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4-Patents: Patenting biological pathways

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TITLE:  Patenting biological pathways
        Ariad suit raises questions on laying claim to processes in
        treating disease
SOURCE: The Boston Globe, USA, by Naomi Aoki
DATE:   July 24, 2002

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Patenting biological pathways
Ariad suit raises questions on laying claim to processes in treating disease

Among the inventors listed on US Patent No. 6,410,516 are three of the 
nation's most influential biologists, and their discovery, made in the mid-
1980s while the scientists were at Harvard University, the Massachusetts 
Institute of Technology, and MIT's Whitehead Institute, promised to open an 
entirely new avenue of research into treating disease.

But the patent, awarded last month after 16 years of review by Patent and 
Trade Office examiners, is now at the center of a legal controversy 
potentially worth tens of millions of dollars a year. Immediately after it 
was issued, the Cambridge biotech firm that holds an exclusive license to 
the patent, Ariad Pharmaceuticals Inc., filed suit against Eli Lilly & Co., 
claiming that two of the Indiana drug maker's products infringe the patent.

Outlining 203 separate claims, the patent covers methods of treating 
disease by regulating a family of molecules known as NF-kB, a biological 
trigger believed to play a role in a wide range of illnesses from cancer to 
osteoporosis to bacterial infections. Ariad argues that the patent applies 
even to treatments discovered before 1986 when the patent was filed and 
that its breadth befits the pioneering nature of the discovery.

"Few recognized the profound clinical impact of this pioneering work at the 
time," said Dr. Harvey J. Berger, Ariad's chairman and chief executive. 
"Today, over 10 years and thousands of papers later, the full impact of 
this discovery in treating human disease has become more widely 

The same day the company filed suit against Lilly, it also sent letters to 
50 other companies with products on the market or in development that work 
through the NF-kB pathway, asking them to license its methods. Berger said 
the company is only defending its interests and those of the 13 scientists 
whose work shed light on the potential of NF-kB in treating disease.

"We're not trying to keep anybody off the market," Berger said. "We're 
trying to create value for the scientists and shareholders who took a risk 
early on to invest in this work. There's nothing unusual about this patent 
and how it has played out."

Attorneys say the patent and looming legal battle raise some nettlesome 
issues, however. Patents are meant to spur scientific advance by making 
public key discoveries. But if a researcher or a company can lay claim to a 
significant piece of the biological landscape and any drug that treads upon 
it without actually discovering a drug, some question whether society is 
giving up more than it is gaining.

"It's a touchy area," said Leon Yankwich, a patent attorney in Boston. 
"Your research has laid the foundation for all further research. Yet you 
yourself have not discovered a drug that has any effect. You've made it 
possible, shown the direction of future research. But you haven't 
contributed directly to the pharmaceutical art."

The law allows anyone who invents or discovers "a new and useful process, 
machine, manufacture, or composition of matter" to get a patent. The 
discovery can not be obvious to those who are trained in the field, and it 
must be sufficiently detailed as to allow others schooled in that field to 
reconstruct the invention.

Describing the importance of blocking a biological cascade of events in 
treating disease and methods of doing so in lab experiments is a major 
scientific contribution. But it is a far cry from discovering and 
developing a drug that acts on the biological pathway to effectively treat 
disease. And legal scholars are split on whether the discovery is 
sufficient to merit a patent that lays claim to any treatment acting on the 

Medically, the implications are potentially vast. A single pathway may be 
involved in a number of diseases, and a patent on it could be used to block 
research that could result in a variety of treatments. Even if the patent 
holder didn't aim to block competition, some fear the very existence of 
such patents would discourage others from working on the pathway out of 
fear of litigation.

"In my mind, it may actually inhibit the progress of scientific research," 
said Anthony Butler, a pharmaceutical analyst with Lehman Brothers. "The 
discovery of a pathway can be a great piece of science. But it is not equal 
to the practical result. If you stake out a pathway, which never results in 
a practical invention, then it makes the idea of an invention an anomaly."

Patent attorneys say it could also give rise to an ever-increasing number 
of conflicting patents and a morass of litigation. Drug discovery is still 
more art than science. Researchers may know a drug is effective without 
fully understanding how it works. As biological advances are made and 
patented, however, researchers could find themselves unwittingly infringing 
patents and many drugs could be found to infringe patents that were issued 
long after the drugs themselves were discovered.

The legal arguments quickly become bogged down in a quagmire of logic, said 
J. Charles Mokriski, a patent attorney with Day, Berry & Howard. If a 
researcher discovers a drug without ever knowing the drug acts on a 
patented pathway or before the pathway is understood, does that constitute 
infringement? If the drug was acting on the pathway before the pathway was 
discovered, does the existence of the drug invalidate the patent on the 
pathway by rendering it not "new"?

"People presume patent law is a precise logical corpus of rules and 
regulations," Mokriski said. "In fact, it's not precise. Technology moves 
much faster than law moves. This case raises some issues that will likely 
have to be sorted out by the courts."

Three research teams - headed by David Baltimore at the Whitehead 
Institute, Philip Sharp at MIT, and Tom Maniatis at Harvard - did the 
original work on NF-kB in the mid-1980s. Found in all mammalian cells, NF-
kB is bound to another molecule called IkB, which keeps it biologically 
inert. A host of different signals from inside or outside the cell can 
activate NF-kB, however, and once active, it moves into the cell nucleus 
where it triggers genes to produce proteins.

Because NF-kB can activate so many genes - more than 150, at last count - 
it is implicated in many diseases and could prove key in treating those 
diseases. Patent No. 6,410,516 describes more than a dozen ways of blocking 
NF-kB in various cell types - some of which are identical to the mechanisms 
of action of drugs now in development or on the market, including Lilly's 
osteoporosis drug, Evista, and its sepsis therapy, Xigris.

Ariad's Berger said papers published by Lilly's own researchers clearly 
elucidate the infringement. He said he has tried in vain to engage Eli 
Lilly in discussions to negotiate a licensing deal. Those two facts are in 
large part why Ariad, a company of just 70 employees, decided to take on a 
giant like Lilly, Berger said.

Berger brushes aside Lilly's claim that its drugs do not infringe. He said 
other companies, looking at the same basic facts, are negotiating licenses. 
He adamantly denies any allegation that Ariad is trying to impede research 
or free ride off the success of others. The company is seeking "reasonable 
royalties" that are in line with industry standards, he said, and there are 
no plans to file additional lawsuits.

But the financial lure is undeniable. Evista generated $665 million in 
sales last year. Xigris, which was approved late last year, reaped $22 
million in sales in the first three months of this year. Analysts predict 
that both drugs could reach $1 billion in sales a year. At their peak, 
Berger noted in a conference call to analysts, patents seminal to the 
biotech industry have generated more than $100 million a year in revenue 
for their owners.

"We are very committed to fighting as hard as is necessary," Berger said. 
"We believe very strongly that we are in the right."

Robert Armitage, Eli Lilly's vice president and general patent counsel, 
however, could not disagree more vehemently. The initial patents on Evista 
and Xigris were filed in 1981 and 1985, respectively, Armitage said, and as 
a matter of law, Ariad can't reach back and claim a prior invention. 
Moreover, he said, the very existence of Evista and Xigris likely 
invalidates the Ariad patent.

"Unfortunately for them, if they are correct that they have successfully 
patented our prior work, their patents are invalid," Armitage said. "The 
patent has to be limited to subject matter that is novel and not obvious. 
If the patent is so broad that it covers activity that was already in 
practice, then the patent falls like a house of cards."


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