Six years before the pandemic, fledgling Cambridge biotech Moderna was searching for a way to get its revolutionary RNA technology to work in humans. One of the biggest problems was figuring out how to wrap up the fragile molecule in a protective package that would deliver it to the right parts of the body. Alnylam Pharmaceuticals had a solution.
The Kendall Square neighbor to Moderna had spent a decade developing a complex mixture of natural and synthetic fat molecules that cling to RNA like packing peanuts and protect it during transit. Without this protective packaging, called a lipid nanoparticle, RNA falls apart before it can get inside our cells and do its job.
In April 2014, Moderna executives, including the company’s current president, Stephen Hoge, met with Alnylam to learn about the firm’s lipid nanoparticles. Discussions continued through at least September, but Moderna ultimately decided that it would develop its own lipid nanoparticles without securing a license to Alnylam’s technology, according to a recent court filing.
Last Thursday, Alnylam announced it was suing Moderna and Pfizer for infringing its lipid nanoparticle patents. Both companies rely on lipid nanoparticles to protect mRNA — the main ingredient of their COVID-19 vaccines — and deliver it into the body. Moderna and Pfizer expect to sell more than $105 billion worth of those shots between 2021 and this year. Now Alnylam wants a slice of the pie.
“Am I surprised? Not really,” said Raju Prasad, a biotechnology analyst at the investment firm William Blair. “There are billions of dollars being made from these vaccines, so even a small royalty would be meaningful.”
A 1 percent royalty, which experts say is plausible if Alnylam wins, could earn the company upwards of $1 billion, 50 percent more than the $662 million it made from sales of its own three drugs last year.
Moderna was incensed by the lawsuit. A spokeswomen for the company accused Alnylam of “blatant opportunism.” Alnylam shot back that it has a “fiduciary duty to shareholders to seek fair compensation for the use of our technology.”
The lawsuit is the most high-profile case yet in a dizzying web of accusations over who deserves credit for or, more important, who deserves to profit from lipid nanoparticle technology. Arbutus Therapeutics and its affiliate Genevant are suing Moderna for infringing one of its patents for the technology. And a small Canadian firm called Acuitas Therapeutics, which licensed its lipid nanoparticle technology to Pfizer, recently sued Arbutus and Genevant.
The timing of these lawsuits comes as the pandemic appears to be receding in much of the United States and there is no longer a shortage of vaccines in the country. None of the firms in these lawsuits are asking Moderna and Pfizer to pull their shots off the market.
“I think that is obviously a smart move,” said Zachary Silbersher, a partner at the intellectual property-focused law firm Kroub, Silbersher & Kolmykov. If these firms tried to force Moderna and Pfizer to stop selling their vaccines, he added, “there would be a huge PR backlash.”
Instead, Alnylam said it was seeking “no less than a reasonable royalty.” Exactly what constitutes “reasonable” is up for debate, but Silbersher said that royalty sizes are usually determined based on how important a patent is to a product. And there is little doubt that lipid nanoparticles are key to making mRNA vaccines work.
“The lipid nanoparticles are crucial,” said Mansoor Amiji, a pharmaceutical scientist at Northeastern University. In the microscopic world of cells, mRNA is a bulky molecule that can’t get into cells on its own. Enzymes patrolling the perimeters of cells can also chew up stray mRNA, which often indicates a viral infection.
Lipid nanoparticles solve both problems. They effortlessly help sneak mRNA into cells and shield the delicate molecule from destructive enzymes. “It is because we have these lipid nanoparticles that mRNA vaccines became a reality,” Amiji said.
None of the companies involved in the lawsuits claim to have invented lipid nanoparticles. The origins of the technology stretch back decades. The lawsuits instead center on particular ingredients or recipes used in the COVID shots.
Lipid nanoparticles are made from specific ratios of four kinds of fat molecules, called lipids, that encapsulate RNA. Arbutus has a patent for the recipe, which specifies how much the ratios of those four ingredients can be tweaked and still allow the nanoparticle to form, much like different recipes for chocolate chip cookies call for varying amounts of flour, sugar, and butter.
Alnylam has a patent for one of those four fat molecules, which scientists call a cationic or ionizable lipid. These molecules are positively charged and are attracted to the negatively charged RNA. It is the key ingredient that helps the nanoparticle stick together. “Without this ionizable lipid, the mRNA lipid nanoparticle will not form,” Amiji said.
Early iterations of nanoparticles with these ionizable lipids were toxic, so Alnylam’s chemists made biodegradable versions that break down more easily. Although Alnylam began filing patent applications on those lipids in 2011, the lawsuit against Moderna and Pfizer is based on a patent for lipids granted in February 2022.
Alnylam uses one of the lipids in its commercial therapy Onpattro. In an e-mail, Kathryn Whitehead, a nanoparticle scientist at Carnegie Mellon University, said that the lipid nanoparticle formulation in mRNA vaccines is “essentially identical” to Onpattro, except for the ionizable lipid.
Moderna uses its own ionizable lipid and Pfizer uses one that it licensed from Acuitas. Curiously, the Moderna and Acuitas lipids are more chemically similar to each other than either of them is to the Alnylam lipid. But people following the nanoparticle field closely caution that it’s too soon to know how the lawsuit will play out in court.
“It is really tough from where we sit to say who came up with it first,” Prasad said.
Moderna said that its lipid nanoparticles “do not resemble Alnylam’s work, and any assertion that the Alnylam patent covers Moderna’s COVID-19 vaccine is specious.”
The firm also emphasized that Alnylam’s nanoparticles were designed for infusion in the blood and delivery to the liver, whereas Moderna’s vaccines needed nanoparticles that could be injected into the arm.
Alnylam didn’t invent its lipid nanoparticles to deliver mRNA. Onpattro is based on a different kind of technology called RNA interference, which uses short RNA molecules to turn off disease-causing genes. Early in the pandemic the company worked on an RNA interference therapy for COVID-19, but the firm dropped the program last year.
Amiji said that the lawsuit is unlikely to affect distribution of COVID vaccines.
But the cases could have important repercussions beyond COVID shots. Most experimental mRNA therapies and vaccines rely on lipid nanoparticle ingredients and recipes that are similar to those used in the COVID shots. If Alnylam wins, it could be well poised to profit from future mRNA products as well.
“You are not going to see this get dismissed very quickly,” Silbersher said. “It is hard to say how strong the case is, but this is not a bozo complaint. This is a real lawsuit.”