Moderna’s vaccine lawsuit has a Philadelphia backstory

It came as little surprise to drug-industry observers Friday when Moderna sued Pfizer and its partner, BioNTech, accusing the two companies of copying its “groundbreaking discovery” to make a COVID-19 vaccine. Moderna had hinted at the possibility of legal action months ago.

But now that Moderna has spelled out details of that discovery in the 39-page complaint, it sounds a lot like one that took place years earlier — in a lab at the University of Pennsylvania.

The dispute involves the genetic molecule called messenger RNA (mRNA), and who gets credit for discovering how to use it in a vaccine.

Billions of people have now gotten the mRNA vaccines, which proved to be safe and highly protective against severe disease. With new boosters tailored to the omicron variant expected in September, the technology is almost taken for granted. But the lawsuit, filed in U.S. District Court in Massachusetts, offers a reminder that just two years ago, the success of mRNA-based vaccines was very much an open question.

Whatever the outcome of the legal battle, there is little dispute that a major turning point came long before COVID, two decades ago in Philadelphia.

That’s when Penn scientists Katalin Karikó and Drew Weissman discovered how to tweak the RNA molecule so that it would not trigger a harmful overreaction by the immune system. The pair published the first in a series of key studies in 2005.

Moderna, based in Cambridge, Mass., would not be founded for an additional five years, in 2010. COVID emerged a decade after that, providing the first big real-world test of mRNA.

Once the COVID vaccines turned out to be such a success, the scientific community bestowed a slew of awards on Karikó and Weissman, including a $3 million Breakthrough Prize.

Moderna cofounder Derrick Rossi told STAT, a media outlet that focuses on medicine and life sciences, that the pair deserved a Nobel Prize.

“I would put them front and center,” he said in November 2020. “That fundamental discovery is going to go into medicines that help the world.”

Time for a brief biology recap.

Messenger RNA is a twisty strand of genetic material, carrying the recipe for making all kinds of proteins — from the physical building blocks of muscles and skin to the enzymes that drive the chemistry of life. These recipes are spelled out with different combinations of four chemical “bases,” abbreviated A, G, C, and U.

For years, scientists hoped they could insert their own customized mRNA recipes inside living cells, coaxing them to make proteins that would be useful in vaccines and other drugs. But when researchers tried this in lab mice, the animals’ immune systems saw the mRNA as foreign, and attacked it. The mice made very little of the desired proteins. Some got sick and died.

Evidence suggested that the harmful immune response was being triggered by a chemical structure called uridine, which is attached to the “U” in mRNA. So in their labs at Penn, Karikó and Weissman tried replacing the uridine in mRNA with a variety of similar substances, and finally found one that worked, called pseudouridine.

Not only did the mice survive, but their cells produced the customized proteins that the scientists had spelled out with their customized mRNA.

Years later, Moderna reported that it had improved the performance of these synthetic mRNA molecules still further, substituting a slightly different structure for the original uridine, called 1-methyl pseudouridine. That’s the version that Moderna patented and ended up using in its COVID vaccine. The vaccine from Pfizer and BioNTech uses that version, too. (Both mRNA vaccines carry the recipe for the “spike” protein of the coronavirus, giving the immune system a chance to practice on a harmless fragment of the virus in case it ever encounters a real infection.)

So was adding the 1-methyl a significant advance over what the Penn scientists had done years earlier? Can Moderna force Pfizer and BioNTech to pay royalties?

Under patent law, a court will have to decide whether Moderna’s additional tweak of mRNA was “nonobvious” to someone with “ordinary skill in the art,” said Jacob Sherkow, a professor of law and medicine at the University of Illinois. In other words, was Moderna’s modification a true innovation — something that wouldn’t readily occur to a typical biochemist?

Pfizer could fight that argument in court, and may also ask the patent office to reevaluate Moderna’s patent, said Paul Gugliuzza, a professor at Temple University Beasley School of Law.

“What Pfizer will argue in response to this lawsuit is that the patent office should have never issued this patent to Moderna, because Moderna’s patent is merely an obvious variation of what Penn had done before,” he said.

Penn also took out patents to protect the work of its scientists, licensing them to another company that in turn “sublicensed” the technology to both vaccine-makers.

In other words, however the dispute plays out between Moderna and Pfizer-BioNTech, Penn would still earn royalties for the original work by Karikó and Weissman — a sum that so far is thought to have approached $1 billion.

» READ MORE: Research behind vaccines reaps close to $1 billion for Penn

“You can imagine the original Penn patent as broad, and then what the Moderna patent claims is narrower, if it better defines or refines the modification that you make to the molecule,” Gugliuzza said.

Sorting out who gets credit (and money) for what will take years. Moderna is facing lawsuits from other companies over patents that involve other aspects of the vaccines. Whatever the outcome, the legal fracas illustrates how scientific progress involves dozens of incremental advances by many competing teams working on the same thing, the Temple professor said.

“There definitely is this perception of the lone inventor toiling away, and all of the sudden the proverbial lightbulb going off,” Gugliuzza said. “But in reality, innovation today is so complex that it’s done by huge teams making incremental changes.”