By Aaron Krol
February 24, 2016 | Illumina, the world’s leading producer of DNA sequencing instruments, has filed a lawsuit against Oxford Nanopore Technologies, alleging that Oxford’s MinION and PromethION sequencers infringe on patents licensed exclusively to Illumina. The dispute concerns a particular method of nanopore sequencing, in which a DNA molecule is guided through a barrier with pores so small that only a single nucleotide, or DNA letter, can squeeze past at a time. As the DNA travels through the pore, it disrupts an electrical charge that is passing across the barrier, and the exact changes to the current can be measured to decode the DNA sequence.
The MinION, which Oxford released in mid-2014, is the first and only nanopore sequencer on the market. Illumina’s instruments use a radically different approach called sequencing-by-synthesis, which has dominated genetics for roughly a decade. Steady advances in sequencing-by-synthesis have allowed Illumina to build the world’s largest and fastest DNA sequencers, culminating in the HiSeq X Ten system that can sequence as many as 18,000 whole human genomes a year. When the UK government decides to sequence 100,000 British genomes, or J. Craig Venter’s company Human Longevity, Inc., builds a facility scaling up to 100,000 genomes a year, it is Illumina technology that makes these projects possible.
Illumina also overwhelmingly controls the low end of the market, with its MiSeq and newly released MiniSeq machines that small labs can buy for as little as $50,000.
Nanopore sequencing, however, has profound advantages that are just beginning to reshape the practice of genetics. The MinION is literally handheld―just three inches long―and can be operated with a minimum of training and equipment. Users have successfully brought MinION sequencing to such extreme environments as mobile labs in Guinea in the middle of the 2014-15 Ebola epidemic. Nanopore data can also be analyzed in real time, making it possible to identify species of bacteria and viruses in the middle of a sequencing run. One recent preprint even showed that the MinION can selectively reject DNA molecules it has already started sequencing, which might let users, for instance, feed DNA from whole blood into the sequencer and reject any human reads as they search for the cause of an infection.
Most of all, nanopore sequencing is cheap. The $1,000 MinION is too quirky to directly compete with any part of the Illumina line―its output is dwarfed even by the tiny MiniSeq―but the same can’t be said of the forthcoming PromethION, which Oxford is already taking orders for. This machine, which will be not unlike a battery of 48 sextuple-sized MinIONs linked together, could become the new state-of-the-art for even the largest genomics projects, and is certain to be priced far below Illumina’s HiSeq series.
Illumina has plenty of competitors besides Oxford Nanopore. But while companies like Pacific Biosciences, Thermo Fisher, and QIAGEN all make machines that fill useful niches, they’re just nibbling at the edges of the genomics market. Oxford―despite lingering problems with accuracy, and a history of delivering spectacularly behind schedule―is the only firm that looks like it might be an existential threat.
Illumina’s Stake in Nanopores
No one thinks that Illumina invented the MinION or anything like it. But it is just possible that Illumina holds the rights to one key component of the instrument.
The basic idea behind nanopore sequencing has been floating around academia since the late 1980s. Scientists including David Deamer and Mark Akeson of the University of California, Santa Cruz, and George Church of Harvard, filed a series of patents related to nanopore sequencing as early as 1995. Oxford Nanopore, which licenses these patents, was formed a decade later, as early prototypes in university labs began to show progress in turning the idea into a workable instrument.
Illumina, too, has been working on nanopore sequencing for a long time. (To its credit, Illumina has never been a rent-seeker, repeatedly making huge technological advances even as its own older machines were the ones being made obsolete.) One of its earlier forays into nanopores was actually a partnership with Oxford, forged in 2009 and including an $18 million investment in the younger company, to market a form of nanopore sequencer that never materialized. The partnership turned sour when Oxford started focusing its energies on a technology not covered by the agreement, and the now-irrelevant terms will expire this June.
More recently, in 2013 Illumina licensed patents from Jens Gundlach of the University of Washington and Michael Niederweis of the University of Alabama, Birmingham, to pursue an in-house nanopore program. It is these patents that are now the object of Illumina’s lawsuit against Oxford.
Whether Illumina is narrowing in on its own nanopore sequencer is a mystery. The company did receive a 2014 grant from the National Human Genome Research Institute related to a nanopore project; this seems to be the most recent public evidence that the program is active. It is suggestive that Illumina has recently been touting a project called Firefly, completely unrelated to nanopores, that CEO Jay Flatley says will produce a miniaturized sequencer by late 2017.
But whatever Illumina is doing with its patent licenses, the company seems to think they are sufficient to throw a wrench in Oxford Nanopore’s progress. Both patents cover the use of a particular protein, Mycobacterium smegmatis porin A (MspA), as a nanopore, as well as mutated versions of this protein and bacteria engineered to produce it. Gundlach and Niederweis used MspA in a 2012 study that was, at the time, one of the best proofs-of-principle for nanopore sequencing ever demonstrated.
Illumina reserves the right to make nanopore sequencers in which DNA passes through MspA or its derivatives.
A Narrow Dispute
Does Oxford Nanopore even use MspA in its sequencers? Very few people are in a position to know; Oxford Nanopore does not disclose the makeup of its nanopores. The company was founded on the work of Hagan Bayley, a biochemist at the University of Oxford, whose published research has mostly concerned a different nanopore-forming protein, α-hemolysin. But many different proteins have been suggested as promising nanopore materials, and Oxford could easily have changed course during the MinION’s development.
Whatever protein was the original inspiration for its sequencers, the company’s biochemists will have radically altered it by now, mutating its sequence of amino acids to let DNA pass through the pore as stably as possible.
It would be interesting to know if Illumina has learned that the proteins inside a MinION flowcell are derivatives of MspA. If it has, this might explain why Illumina waited until now, more than a year and a half after the launch of the MinION, to file its lawsuit. Eric Endicott, Illumina’s Director of Global PR, told Bio-IT World only that “Illumina doesn’t comment on pending litigation.”
Even if Oxford does have MspA-based nanopores inside the MinION and PromethION, Illumina’s lawsuit is far from a slam dunk. Oxford holds or licenses a wide array of intellectual property―some from its co-founder Bayley, but also from Deamer, Akeson, Church, and many others. These patents cover the foundational concept of nanopore sequencing; the engineering of protein nanopores; and other aspects of the technology not at stake here, like the enzymes that help guide DNA through the system.
Several of these could be argued to anticipate the most general claims in the patents Illumina now licenses. For example, one of Bayley’s patents mentions MspA in passing as an example of a protein that would be suitable for nanopore analysis, although he does not follow up on this train of thought in future filings. That patent was filed in 2008, more than two years before the patents held by Gundlach and Niederweis. If claims like this one are held to invalidate Illumina’s broader patent on all MspA-based nanopore sequencers, the company will only hold the rights to certain specific derivatives of the protein.
There is also a wealth of prior art in the scientific literature that may complicate the dispute.
What is abundantly clear from looking through Oxford’s intellectual property is that nanopore sequencing took a truly distributed effort to get off the ground. Scientists from numerous universities in the US and the UK have played significant roles in bringing the world a working nanopore sequencer. So has the US government, through grants from the National Human Genome Research Institute and direct contributions from members of the National Institute of Standards and Technologies. What Oxford has done―and what Illumina will have done, if it ever invents a nanopore sequencer of its own―is run the last, steepest mile, to engineer an instrument reliable enough for use in the real world.
For his part, Oxford Nanopore CEO Gordon Sanghera, in a brief statement released today, said that Illumina’s lawsuit is without merit and will not affect his company’s commercial prospects.
“It is gratifying,” he said, “to have the commercial relevance of Oxford Nanopore products so publicly acknowledged by the market monopolist for [next generation sequencing].”
UPDATE 2/25/16: The text of Illumina’s lawsuit against Oxford Nanopore makes clear why Illumina has inferred that Oxford’s sequencers use MspA pores. Though the suit does not claim direct knowledge of Oxford’s technology, it does cite several pending patent applications in which Oxford more explicitly stakes out space in MspA development. It also cites emails between Oxford representatives, including Gordon Sanghera, and Jens Gundlach suggesting a collaboration on commercialization of an MspA-based nanopore sequencer. Hat tip to Antonio Regalado’s story in MIT Technology Review for the link to the suit.