Authors: Barry Werth
Tags: #Biography & Autobiography, #Business & Economics, #Nonfiction, #Retail, #Vertex
More to the point, Searle filed a so-called Markush structure. In the 1920s, chemists, to protect their inventions, sought a way to avoid having
to patent individually each member of a class of compounds that would have a similar function. Eugene Markush, a dye manufacturer, filed for and won a patent for a class of compounds with a replacement group of atoms at several positions, meaning it covered potentially thousands of molecules. Based on the alluring but false premise that combinations of different groups of substituents around a common core generate molecules that have the same activity and biological properties, Markush structures amount, legally speaking, to hurling kegs of nails off the back of a moving truck.
Boger delayed revealing VX-478’s structure until after the company’s European patent application was made public. Merck, meantime, stumbled. At the retroviral conference in December, attendees had crammed into a presentation in the Washington Sheraton Hotel to hear the company report that patients getting the Merck drug had a 42 percent drop in HIV after just two days of treatment, compared with 1 percent for those on AZT. “We were beside ourselves,” Scolnick would recall. “We thought we had the cure for AIDS.” Then, six weeks later, a molecular biologist examining blood samples from trial participants discovered that the virus had mutated, building resistance to the drug. Another test indicated the virus hadn’t developed resistance. Scolnick called Anthony Fauci, the government’s top AIDS researcher, to get his read. “You’ve got resistance,” Fauci told him. Scolnick protested, bringing up the conflicting data. “I don’t care,” Fauci said.
“You’ve got resistance.”
Boger, Sato, and Tung conferred throughout the spring. Formulation and other problems had slowed the work at Wellcome to a crawl. There were so many treatments being tested in humans that it had become difficult to enroll patients for new trials, and it now looked as if Vertex’s molecule wouldn’t be in the clinic until the end of 1994. Pressured to show their hand, they opted to disclose the chemical structure at the Third International Conference on the Prevention of Infection in Nice, France, in June. The audience seemed skeptical from the outset. Despite hoping for a breakthrough, many were eager to see Vertex come down a notch. The compound was a sulfonamide, one of the class of molecules that were the first antibiotics—the sulfas—and now were also sold
as anticonvulsants and diuretics. Novel functional groups extended from a core that shared common features with other protease inhibitors.
Reactions ranged from qualified optimism to mild disappointment. No one felt that Vertex had been blowing smoke, but neither was anyone immediately convinced that VX-478 was all that the company had claimed. There remained major questions: Was it small enough to get inside the brain, something Searle’s compound had not been able to do? What of possible allergic reactions? VX-478 had chemical groups similar to those thought to cause some people to react violently to the antibiotic Bactrim. Carl Dieffenbach, the NIH point man for assessing new AIDS drugs, mused to a reporter, “I’m not sure their patent is as secure as they think it is.”
Boger weighed these questions only to brush them aside, especially the last. As part of its due diligence, Wellcome had satisfied itself that Vertex’s patent claim was clean. Its lawyers had won—and held on to—the rights to AZT through ten years of intense legal strife, providing an intimidating ally. A few months later, during a November conference call with Wall Street analysts, Searle announced it was stopping development of its protease inhibitor. Two clinical trials had showed no indication of antiviral activity, and Searle researchers believed that the compound was soaked up by a blood protein and removed by the liver. Boger was relieved to learn that the problem was unique to Searle’s molecule, and he considered himself fortunate to have the threat of a patent war suddenly diminished.
Murcko, as usual, thought well beyond the problem at hand. With the genetic material from Charlie Rice, the main scientific challenge was to discover how the hepatitis C protease worked and how to disable it. But Murcko had a secondary question, one more central to Boger’s mission: How do you evaluate new targets without knowing their structures? Could you predict, say, degree of difficulty? When was it wise to invest in new projects and when wasn’t it? “Up to now at Vertex, we said we either want to have a crystal structure available or we want to know that we can get there first,” Murcko says. “But sometimes maybe you wouldn’t be able to get the crystal structure as quickly as you’d like. Maybe if you had
a model it could help steer you away from certain projects. Or say this one isn’t going to appear so easy.”
Murcko did the experiment. Having no new positions but recognizing the uncommon gifts of a recent Harvard postdoc named Paul Caron, he hired Caron as a temp. Caron was advanced in thinking about gene sequencing and physical similarities among proteins, which fold into spirals and loops and cascading sheets according to the ordering of the amino acid residues out of which they’re made, following the text encoded in their DNA. In other words, if you had the genetic code for a target you might be able to model its active site
by mapping it against other known proteins. Sitting at a workstation in the modeling room, with a second PC at his side so he could calculate atomic charges and distances, Caron lined up the structures of the few other viral and mammalian proteases that were available and quickly noted that HCV lacked the usual cleft that caused the binding site to be buried in a pocket. “What we saw was virtually a bowling ball,” he said. “Very smooth. All the big loops that come around and make the channel weren’t there.” The target was going to be far more difficult than anything they’d done before.
One of the company’s advisors, Harvard structural biologist Steven Harrison, categorically dismissed the model, saying it couldn’t be true. Others confessed equal doubts. No one wanted to stop the project, but Murcko and Caron, knowing that the featureless active site presented a steep challenge to design, wanted people to be realistic. “The question at the time, once we had this model, was, ‘Do we continue?’ ” Caron recalls: “It’s going to take a relatively large inhibitor to get enough binding energy, and it’s not going to be an easy thing. We said, ‘This isn’t going to be HIV again. This is going to be a long, hard project.’ ”
Thomson and his protein group also were learning that HCV protease might not be as tractable as the company’s earlier targets. “We knew enough about the polyprotein that gets made by the virus that it was not a dead ringer for HIV,” he says. “It had some funny new funky ways for creating proteins, including this little cofactor that was essential. It was very conspicuous that there were two adjacent regions that interacted with one another very significantly, and then another third piece that
was key to the activity of the protease. And it was a puzzle as to what the architecture was going to look like in the end. More particularly, it gave us this chicken-or-the-egg problem of: we couldn’t make the protein, and we didn’t have a reliable assay to test whether we had
protein. That was really the bind that kept everyone on the planet anchored in the early days.”
Throughout 1995, the pressure mounted to solve the structure. Merck, Roche, structure-based rival Agouron, and many others were pouring major resources into the race. Meanwhile, public health officials were reaching the conclusion that many more people were infected with HCV than previously predicted, perhaps twice as many as with HIV. Vertex’s attempts at protein production stalled, cycling blindly in a cul-de-sac; the scientists didn’t know what material they had made and couldn’t test it to determine what to do next. With a reliable assay they could try hundreds of subtle changes in conditions to isolate more protein, but that wasn’t an option. “The Dark Ages,” Thomson called it.
“Everyone along the way had some different cross to bear,” biophysical chemist Ted Fox, who led the lab effort, recalls. “Those project councils were really tough. You got a lot of really energetic people, excited passionate scientists, and you’re getting beaten over the head week after week. I remember at one point, we finally had some active enzyme—doesn’t look good, not very much; maybe we have an assay—and Josh saying, ‘My God. This thing wouldn’t survive if it were this inefficient in the real world. Guys, you’ve got to work harder, or you’ve got to do more.’ ”
It was Thomson again who broke the logjam, though others at Vertex were thinking along the same lines. He asked Rice’s group to calculate the space between two regions by mapping the interceding genes, then asked the chemists to synthesize chains of amino acids that could be whittled, atom by atom, roughly to that same length. The chemists fashioned tiny artificial spanners, ten or twelve residues across, to form the most intimate molecular “embrace.” The exercise worked. “You took your protein from the bacteria that were engineering it, then you mix it with this little synthetic peptide, and bingo, you’ve got active protease,” he says.
As Murcko anticipated, some targets are much harder to isolate
and purify than others. Nearly two years after receiving Rice’s clones, Fox’s group delivered the first Thomson Unit of HCV protease to the crystallographers.
In February 1995, a year later than Boger had predicted to Wall Street, VX-478 was given to eighteen AIDS patients in a Phase I clinical trial, a dosing study of oral availability, pharmacokinetics, and tolerability—not its effect on HIV. Less than three weeks later, US regulators cleared a merger between the Burroughs Wellcome Company and Glaxo, creating the world’s largest prescription drugmaker. During the next fourteen months, Aldrich and Boger’s brother Ken, the company’s lead outside counsel, joined with Glaxo Wellcome’s lawyers to try to convince Searle to come to a reasonable solution over its patent claim.
“Searle had this guy, total jerk, totally irrational about this stuff, but by virtue of that, he ended up being quite effective,” Aldrich recalls. Early in the negotiations, he and Boger flew to Chicago to meet with a group from Searle. Never one to hide his contempt for the practice among drugmakers of aggressively pursuing patent claims for molecules in areas where they already had shut down their own projects, Boger ridiculed Searle’s Markush structure. Searle hadn’t made a sulfonamide and had no experimental data on whether it would work. Aldrich told them Vertex wanted to “work something out and get this important drug to patients.” The discussions dragged on for months afterward, until Glaxo Wellcome’s lawyers also took an unsuccessful stab at it.
In April Boger got a fax from Glaxo Wellcome. “I remember I was on vacation, golfing in Hilton Head, and Josh sent me an email saying we just took a torpedo below the waterline,” Aldrich recalls. “Josh is always very positive about things and always pooh-poohs anyone else’s science or any problem, but this was clearly a problem that shook him up. Searle was a problem for us and Glaxo.”
A delegation from Glaxo Wellcome arrived at Vertex to tell Boger and Aldrich that they were shutting down the VX-478 clinical trials because they couldn’t get the patent cleared. The timing—on the cusp of testing whether the drug worked—could scarcely be worse. “We’re a public company and HIV is our lead program, so we’re looking into the
freakin’ abyss,” Aldrich says. “I said, ‘Before we do this, there’s one thing we could try.’ ” Searle’s position made no sense: if Glaxo and Vertex shut down the program, Searle got nothing. Aldrich suggested sending a joint letter offering to pay $25 million and a 5 percent royalty in exchange for the exclusive license to all Searle’s patent applications in the area of HIV protease inhibition, and warning that if they didn’t hear back in a week they would go the
New York Times
with the story that they were shutting down the trial because of an IP dispute with Searle. “A Hail Mary pass,” Aldrich called the proposal. Searle took the deal.
“We would have been blown up. We were toast. We wouldn’t have been able to raise money. Our stock would have gone from fourteen dollars to two. It was very stressful. It was a very nervous place. People could just see that Josh and I were freaked out. That Friday after we got that yes, I had a few pops.”