Illumina Sues Oxford Nanopore

In case you missed it, Illumina announced that it is Oxford Nanopore Technologies for violating Illumina’s two patents on nanopore sequencing in Oxford Nanopore’s MinION and PromethION devices.

Illumina press release says that

The lawsuits are based on U.S. Patent Nos. 8,673,550 and 9,170,230, which are entitled “MSP NANOPORES AND RELATED METHODS.”Illumina has exclusively licensed the patents in the field of nucleic acid sequencing from the UAB Research Foundation and the University of Washington. The lawsuits focus on ONT’s MinION and PromethION devices.

Illumina has made substantial investments to obtain licenses and develop the nanopore sequencing technology invented by researchers at the University of Alabama at Birmingham and University of Washington. Illumina filed the lawsuits to protect its investment and patent rights in this technology.

Swiftly, Oxford Nanopore shot back in a press release, where Dr Gordon Sanghera, CEO of Oxford Nanopore said

It is gratifying to have the commercial relevance of Oxford Nanopore products so publicly acknowledged by the market monopolist for NGS.

We do not anticipate any disruption to our ongoing commercial progress as a result of Illumina’s action, which we believe is without merit.

The two patents in question here is on the molecule Mycobacterium smegmatis Porin (MSP), that Oxford Nanopore could be using as the nanopore for sequencing. M. smegmatis Porin is a beautiful protein made of beta sheets.

Mspa

The two patents  named “MSP nanopores and related methods”, were filed by  from UW Washington and Univ. Alabama Birmingham.

Oxford Nanopore has never mentioned what types of nanopores is used in MinION and PromethION devices. However, early on, the founders of Oxford Nanopore has mainly used alpha Hemolysin as a pore for sequencing. One of their early demonstrations of Nanopore DNA sequencing in 2009 used alpha Hemolysin mutant form.

  • Continuous base identification for single-molecule nanopore DNA sequencingNature Nanotechnology DOI: 10.1038/nnano.2009.12, James Clarke, Hai-Chen Wu, Lakmal Jayasinghe, Alpesh Patel, Stuart Reid, Hagan Bayley (2009)
Mutant Alpha-hemolysin as Nanopore

Mutant Alpha-hemolysin as Nanopore

Oxford Nanopore also seems to have patents on other types of pores including graphene based solid-state nanopores and mutant Mspa.  One of the Oxford Nanopore’s patents, titled “Mutant pores“, is all about mutant forms of Mspa. The patent seems to indicate that Hemolysin pores show high variance in observed current.

While the current range for nucleotide discrimination has been improved through mutation of the hemolysin pore, a sequencing system would have higher performance if the current differences between nucleotides could be improved further. In addition, it has been observed that when the nucleic acids are moved through a pore, some current states show high variance. It has also been shown that some mutant hemolysin pores exhibit higher variance than others. While the variance of these states may contain sequence specific information, it is desirable to produce pores that have low variance to simplify the system. It is also desirable to reduce the number of nucleotides that contribute to the observed current.

The patent goes to claim that multiple mutations on Msp porins seem to “strikingly” improve nucleotide discrimination, low variance, and high signal-to-noise ratio.

The inventors have surprisingly demonstrated that novel mutants of Msp display improved properties for estimating the characteristics, such as the sequence of nucleic acids. The mutants surprisingly display improved nucleotide discrimination. In particular, the mutants surprisingly display an increased current range, which makes it easier to discriminate between different nucleotides, and a reduced variance of states, which increases the signal-to-noise ratio. In addition, the number of nucleotides contributing to the current as the nucleic acid moves through the pore is decreased. This makes it easier to identify a direct relationship between the observed current as the nucleic acid moves through the pore and the nucleic acid sequence.  The inventors have also surprisingly shown that Msp shows improved sequencing properties when the movement of the nucleic acid through the pore is controlled by a Phi29 DNA polymerase.

It is interesting see that the 2012 Nature Biotechnology paper using MSP pore for sequencing by Manrao et al from Jens H Gundlach group acknowledges M. Akeson and G.M. Cherf for their help with phi29 DNA-polymerase.

We thank M. Akeson and G.M. Cherf for getting us started with the blocking oligomer phi29 DNAP technique, sharing their CAT DNA and reading the manuscript.

The same Nature Biotechnology issue also has the paper from M. Akeson group demonstrating sequencing with  alpha-Hemolysin pore and around the same time Oxford Nanopore made the big announcement on their products at AGBT.

It is really sad to see such a lawsuit, especially the idea of nanopore sequencing has been around for a while and just when Oxford Nanopore seems to gain a lot of traction in the last few year. Here are links to some other interesting blog posts on the lawsuit and comments on Twitter.

  1. Mick Watson: Shots fired – nanopore wars part II
  2. BioIT World: Illumina Sues Oxford Nanopore Technologies Over Composition of Nanopores

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