[Ip-health] With New Patent, Mayo Clinic Owns a Cure for the Sniffles (WSJ)

[Alexander Tsai]

http://online.wsj.com/article/0,,SB105165185464609900,00.html

April 30, 2003
PAGE ONE

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.
[Ponikau]

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."

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."

---- Vanessa Fuhrmans in Frankfurt contributed to this article.

Write to Peter Landers at peter.landers@wsj.com3
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Updated April 30, 2003