Experiment Eleven (31 page)

The companies sought the much-envied product patent, successfully argued by Waksman and Merck. Product patents were becoming more important than process patents because they gave the company the right to exclude the competition, even in derivatives. In the case of streptomycin, the product patent turned out to cover four chemically different compounds, and even covered dihydrostreptomycin, because to make the new drug you had to start with the old one.

At the beginning of the 1950s, hundreds of antibiotic patent applications were sailing through the Patent Office. (More than six hundred antibiotic patents were issued through 1956.) This flurry would lead to new patent law. The large-scale industrial screening of microbes was adding pressure on the Patent Office to change its original standard for an invention.
The courts had previously required inventions to show a “flash of genius”—something inspired and out of the ordinary—in order for a patent to be granted. The essential distinction made was between a traditional inventor and a “skillful mechanic.” In the antibiotic revolution, Fleming had certainly had a flash of genius when he had discovered penicillin, and the discovery of streptomycin had been made in the old-fashioned way—by one indefatigable researcher in a basement lab.

Now the big companies engaged in massive screenings of tens of thousands of cultures involving millions in industrial investment. The company researchers could hardly be viewed as genius inventors in the old sense, but they were certainly “skillful mechanics.” As William Kingston, of the School of Business at Trinity College Dublin, has written, “a new law which would frankly recognize the change from individuals to investment as the source of what is to be protected, would have needed an amendment to the Constitution. Since this was out of the question, change could only be made in a way that forced the reality of invention by investment into the
pretence of invention
by individuals.”

To accommodate this need, the U.S. 1952 Patent Act provided that “patentability shall not be denied because of the way in which the invention was made.” No more flash of genius. That key phrase was replaced with the “inventive step” or “non-obviousness test.” A patent was now be granted for something that was new and was “not obvious to one skilled in the relevant art.”

In the case of antibiotics, if a company tested a wide variety of microbes from different samples of soil for long enough, it was almost certain to find something patentable. But it would not be “obvious” where to start this treasure hunt. Should it begin, as with Albert Schatz's streptomycin, among the microbes living in a manure pile or on Doris Jones's swab of a chicken's throat? Or in soils on the other side of the world, like Donald Johnstone's coral soils on the Bikini Atoll? At the time, neither of these was an obvious source for medicine. The new “non-obvious” standard was soon adopted internationally and gave the pharmaceutical industry yet another boost.

THE RATE AT
which new patents were being granted for substances that were similar in their chemical makeup, and also in their effects, led to another, quite separate trend: companies that sought to keep drug prices
high by restricting licenses for their patented products. The result was an antibiotic oligopoly.

Benjamin Duggar, a seventy-two-year-old former professor of botany at the University of Wisconsin and the head of the research department of Lederle Laboratories (American Cyanamid Company), had like Burkholder also been collecting soils from all over the world. He had screened around seven thousand actinomycetes before finding a golden culture,
Streptomyces aureofaciens,
named for its color (after the Latin for “gold”). It produced an antibiotic with a broad spectrum of activity, but it came from a soil sample found relatively close to home—in Columbus, Missouri. He called the drug aureomycin.

Pfizer was also looking for a broad-spectrum antibiotic when it found terramycin. It turned out to be chemically similar to Duggar's aureomycin. The Pfizer chemists fiddled with the structure and produced a more effective product, which the company marketed under a different name, tetracycline. Lederle also discovered tetracycline by the same method and filed its own patent application. Three other companies—Bristol, Squibb, and Upjohn—found tetracycline by another route and filed their patent applications—a total of five.

The Patent Office declared “interference,” which usually means a long, hard-fought battle to establish which applicant discovered the new invention first and therefore has “priority” and the right to a patent. Instead of fighting it out in court, however, Pfizer and Lederle got together and settled the matter in a backroom deal in which Lederle conceded priority to Pfizer, which then licensed the drug to Lederle and the three other companies, thus cornering the market for tetracycline for
the five companies
at a fixed price. Tetracycline would soon become the nation's best-selling antibiotic, with sales topping
one hundred million dollars
. The maneuver did not go unnoticed by the federal government, however.

THE SECOND GENERATION
of anti-infective drugs reached the market in the early 1950s, during the Korean War, when the U.S. military became the primary consumer of such drugs. Congress and the federal government started to take notice of the price of drugs produced in America and, if it was too high, looked elsewhere, importing generics from abroad. The “tetracycline five” attracted a U.S. Senate inquiry, and the government brought a
criminal antitrust case against the five companies under the Sherman Act. They were found innocent of collusion, but a damning Senate report concluded that the oligopoly had arisen from three factors: patents; the large sums spent on promotion; and “the well-entrenched practice of physicians of dealing with pharmaceuticals by their brand names rather than their generic categorization.”
Half a century later
, drug industry observers would look back at the Senate report and remark how little had changed.

By the end of the 1950s, some companies would be screening fifty thousand cultures a year. The companies began investing in research and development, and would eventually spend
more than 50 percent
of their recorded profits on R&D. In 1956, eleven principal drug companies owned 500 antibiotic patents, led by Merck with 111. Fifty percent of all antibiotic patents were for penicillin, 100 patents were for streptomycin and dihydrostreptomycin, and 69 were for broad-spectrum antibiotics.

As the search for antibiotics reached a peak in the mid-1960s, researchers had fun with finding new names. A Greek researcher named one zorbamycin, after the book and movie
Zorba the Greek
, and another melinacidin, after Melina Mercouri, the star of
Never on Sunday.
One isolated by an Italian researcher on February 29 was christened lipiarmycin (“leap-year-mycin” with an Italian accent). By the end of the 1970s, the rate of discovery had fallen off, but
more than five thousand
potential antibiotics had been found, half of them from the
Streptomyces
genus of the actinomycetes.

Under the new rules of the Food and Drug Administration, the drugs were available only with a doctor's prescription, so the companies soon began to target doctors, who did not pay for the drugs they ordered and often did not know how much the drugs cost the patient. Companies such as Merck and Pfizer began combining discovery, patenting, packaging, and selling, creating the new
so-called integrated drug company
. When introducing aureomycin, American Cyanamid shipped samples to physicians worth about two million dollars. The sudden increase in the number of
advertisement pages
in the
Journal of the American Medical Association
told the story. In 1949, there were 32 pages; in 1951, 157 pages; and in 1957, 534. Big Pharma was on its way.

BASKING IN HIS INTERNATIONAL fame, Waksman
continued his foreign tours and, in Japan and France, announced that streptomycin patent royalties would be used to set up Waksman Foundations, to give local students fellowships. In 1954, he also published his memoir.

It would be his
fourth publishing opportunity
to address the historical record, but Waksman was still angry about Schatz's challenge to his authority. Instead of clearing the fog over the discovery of streptomycin, he still wanted to teach Albert Schatz a lesson.

Waksman sent a draft of the chapter in his memoir describing the discovery to Russell Watson, who spotted many potential libels in Waksman's portrayal of Schatz as a mere pair of hands. “
What are you trying to prove
by this chapter?” Watson asked. “The intendment [
sic
] of the chapter is that his [Schatz's] part in the discovery was scientifically negligible.” This clearly “opened the door for libel action.” Although it was impossible to say whether Schatz would go that far, in Watson's view Schatz was “egotistical, abnormal, possessed of delusions of grandeur and ... financially able to prosecute a libel action.” He could charge that Waksman had unduly minimized his part in the discovery.

“It is impossible to forecast the result of such an action,” Watson continued. The original case against Waksman had been heard by an experienced, impartial trial judge, but a libel case would be tried by a judge and jury, and “the outcome would be unpredictable.” Schatz could bring up such
tricky areas as “the financial arrangement” between Waksman and the university, about which “the reading public would be curious.”

Watson also wondered why Waksman kept bringing up the story of the stolen notebook, supposedly taken by Uncle Joe in May 1946 but, according to Watson's brother and law firm partner, Dudley Watson, not stolen at all—they had been in the possession of Merck's lawyers at the time of the alleged theft. Russell Watson insisted that the “missing page” from Schatz's notebook was “insignificant.”

The entire chapter about the Schatz case, he commented, would certainly make the book more controversial and increase its sales, but he reminded Waksman that any advice on this matter from his publisher, Simon & Schuster, should be seen as what it was: biased in favor of the marketplace.

In conclusion, Watson said that the various facts of the Schatz case and the proposed chapter were too numerous, and he suggested a meeting. There is no public record of such an event, but Waksman would eventually cut out all references to Schatz by name and removed the parts that Watson had criticized.

MY LIFE WITH THE MICROBES
was published by Simon and Schuster in 1954. There was no index, and no references to scientific publications. In discussing the discovery of antibiotics in his laboratory, Waksman mentioned the help of many “assistants,” and the discovery of streptomycin itself was described in seventy-five words.

“On August 23, 1943,” Waksman wrote, “we isolated a culture of an organism, long known to me,
Streptomyces griseus
.
This culture was found
, by the methods developed for the production of streptothricin, to produce a similar antibiotic, which we designated streptomycin, a name coined in the laboratory the previous January. Further tests carried out in our laboratory and in the laboratories of Merck & Co, proved it to be a highly desirable substance with potential chemotherapeutic properties.”

In the antibiotics program, Waksman said, he had been assisted by nearly fifty graduate students. “They were the
fingers of my hand
... This teamwork might be compared to that of an orchestra, with the conductor leading and assigning the task to each member, none of which [
sic
] would
have produced any symphony otherwise.” He was not the kind of conductor who picked out his first violin for special recognition and applause. “
To name only a few
would be a disrespect to others,” he wrote.

FOR THE NEXT
two decades, Waksman continued to promote himself and streptomycin, at home and abroad. New editions of his autobiography were published in Britain (1958) and Japan (1975, posthumously), still with no mention of Schatz. He wrote and edited several more books on streptomycin and on the actinomycetes. Simon and Schuster turned down his next book,
The Conquest of Tuberculosis
, because, it said, it could not find a market for it.

The book was eventually published in 1964 by the University of California Press, which insisted on an index. Schatz's name appeared six times, in journal references. In telling the story of the discovery, Waksman once again repeated his
parable of the sick chicken
. The chicken had been responsible for the isolation of streptomycin, not Schatz.

AMONG THE EVENTS FROM THE SPRING
and early summer of 1954
recorded on world-history Web sites
are the release of Elvis Presley's first hit single, “That's All Right”; the New York Yankee Joe DiMaggio's marriage to Marilyn Monroe; the sale of the first TV dinners; and the fruition of Selman Waksman's personal dream, the opening of the first Institute of Microbiology, on the Rutgers campus. Waksman's Rutgers monument was a $3.5 million neo-Georgian structure with a gleaming white clock tower, and it was built principally from the streptomycin royalties paid to the Rutgers Foundation.