Moderna’s mysterious coronavirus vaccine delivery system

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U.S. Vice President Mike Pence helped launch Moderna Therapeutics’ large, late-stage trial of the Covid-19 vaccine on Monday. “It’s remarkable to think that Moderna – which will launch this Phase 3 clinical trial – actually entered Phase 1 in March,” Pence said.

Moderna has evolved at lightning speed and is doing work based on advanced messenger RNA technology that could result in a viable vaccine. There is widespread hope that Moderna’s vaccine will play an important role in the fight against the pandemic. To support the effort, Moderna secured $ 955 million in pledges from the federal government’s Biomedical Advanced Research and Development Authority.

Wall Street also has high expectations for the vaccine, and Moderna’s stock has quadrupled this year to a market valuation of $ 30 billion, allowing Moderna to raise $ 1.3 billion in a stock offering. in May. Moderna insiders sold some $ 250 million in shares as the stock skyrocketed.

With the stakes incredibly high, the mystery surrounding a key technological component of Moderna’s coronavirus vaccine is only getting deeper. The US Patent Trial and Appeal Board last week dismissed Moderna’s challenge to a patent owned by Arbutus Biopharma

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related to lipid nanoparticle (LNP) technology which is crucial for Moderna’s mRNA drugs.

For a decade, Moderna has worked on developing mRNA technology that could turn body cells into drug factories. For the approach to work, Moderna must safely deliver mRNA to body cells without the payload breaking down in the bloodstream. Accordingly, any mRNA or therapeutic vaccine consists of two components, the actual sequence mRNA and the delivery mechanism. Moderna clearly designed the first component, but there are still questions about the second. No vaccine or mRNA drug has ever been approved by US or European regulators.

Even though Moderna went to the trouble of trying to invalidate the patent held by Arbutus, a small Canadian biotech company, Moderna said after losing its patent challenge that its LNP technology had advanced far beyond the technology described. in the Arbutus patent. Moderna claimed that the LNP used to make mRNA-1273, its Covid-19 vaccine candidate, is not covered by the Arbutus patent. “Moderna is not aware of any significant intellectual property barriers for the products we intend to commercialize, including mRNA-1273,” the company said.

In June, researchers at NIH and Moderna performed a handwritten preprint of preclinical data for mRNA-1273 available on bioRxiv, an open access preprint repository. The preprint described Moderna’s coronavirus vaccine candidate as using delivery technology that appears to be covered in the Arbutus patent that was confirmed last week. The preprint from the study that tested the vaccine in mice described mRNA-1273 mRNA as being encapsulated in LNP “at a molar ratio of 50: 10: 38.5: 1.5 (ionizable lipid: DSPC: cholesterol: PEG-lipid). ”

The first claim of the confirmed Arbutus patent describes “a cationic lipid comprising from 50 mole% to 65 mole% of the total lipid present in the particle; “A non-cationic lipid comprising a mixture of phospholipid and cholesterol, wherein the” phospholipid comprises from 4 mole% to 10 mole% “and the cholesterol comprises” 30 mole% to 40 mole% “; and a conjugated lipid “comprising from 0.5 mole% to 2 mole%”.

In a statement to FORBES, Ray Jordan, general affairs director of Moderna, said the June pre-print described data generated using a preclinical research formulation of a SARS-CoV vaccine. 2 which is not the same as the vaccine itself.

“While the authors of the preprint used the term ‘mRNA-1273’ for the convenience of the reader, the preprint does not describe the cGMP process by which we make our messenger RNA and LNP or the final composition of the product. drug in our commercial candidate (mRNA -1273), ”Jordan wrote in a statement.

When asked if Moderna would provide the molar ratios at which mRNA-1273 encapsulates its LNP, Jordan replied, “No, we are not disclosing our proprietary ratios at this time.”

MORE FORBESFueled by $ 500 million in federal cash, Moderna races to make a billion doses of unproven cure

In another preclinical study testing Moderna’s vaccine in non-human primates, published in Le New England Journal of Medicine On Monday, the authors wrote that mRNA-1273 is encapsulated in LNP as described in a 2019 article, which stated that mRNA was encapsulated at the same molar ratios as in the mouse study.

The description of the phase 1 study of the Moderna coronavirus vaccine registered with the federal government shows that the LNP for mRNA-1273 is composed of an ionizable (cationic) lipid; cholesterol; DSPC (phospholipid) and PEG2000-DMG (conjugated anti-aggregation lipid). The percentages of the four components in the formulation of mRNA-1273 were not disclosed in the clinical trial registration or in the July publication of an interim review from the Phase 1 study of the MRNA-1273 in Le New England Journal of Medicine. The annex of the interim analysis sets out the information associated with LNP.

For years, Stephane Bancel, the billionaire CEO of Moderna, has said the company has overtaken the delivery technology owned by Arbutus. “We knew it wasn’t very good,” he told Forbes in 2016. “It was just good. He said Moderna is producing its own nanoparticle lipids, such as N1GEL, and authorizing another from Merck.

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. He added that Moderna was only using Arbutus technology initially and had stopped using it for new drugs in 2016.

When Moderna first started, Bancel turned to a small company called Acuitas for access to delivery technology for its mRNA vision. Acuitas was headquartered in Vancouver, British Columbia, home of Thomas Madden, who founded it in 2009. Madden had been involved in a lawsuit with Tekmira Pharmaceuticals, which had merged with a company for which Madden had worked and had. eliminated his post. Through litigation, Madden was granted a license for the LNP technology he had helped develop. Bancel decided to license the LNP technology from Acuitas and not from Tekmira, who later changed its name to Arbutus.

In 2016, Arbutus terminated Acuitas’ license for the LNP technology, which resulted in Acuitas suing Arbutus in a British Columbia court. Arbutus countered, claiming Acuitas did not have the right to sublicense LNP technology to Moderna. A British Columbia judge issued a temporary injunction in 2017 preventing Acuitas from sub-licensing further LNP technology.

A year later, in 2018, Arbutus struck a deal with Madden that terminated Acuitas’ license and stipulated that Moderna could only use the technology in four vaccines targeting viruses already identified.

The Arbutus patents have since been taken over by Genevant Sciences, a subsidiary of Roivant Sciences, the largest shareholder of Arbutus and managed by Vivek Ramaswamy. Arbutus retains a stake in Genevant and a right to part of the patent economy. Genevant declined to comment.

In the years following the Acuitas settlement, other candidate vaccines developed by Moderna were described in publications with LNP technology comprising the four components listed in the Arbutus patent with formulated percentages that appear to cross the patent. For example, the publication of a study of an HIV vaccine listed on Moderna’s website in July described mRNA as being encapsulated by LNP “at a molar ratio of 50: 10: 38.5: 1. , 5 (ionizable lipid: DSPC: cholesterol: PEG-lipid). ”

Moderna has challenged three of the Arbutus patents with the adjudicator of the US Patent and Trademark Office. One of his challenges was successful, another was partially successful, and the challenge against the third card was lost last week. There are three other relevant Arbutus patents that Moderna has not attempted to challenge.

Whatever happens on the intellectual property front, it is highly unlikely that a patent issue will hinder the development or distribution of a Covid-19 vaccine. But shareholders in Moderna’s hot stock were widely warned in a May securities filing the company instituted. inter-parties reexamination proceedings against issued US patents related to the granting of mRNAs and the unsuccessful invalidation of those patents could lead to the type of litigation that could result in significant damage.

Taxpayers may also have an interest in knowing the ownership of delivery technologies used by an mRNA vaccine supported by nearly $ 1 billion in federal government funding. Asked about the delivery technologies, a spokesperson for the Department of Health and Human Services, which hosts BARDA, said intellectual property is assessed for any company submitting a proposal to BARDA, as part of the assessment process. offers.

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