Highlights
Moderna is suing Pfizer and BioNTech for patent infringement over a messenger RNA (mRNA) technology platform that served as the basis for vaccines against COVID-19 infection caused by the SARS-CoV-2 coronavirus.
Moderna believes that the mRNA vaccine Comirnaty (tosinameran; BNT162b2), developed and promoted by Pfizer and BioNTech, infringes the patented intellectual property that gave rise to its mRNA vaccine Spikevax (elasomeran; mRNA-1273). According to plaintiff, defendants copied the mRNA technology without permission, on the basis of which Moderna continues to develop drugs for the treatment and prevention of a host of diseases beyond COVID-19, including infectious, autoimmune, cardiovascular, and cancer.
Moderna understands the seriousness of the ongoing COVID-19 pandemic and is therefore not seeking to have Comirnaty removed from the market or a court injunction prohibiting its sale, nor is it seeking financial redress. This is true for 92 low- and middle-income countries.
In the case of high-income countries that have no problem accessing COVID-19 vaccines, Moderna is demanding that Pfizer and BioNTech purchase a commercial license for the mRNA inventions from it and pay fair compensation for the use of the patented technologies, beginning in March 2022.
Billions of dollars are at stake in the legal dispute. mRNA vaccines Spikevax and Comirnaty were first authorized for use in December 2020, but while the former earned $28.33 billion over the entire time, sales of the latter totaled $59.01 billion. The twofold difference is due equally to Pfizer’s strongest global market presence and loyalty to its branded products. Moderna had no commercialized products at all before the debut of Spikevax.
In the pharma industry, litigation is routine, occurring on a regular basis, and the debate between Moderna and Pfizer/BioNTech will follow the traditional path. There is never a breakthrough biotechnology that goes without a flurry of patent lawsuits; all the players in the market are tied together. An expensive legal dispute resolution is expected to take years due to the complexity of the issues at stake, minimizing the impact on the stock in the short term. Most likely, it will end with a settlement in the form of a modest royalty. Moreover, Moderna’s entry into the court arena means acknowledging the end of the pandemic.
Moderna’s possible victory in the Pfizer/BioNTech lawsuit would have far-reaching implications. After the recognition of the validity of mRNA technology, which before Spikevax and Comirnaty was even considered a kind of multi-billion dollar scam, many players in the pharmaceutical industry rushed into mRNA drugs and vaccines. All of them, when they go commercial, will have to deal with the vast patent pool accumulated by Moderna. In other words, Moderna will receive a steady stream of financial royalties.
Gist of Claims
Moderna accused Pfizer and BioNTech of misusing three inventions saying that the defendants did not have the kind of extensive mRNA expertise that would allow them to offer a ready-made vaccine so quickly.
First, Pfizer and BioNTech developed Comirnaty by supposedly copying the approach of Moderna and its Spikevax to mRNA coding exactly the full-length S protein of the coronavirus in order to maximize the degree of vaccine protection. Second, they used what appeared to be exactly the same chemical modification of the mRNA as in Spikevax to avoid provoking an unwanted immune response when the mRNA instructions were injected into the body. Third, the alleged infringers of the Moderna’s patents encapsulated the mRNA sequence in a similar formulation of lipid nanoparticles necessary to protect the mRNA instructions from degradation and their successful targeting delivery.
The lawsuit concerns the protection of Moderna’s intellectual property described in three patents 108,98,574, 10,702,600, and 10,933,127.
Antigen Sequence
Any antiviral vaccine involves the delivery of an antigen specific to a particular virus, in response to which the immune system begins to produce antibodies, thereby preparing the body for a possible viral attack.
Structurally, the Spikevax vaccine is a set of mRNA instructions encoding the coronavirus S (spike) protein, which is full-length and stabilized in the “before fusion” conformation. S protein, which, along with other proteins (E and M), forms the envelope of the coronavirus, is responsible for receptor-recognition functions necessary for virus attachment to the host cell and fusion with its membrane, which further leads to its penetration into the cell.
A few hours or days after the administration of Spikevax to humans, the cells begin to synthesize protein antigens. Their presentation to the immune system activates the production of antibodies and T cells as well as memory B and T cells, “charging” the body with the readiness for a possible viral attack. If infection with the SARS-CoV-2 coronavirus happens after vaccination, the immune system, even “without thinking,” will easily defeat it.
During experimental work on the Middle East respiratory syndrome coronavirus (MERS-CoV) vaccine, Moderna was convinced that mRNA instructions, which encode a full-length S protein rather than any of its individual parts, provide the maximum protective effect, manifested by the production of neutralizing antibodies.
Immunological Surveillance
The innate immune system protects the body against foreign RNAs, including viral RNAs, by inducing inflammation and suppressing mRNA translation as soon as the latter are detected. The body’s cells monitor their surroundings through a multitude of sensors, collectively called pattern recognition receptors (PRRs).
One of these are toll-like receptors (TLRs), transmembrane proteins whose family includes a dozen different representatives and which recognize molecules that are common and widely present in many pathogens. For example, TLRs can be activated in the presence of foreign double-stranded RNA (TLR3) or uridine-containing single-stranded RNA fragments (TLR7, TLR8).
Cells also have other PRRs located in the cytoplasm. Thus, retinoic acid-inducible gene-I-like receptors (RLRs) that are activated in the presence of viral RNA that has entered the cell. The RLR family includes retinoic acid-inducible gene I (RIG-I).
Moderna chemically modified the uridine nucleotides within the vaccine mRNA sequences to minimize the risks of recognition by the TLR3/7/8 and RIG-I receptors. This resulted in a clear inhibition of immunocyte activation, including B cells, a decrease in immunoglobulin secretion, and a decrease in cytokine expression. Importantly, the inclusion of modified uridine (1-methylpseudouridine) was not reflected in a significant change in the ability of ribosomes to read and translate synthetic mRNA instructions.
Liposomal Encapsulation
Things would be simpler if vaccine mRNA sequences could be injected directly into the body. But this is not the case. First, any extracellular mRNA would be immediately destroyed by enzymes. Secondly, cell membranes act as a significant obstacle for large negatively charged mRNA molecules to penetrate into cells.
For its mRNA sequences, Moderna developed a proprietary lipid nanoparticle (LNP) shell, which, mimicking natural low-density lipoproteins (LDLs), are rapidly taken up by endogenous cell transport proteins, delivered to the cells and, by undergoing endocytosis, get inside. Through the use of pH-sensitive components within the LNP shell, it is degraded, releasing mRNA instructions.
During mRNA drug preparation, the organic solvent containing lipids and the aqueous solution containing mRNA molecules are fed to the inlet of a special device, where they mix completely under laminar flow conditions. This causes the polarity of the solvent to change, which initiates self-assembly of LNPs loaded with mRNA molecules.
The liposomal disperse structure of LNP proposed by Moderna includes the proprietary ionized cationic lipid SM-102 and three commonly available lipids: the neutral lipid distearoylphosphatidylcholine (DSPC), cholesterol, a conjugate of high molecular weight polyethylene glycol 2000 (PEG2000) and dimyristoyl glycerol (DMG).
The composition differs from the traditional one, which involves a cationic lipid (amino lipid), a non-cationic lipid (phospholipid and cholesterol), and a conjugated lipid (polyethylene glycol in a link with some lipid). Each component performs its task: for example, cholesterol provides stability in vivo and during storage, phospholipid confers fusogenicity, and conjugated lipid inhibits particle aggregation.
Initially, Moderna looked to LNP formulations based on known lipid systems. But, as it turned out, such inherited formulations are characterized by a number of limitations, including reactogenicity (the ability to cause unwanted local inflammatory reactions), which negatively affects tolerability and therapeutic index.
In addition, there were questions about unwanted recognition by the immune system: When the mRNA drug was repeatedly injected, the nascent immune response resulted in rapid clearance from the bloodstream and increased inflammation. Again, the inherited LNP formulations did not always ensure proper protein expression.
They had to invent their own composition of LNPs, which made it possible to evade the immune response (reducing reactogenicity), accelerate biodegradation (for rapid clearance of lipid components from plasma and tissues to avoid liver damage), increase the number of mRNA modules entering one cell (protein production increased 6-fold).