Genomics is messy. Honestly, if you’ve ever looked at the raw data coming off a sequencer, it’s a miracle we can make sense of it at all. For years, the industry was dominated by "sequencing by synthesis"—basically taking pictures of glowing nucleotides. But Oxford Nanopore Technologies (ONT) decided to do something weirder. They wanted to pull a strand of DNA through a tiny hole and measure the electrical current. It sounds like science fiction. It’s also the reason why the Oxford Nanopore MspA patent US filings became a high-stakes battlefield in the biotech world.
Think about it.
If you control the hole, you control the data. In the world of nanopore sequencing, the "hole" is a protein pore. While ONT started with a pore called alpha-hemolysin ($\alpha$HL), they eventually ran into a wall. The resolution just wasn't sharp enough. They needed something tighter, something more accurate. That’s where Mycobacterium smegmatis porin A, or MspA, entered the frame. It changed everything. But it also sparked a massive legal headache regarding who actually owns the right to use this specific biological door for reading genetic code.
The Problem With Alpha-Hemolysin
Early nanopore attempts were... frustrating. Alpha-hemolysin is a mushroom-shaped protein. It’s great for sticking into membranes, but the "sensing zone"—the part of the pore that actually reads the DNA—is long. Because it’s so long, multiple nucleotides (the A, T, C, and Gs) are inside the sensing zone at the same time.
It’s like trying to read a book through a straw, but you can see five words at once and they’re all blurry.
You can try to use complex algorithms to guess which nucleotide is causing which electrical dip, but your error rate is going to be garbage. Oxford Nanopore knew this. They needed a shorter sensing zone. They needed a pore that looked more like a funnel and less like a long pipe.
Enter MspA: The Game Changer
MspA is a different beast entirely. It’s a porin from a bacterium, and its geometry is almost perfect for sequencing. The "constriction" point—the narrowest part of the pore—is remarkably short. This means that when a DNA strand zips through, the electrical signal is dominated by just one or two nucleotides at a time.
Suddenly, the signal gets crisp. The noise drops.
Researchers at the University of Washington, led by Jens Gundlach, were the ones who really cracked the code on using MspA for sequencing. They realized that the natural version of MspA wouldn’t work because the inside of the pore was too negatively charged. DNA is also negative. Since like charges repel, the DNA basically refused to go into the hole. It’s like trying to push the wrong ends of two magnets together.
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The UW team, alongside collaborators like Mark Akeson at UC Santa Cruz, engineered a mutant version of MspA. They swapped out the negative amino acids for neutral or positive ones. This allowed the DNA to be pulled through by an electric field with incredible precision. This breakthrough is what underpins much of the Oxford Nanopore MspA patent US landscape. When you look at patents like US Patent 8,673,550 or US Patent 9,121,836, you’re looking at the legal boundaries of this specific biological engineering.
The Legal Tug-of-War
It wasn't just a "eureka" moment in a lab; it was a land grab.
Oxford Nanopore didn't actually invent MspA sequencing in-house from scratch. They licensed the technology. Specifically, they secured exclusive rights to the work coming out of the University of Washington and other institutions. This is standard practice in biotech, but it creates a massive "moat." If you are a competitor—let's say Illumina or a startup like Stratos Genomics (which Illumina eventually bought)—and you want to use a pore that actually works, you're stuck.
MspA is so much better than almost any other natural pore that it became a bottleneck for the entire industry.
The patent disputes often center on "method of use." It’s one thing to discover a protein in a lab; it’s another to patent the specific process of pulling a polymer through that protein to identify its components. The Oxford Nanopore MspA patent US portfolio covers everything from the specific mutations of the pore to the buffers used and the way the electrical signal is processed.
Some critics argue these patents are too broad. They say it’s like patenting the idea of using a magnifying glass to read small text. But in the eyes of the USPTO, the specific engineering required to make MspA "sequencing-ready" is highly non-obvious.
Why This Matters for Your Health
You might wonder why anyone outside of a lab should care about patent litigation.
It's about speed.
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Because of the MspA pore (and its subsequent iterations like the R9 and R10 series, which are evolved from similar principles), we can now sequence an entire human genome on a device the size of a Snickers bar. This is the MinION. During the COVID-19 pandemic, these MspA-derived pores were on the front lines. Scientists in remote areas could sequence viral variants in real-time without needing a multi-million dollar lab.
If the patent landscape had been different—if the technology had been locked away or if the licensing fees were too high—that decentralized sequencing revolution might never have happened.
The R10 Evolution
While the original MspA was a massive leap, ONT didn't stop there. The current "gold standard" for Oxford Nanopore is the R10.4.1 pore. Now, ONT is somewhat secretive about the exact lineage of every pore they release, but the industry consensus is that R10 is a heavily "directed evolution" version of a porin similar to MspA (specifically CsgG, another bacterial porin).
The goal remains the same:
- Make the constriction point narrower.
- Make the sensing zone dual-headed so you get two reads of the same base.
- Reduce the speed of the DNA translocating through the pore.
The MspA patents laid the groundwork for how these later pores are protected. Even if the pore itself changes, the methods described in those early US patents often still apply.
Misconceptions About the Patent
People often think a patent means "we invented this protein."
That’s wrong.
Mycobacterium smegmatis invented the protein millions of years ago. The patent covers the modified version of the protein and its application in a sequencing system. You can go find MspA in nature all you want, but the moment you try to use a modified version of it to identify DNA bases for commercial gain in the US, you’re going to get a cease-and-desist letter faster than a MinION can sequence a plasmid.
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Another common myth is that these patents expire and then "anyone can do it." While patents do expire (usually after 20 years), ONT has a "patent thicket." By the time the original MspA patent expires, they have twenty new patents covering the motor protein that slows the DNA down, the membrane it sits in, and the AI-based basecaller that interprets the wiggle of the current.
It’s a moving target.
What Happens Next?
The focus is shifting away from just "the hole" and toward "the prep."
We're seeing new filings that look less at the pore and more at how we can use MspA to sequence proteins (proteomics). DNA is easy because it has a uniform charge. Proteins are a nightmare. They have different charges, shapes, and sizes. Using the MspA pore to identify individual amino acids is the next great frontier.
If ONT—or a competitor—can successfully patent a reliable way to do protein sequencing through a nanopore, the market for the Oxford Nanopore MspA patent US will look tiny by comparison. We're talking about a fundamental shift in how we diagnose diseases like Alzheimer's or cancer.
Actionable Insights for Researchers and Investors
If you are navigating this space, don't just look at the primary patent numbers. Here is what you actually need to do to understand the landscape:
- Check the "Assignee" History: Often, patents are filed by universities (like UW or Harvard) and licensed to ONT. The terms of these licenses are where the real power lies. Look for "Exclusive License" agreements in SEC filings.
- Monitor the R10 vs. MspA Distinction: If you are developing third-party tools, ensure you know which pore version your software is optimized for. The signal profile of an MspA-derived pore is fundamentally different from the older $\alpha$HL pores.
- Watch the Unified Patent Court (UPC): While we're talking about US patents, the global strategy of ONT is what drives their valuation. Legal wins or losses in Europe regarding pore structure often predict how they will settle or fight in the US.
- Focus on the Motor Protein: The pore is only half the story. The patents on the helicases (the motors) that "ratchet" the DNA through the pore are just as critical for accuracy. Without the motor, the DNA flies through the MspA pore too fast to be read.
- Analyze the "Sensing Zone" Geometry: If you are a protein engineer, the patent claims specifically around the "constriction site" dimensions are the ones that are hardest to design around.
The MspA story is a reminder that in biotechnology, biology is the hardware, but the patent is the deed to the house. You can have the best technology in the world, but if you don't own the "door" through which the data flows, you're just a guest. Oxford Nanopore has spent a decade making sure they aren't just guests—they're the landlords of the nanopore world.