo, asked him to do a report on a handful of seemingly anomalous cases in which fungi -- a common class of organism that includes molds and yeasts -- were detected in patients with chronically inflamed sinuses. The problem: Many patients had symptoms that suggested an immune response to fungi, but actual fungi were detected in only 3% to 4% of them. Dr. Ponikau headed home to his father's small ear, nose and throat clinic in Hof convinced that fungi must exist in more patients.
The answer lay in an unorthodox area of investigation: human mucus. Traditionally, pathologists have studied sinusitis by examining the excised tissue of patients who undergo sinus surgery. In such surgery, doctors usually suction out the mucus first and discard it. By removing the mucus, which traps dust and other particles in the airways, "you destroy the evidence," says Dr. Ponikau, chuckling at the way scientists sometimes miss clues right under their noses. "You won't believe what we all did to make sure we didn't find anything."
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At the Hof clinic, Dr. Ponikau took liquefied mucus samples and ran them through a centrifuge that would force any fungi to drift to the bottom. When he put the solution on a bed of nutrients, fungi grew like crazy, proving they had been present in the original mucus.
He proceeded to offer a few patients at the clinic an antifungal solution. Soon noses that had been stuffed for years cleared up. Dr. Ponikau called Dr. Kern at the Mayo Clinic and told him of the results. "Buy an airplane ticket and get here right away!" Dr. Kern remembers responding.
Dr. Ponikau persuaded his then-girlfriend to go with him to Minnesota. (Today they are married with two children and have settled in Rochester.) He had less luck convincing his father, Joachim, that it was the right move. According to Dr. Ponikau, his father wanted to know: "Why don't you get a real job?" The elder Dr. Ponikau says he was concerned that his son would "toil for years researching something no one would take seriously ... even though he might have the right idea."
Soon after returning to Mayo in 1996 as a full-time researcher, Dr. Ponikau came upon what looked like a fatal flaw in his theory: The fungi were present not only in sick people but also in healthy ones. David Sherris, a Mayo ear, nose and throat doctor who would become Dr. Ponikau's closest collaborator, feared the research was at a dead end and joked with Dr. Ponikau that Mayo might as well put the "crazy German" on a boat back home.
But, Dr. Ponikau wondered, if the fungi were harmless bystanders, why did the antifungal treatments seem to help his patients in Hof? Once again, the answer lay in the patients' mucus. When Dr. Ponikau put samples under an electron microscope, he discovered white blood cells called eosinophils clustering around the fungi. These cells, which help fight off infection, were well-known to occur in the sinus tissue of patients, but the reason for their presence wasn't known.
Dr. Ponikau realized that the white blood cells were marching through the sinus tissue to get to the open space of the sinus, a gathering space for fungi that the patients inhaled. Once there, the white blood cells fired off toxins to subdue the fungi -- but the toxins also were destroying the outer lining of the sinus tissue, clearing the way for a bacterial infection that caused inflammation. Dr. Ponikau then looked at the mucus of healthy people. The eosinophil cells were absent, meaning the destructive immune-system response never got started.
In 1999, Dr. Ponikau published his theory, and many specialists scoffed. "I think it's fundamentally flawed," Dr. Ferguson of the University of Pittsburgh told the Washington Post.
Many veteran nose doctors believe Dr. Ponikau's theory accounts for only a small fraction of sinusitis cases. They think other factors are more likely to be responsible, such as bacterial infections with other causes and different kinds of immune responses. Ralph Metson of the Massachusetts Eye and Ear Infirmary says he's tried antifungal agents on some patients, and "I've not been impressed with the improvement."
Dr. Ponikau insists that some veteran doctors are stuck in old textbooks and want to keep up demand for sinus surgery. The procedure, which removes sinus tissue to give a patient more breathing room, can cost $10,000 or more. "It's such a step out of the box," he says. "We're telling everybody else they've been wrong for 30 years."
Dr. Ponikau has won over one of the field's biggest guns -- Heinz Stammberger, a pioneer in sinus surgery at Austria's University of Graz. Dr. Stammberger says that when he first read the Mayo paper in 1999, he assumed the report of fungus everywhere was a mistake. But when his lab replicated the results, he changed his mind. "We're talking about a significant group of patients," he now says, adding that Dr. Ponikau's research is "the most exciting step in many, many years."
Mayo doctors have now prescribed their antifungal agents to more than 1,000 patients, making it a standard treatment for chronic sinusitis at the clinic, although the method isn't approved by the FDA. A study published last year by the Mayo team showed that a common, generic antifungal drug, amphotericin B, reduced nasal obstruction in 38 of 51 patients, removing it completely in 25 cases. (Daily doses of the drug are needed to prevent recurrence.) A larger placebo-controlled double-blind trial is now under way at Mayo. Long-term effects of the treatment, including potential side effects, aren't known yet. Side effects of amphotericin B -- when used in other treatments -- could include fever and vomiting.
At this point, there's nothing to stop a doctor from prescribing a standard antifungal drug such as amphotericin B for sinusitis. But few doctors are familiar with the treatment, and a pharmacist would have to prepare the drug -- which comes in a variety of forms, from ointments to pills -- so that it could be taken nasally. The Mayo Clinic says it doesn't plan to police individual doctors who might prescribe generic antifungals.
Recently, Dr. Ponikau has been working on an even more explosive theory -- that chronic asthma is essentially the same disease as chronic sinusitis, and can also be cured with an antifungal spray. The theory sprang from anecdotal reports by Mayo patients who said that the antifungal solution for their sinuses cleared up their lungs, too. In asthma, airways in the lungs become inflamed and filled with mucus. It is usually treated with steroids or other drugs to control the inflammation.
Dr. Ponikau says his research shows why that is happening. In a conference room down the hall from Mayo's busy ear, nose and throat clinic, he displays an electron-microscope photo of white blood cells attacking fungi in the sinuses and another photo of the same event in the lungs. The two photos look virtually identical.
Few asthma doctors know of the new research, but it is likely to face broad skepticism. Most specialists believe asthma has multiple, overlapping causes -- meaning an antifungal agent wouldn't help much. "If you fix one thing, can you fix asthma? Highly unlikely," says Meyer Kattan, an asthma expert at New York's Mount Sinai Medical Center.
Dr. Ponikau agrees that asthma can be triggered by a specific allergy, say to dogs or dust mites, but thinks the root cause in chronic cases is the immune response to fungi, which he says sensitizes the lungs to intruders. He acknowledges that he needs to publish papers on his studies before scientists will take the idea seriously.
In 2001, Dr. Ponikau obtained a patent that gives the Mayo Clinic exclusive rights to market any drug that uses an antifungal agent to treat chronic asthma. Some leading doctors who know about the asthma patent, and the similar sinusitis one, accuse Mayo of putting profits ahead of scientific progress. At a meeting of specialists last year in New York, Dr. Ponikau and Donald Lanza, president of the American Rhinologic Society and head of nose and sinus disorders at the Cleveland Clinic, had a hallway tete-a-tete. As both men remember it, Dr. Lanza accused Dr. Ponikau of withholding information from other doctors to protect his patents. Dr. Ponikau denied that and said Dr. Lanza didn't understand American capitalism. "If you don't like it, maybe Russia is a better place to live," Dr. Ponikau remembers snapping. (Dr. Lanza says he doesn't recall the remark.)
Dr. Lanza today says he thinks Dr. Ponikau's research is promising but worries that Mayo has an incentive to hype its discoveries. "You basically have an inherent conflict of interest," he says. "Anyone who denies it would be lying to themselves and everyone else."
Mayo officials say getting broad patents and licensing them to a big pharmaceutical company is the only way to make sure Dr. Ponikau's research reaches patients quickly. Dr. Ponikau and Mayo executives cite the case of Robin Warren and Barry Marshall, two Australians who made one of medicine's biggest discoveries of the 1980s by proving that the bacterium helicobacter pylori is responsible for most stomach ulcers. The two doctors never patented their discovery, and it took 10 years for antibiotic treatment to sink in among doctors because drug companies -- which already sold profitable but less-effective medicines -- didn't pick up on the idea.
Dr. Ponikau, for his part, says he could have made several times his researcher's salary as a sinus surgeon back home in Hof. "I'm doing this out of a passion," he says. "Not many people have a chance to make a significant change for the better." |
