A $325M Patent - 2 Color SBS

In this post I review the $325M settlement Illumina made with MGI over Illumina’s use of 2-Color SBS technology. I review the patents and some of the court documents involved in this case and after the paywall, ponder the ramifications of the settlement and how this might even work out in Illumina’s favor!

Originally Illumina sequencers used 4 different fluorphores or “colors”. That is one for each nucleotide: A, T, G and C. Illumina sequencing occurs “cyclically” reading each position in a template DNA strand one position at a time. So, if the first position incorporates an A, you will get emission in the A channel. Make sense?

To put it even more simply the DNA will light up in one of four colors depending on which of the four bases is present.

But, could you use fewer colors? Two for example? Take a second to think it over…

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If you answered “Yes” congratulations! You could have invented two color sequencing and would now be worth $325M! Unfortunately, you didn't… my commiserations.

For those who didn't figure it out. Essentially you use emissions covering multiple “colors” to encode the nucleotide type. T could light up green, C light up red, A light up green and red, G would just stay dark:

Illumina use this 2 color method in all their higher throughput sequencers (NextSeq’s NovaSeq’s). This lets them take just two images per cycle rather than four, speeding up the process significantly.

Unfortunately for Illumina, Complete Genomes filed a patent on two-color sequencing. Complete then sued Illumina, wining at a jury trial and finally settling for $325M.

There were two patents involved in the trial: US9222132B2 and US10662473B2. They are substantially similar, US9222132B2 being the early patent, the second adding a few more references to sequencing-by-synthesis.

The patents at a high level describe the use of 2 colors¹ for sequencing, mostly in a sequencing-by-ligation context (the original Complete Genomics approach). Based on my reading of these patents this is the claim which would cover 2-color SBS as used by Illumina:

There are only 9 claims (2 independent) the patent itself is relatively short and readable, so I recommend checking it out.

Usually when I go hunting through patents I’m generally trying to figure out what a company is actively working on. This often means looking to the “examples” showing experimental support for the approach. In this patent there are none. This is because it’s reasonably clear that the idea was… well just an idea and that experimental work had not been performed as Illumina noted:

“The lack of disclosure makes sense given the lack of SBS experience of the inventor, Dr. Radoje Drmanac. He testified that he had not performed SBS experiments or two color experiments at all until 2011, three years after the priority date. ... Dr. Drmanac did not even know if two-color would work with his own ligation technology, let alone SBS. ... When BGI finally decided to implement 2-channel SBS after Illumina released its own 2-channel products, BGI reverse engineered and copied every last detail of Illumina’s products and patent filings” - Illumina Post-Trial Brief in Support of Motions

2-Color sequencing also requires changes to the base calling process used. In particular correcting for phasing artifacts (multiple or non-incorporation) is complicated somewhat by 2 color chemistry. Issues around this are not discussed in the Complete patent as Illumina point out:

“There are no teachings regarding the complex bioinformatics, algorithms, or software necessary to make base calls in a two-channel SBS system…. As Dr. Mason explained, these algorithms are critical because two-channel SBS utilizes an unlabeled nucleotide that emits no signal. … When discussing their own development of two-channel SBS, BGI’s corporate representative acknowledged that base calling algorithms were a “major challenge[] if you’re trying to go from a four-color to a two-color system.” ... He also admitted that algorithms capable of making base calls using only two colors were not routine, even after Illumina introduced its two-color sequencers in 2014. … As Dr. Xu testified, it was not until 2015 that BGI had developed the complex algorithms they needed for two-color SBS, none of which are mentioned in the BGI patents…” - Illumina Post-Trial Brief in Support of Motions

Even so, it seems that Illumina failed to show “lack of enablement”. Not being a patent lawyer I wouldn’t want to comment in detail. But it suggests to me that how you would go about implementing the two-color system is pretty obvious once you’ve had the idea and does not require “undue experimentation”.

Illumina overall seem pretty irritated by the judgement. Statements by an Illumina spokesperson suggest that they had already worked on two-color sequencing prior to the BGI/Complete filings. Perhaps they were therefore a victim of the first-to-file system:

"Illumina invented its two-channel technology before the BGI patents, and BGI was unable to make two-channel chemistry work until it copied Illumina's technology," the Illumina spokesperson said. "The evidence also showed that BGI had copied numerous other components of Illumina's technology, including its imaging buffer used in Illumina's sequencing-by-synthesis technology and infringed Illumina's patents related to that technology." - via GenomeWeb

But this maybe isn’t all bad news for Illumina?