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Oxford Nanopore's Silence Stirs Noise at AGBT; Technical Issues, Arbitration May Be Behind Reticence

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This article, originally published Feb. 25, has been updated to clarify the content of a letter from ONT.

As sequencing technology providers showcased their latest developments at the Advances in Genome Biology and Technology meeting in Marco Island, Fla., last week, Oxford Nanopore Technologies stood out by virtue of its silence.

A year ago, the UK-based firm created a stir at the very same venue with its announcement of two nanopore strand sequencing systems – called GridIon and MinIon – that promised to deliver very long reads with high speed and accuracy. At the time, the company said it planned to "commercialize GridIon and MinIon directly to customers within 2012" (IS 2/17/2012).

ONT further told In Sequence at last year's meeting that it was planning to announce early-access customers "in the near future" and that it anticipated them to start reporting on their experience with the two systems in the fall of 2012.

Last November at the American Society of Human Genetics meeting in San Francisco, the company displayed the two instruments publicly but did not reveal any data or early collaborators (GenomeWeb Daily Scan 11/8/2012).

Then, at AGBT last week, Oxford Nanopore fell silent. While ONT representatives were busy meeting with a steady stream of invited guests in a conference hotel suite, the firm did not provide an update on the status of its technology through public presentations. The company is "taking the opportunity to have a number of confidential early-access collaborator meetings," said CEO Gordon Sanghera in a statement provided to In Sequence. "We thank the life science research community for their ongoing support during this commercially sensitive period as well as their continued interest in our highly disruptive platform."

Meanwhile, in the conference hallways, talk about the company and the possible reasons for its lack of public communication was rampant. The noise was heightened by the high expectations Oxford had set a year ago: In a talk delivered at last year's meeting, chief technology officer Clive Brown said that, when launched, both the GridIon and the MinIon would deliver read lengths of up to 100 kilobases and a raw read error rate of about 1 percent, producing data at a rate between 20 and 400 bases per second and nanopore. A stack of 20 GridIon instruments would be able to sequence a human genome at 15-fold coverage within 15 minutes at a cost of less than $10 per gigabase. Company researchers had already sequenced DNA fragments as long as 50 kilobases and achieved raw read errors as low as 4 percent, Brown reported at the time.

No other industry player has promised read lengths of the same order along with near-term commercialization plans, so interest in ONT's platform remains high. "There is still a great need for that kind of technology," said Dick McCombie, a professor at Cold Spring Harbor Laboratory who heads the institute's DNA Sequencing Shared Resource.

Researchers are increasingly realizing the value of long reads, for example to solve structural variants and repeat sequences, as evidenced by the interest in Illumina's new Moleculo technology and PacBio's increased read lengths. "Whoever can ultimately deliver these cost-effectively is going to be very successful," McCombie said.

While it is unclear whether ONT has provided data or instruments to early-access collaborators at this point, the usual suspects – large genome centers that tend to be first in line to gain access to new sequencing technologies, and frequently help to refine them – do not appear to be among them.

Leading scientists from the Broad Institute, the Genome Institute at Washington University, and the Human Genome Sequencing Center at Baylor College of Medicine told In Sequence last week that they had not seen sequence data or received instruments from ONT and did not know anyone else who had. Two other sequencing centers who requested anonymity also said they do not have instruments from Oxford Nanopore.

The company declined to provide an update on its commercialization timeline, or to comment on why that timeline has slipped. Conference attendees suggested either technical problems or issues related to ongoing arbitration with Oxford's commercialization partner and equity stakeholder, Illumina, as possible reasons for the delay.

"Technical issues are always a factor in technology development," said Chad Nusbaum, co-director of the genome sequencing and analysis program at the Broad Institute, pointing out that other sequencing technology companies made bold promises in the past that they could not deliver in time due to technical obstacles.

In order to commercialize its system, ONT has to solve a number of "very difficult problems" in the areas of physics, chemistry, signal detection, and signal-to-noise ratio, said Elaine Mardis, co-director of the Genome Institute at Washington University. "They were overly optimistic with their timeline," she said, adding that Oxford Nanopore is "not the only company that can be accused of this."

Another reason why ONT might have decided to stay mum for now is its arbitration with Illumina.

ONT and Illumina signed a worldwide commercialization agreement with Illumina in 2009, under which Illumina will exclusively market, sell, distribute, and service exonuclease sequencing products developed by Oxford Nanopore, both in research and diagnostic markets. As part of the agreement, Illumina made an $18 million equity investment in ONT to accelerate the development of exonuclease sequencing, and promised to make additional investments based on technical milestones.

Oxford Nanopore had said in the past that developing exonuclease sequencing was a near-term goal, followed by strand sequencing later on (IS 2/27/2007), but was developing the two approaches in parallel. Later on, ONT reversed course, saying in early 2012 that it would commercialize strand sequencing first, independently from Illumina (IS 2/7/2012).

Exonuclease sequencing, formerly branded by ONT as its BASE technology, uses a processive exonuclease to cleave individual bases from a strand of DNA and feed them into a protein nanopore. Strand sequencing, on the other hand, measures signals from intact DNA traveling through a pore.

According to ONT's annual report for 2011, which came out last September, "a dispute arose between Illumina and Oxford Nanopore concerning the terms of the commercialization agreement" in 2011, resulting in Illumina filing an arbitration demand in the state of New York.

Details of the arbitration, which has several phases, are confidential, but the process is not completed yet, Illumina CEO Jay Flatley told In Sequence last week. He added that there is "nothing specific to the arbitration that prevents [ONT] from talking about their technology," or from commercializing it, as long as it is not covered by the agreement with Illumina.

However, several conference attendees suggested that while the arbitration is ongoing, any public statement by ONT could be exploited by Illumina for its own case, so it is likely in Oxford Nanopore's best interest to remain quiet.

Also, while officially still a partner of ONT, Illumina is transitioning into a rival, following its recent announcement that it has been investing in nanopore sequencing development on its own (IS 1/29/2012), another reason for ONT to keep details about its technology under wraps.

Whatever the reasons for Oxford Nanopore's silence, many potential customers at the conference felt disappointed about the lack of visibility on when the technology might finally come to market.

"I'm a bit disenchanted," said Vladimir Benes, head of the genomics core facility at the European Molecular Biology Laboratory in Heidelberg. Last spring, his laboratory sent DNA samples to ONT for sequencing but did not receive any data. Then in the summer, ONT asked EMBL in a letter for a "commitment fee," he said, which would be tied to certain milestones of the project, but the lab declined. However, Benes said he is hopeful the collaboration will be revived in the future.

George Grills, director of operations of core facilities at the Cornell University Life Sciences Core Laboratories Center, said he is not surprised that Oxford Nanopore's commercialization timeline has slipped, "but there is a basic need to have data in the public realm, which is fairly essential for having confidence that the technology is developing in the right direction."

But a number of potential early-access customers remain optimistic about the technology's future. "They seem happy," said the Broad's Nusbaum, referring to his interactions with Oxford Nanopore's team, without elaborating.

Likewise, WashU's Mardis indicated that the question is not 'if' but 'when' the technology will become available. "When it comes along, it will be great, and everyone will conveniently forget about how long it took," she said.

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