DNA sequencing by synthesis patents held valid and infringed

On 17 December 2021, the Court of Appeal, with the leading judgment given by Lord Justice Arnold, handed down its decision in the appeal of the High Court’s earlier decision in Illumina v MGI[1], dismissing MGI’s appeal in its entirety and holding four of Illumina’s patents in the field of DNA sequencing valid[2].


First published in our Biotech Review of the Year publication (Issue 10).

The action had begun with Illumina’s claim for patent infringement against MGI in relation to four of MGI’s high throughput DNA sequencing systems including StandardMPS, CoolMPS and DNBSEQ E.


The validity of four patents were in issue on appeal. There was no dispute as to infringement if the patents were valid. The patents can be conveniently split into two groups based on the technology claimed. The first group consisted of three patents, EP (UK) 1 530 578, EP (UK) 3 002 289 and EP (UK) 3 587 433, entitled either ‘Modified Nucleotides for Polynucleotide Sequencing’ or ‘Modified Nucleotides’ (Modified Nucleotide Patents), which claimed a technique for using a chemical group as a reverse chain terminator during DNA sequencing by synthesis.

Sequencing by synthesis is a high throughput DNA sequencing method that was designed to overcome the limitations of the well-known Sanger DNA sequencing method. Sanger DNA sequencing had been developed in the 1970s and formed the basis of DNA sequencing in the subsequent decades. The Modified Nucleotide Patents had arisen out of research into a form of DNA sequencing by synthesis using reversible chain terminators (RCTs). In Sanger DNA sequencing, the DNA template strand undergoing sequencing is presented with a mixture of the four nucleotides and one type of dideoxynucleotide (wherein the 3’ hydroxyl group has been removed). The template DNA is synthesised by DNA polymerase up until the point at which a dideoxynucleotide is incorporated into the complementary strand, which due to the lack of the 3’ hydroxyl group terminates synthesis. The output of Sanger DNA sequencing is thus a large number of DNA fragments of varying lengths. The DNA sequence is then determined using methods such as capillary gel electrophoresis. Sequencing by synthesis using RCTs differs in that the 3’ hydroxyl group of each nucleotide is reversibly blocked. This means that following incorporation of a nucleotide the synthesis of the complementary strand is temporarily blocked, the nucleotide that has just been incorporated (which is also tagged with a fluorescent label) on the complementary strand is detected and identified, unblocked and then the synthesis process can continue with each new nucleotide being identified in the same way. The Modified Nucleotide Patents claimed aspects of sequencing by synthesis using RCTs, in particular, modified nucleotides with a 3’-azidomethyl group.

The second group consisted of a sole patent, EP (UK) 2 021 415 (EP 415), that claimed a class of compounds including dyes and labelled compounds for use in the base detection stage of DNA sequencing by synthesis. Specifically, the claim in issue was to a nucleotide labelled with a compound formed of a cleavable linker and a fluorescent dye.

The four patents had been found valid and infringed at first instance. On appeal, the issues in dispute were: i) were the Modified Nucleotide Patents obvious over prior art named Zavgorodny; ii) were the Modified Nucleotide Patents entitled to the claimed priority as if not, it was agreed they would be obvious; and iii) was EP 415 obvious as a collocation of non-inventive features?

Obviousness of the Modified Nucleotide Patents

In addressing i), Arnold LJ held that the Modified Nucleotide Patents were not obvious over Zavgorodny. In particular, Arnold LJ held that the first instance judge was correct in deciding that the skilled team working on sequencing by synthesis would not approach Zavgorodny with a particular aim in mind. Although the skilled team would be aware of the concept of reversible chain termination at the priority date they would not approach Zavgorodny with the knowledge that there were problems with existing blocking groups that had prevented reversible chain termination from being successfully implemented. Therefore, the skilled team would not be interested in taking forward a new blocking group over existing ones. Zavgorodny also concerned synthetic chemistry and the use of nucleosides rather than nucleotides and was therefore in a different technical field from sequencing by synthesis. The skilled team would also not consider an azidomethyl blocking group as disclosed in Zavgorodny to be of greater interest than other blocking groups for use in sequencing by synthesis. A reference in Zavgorodny that azidomethyl groups could be removed ‘‘under very specific and mild conditions’’ had to be taken in context of the skilled team’s mindset in approaching the prior art and would therefore not be a basis for further action. Finally, even if the skilled team considered azidomethyl as the blocking group they would have no reasonable expectation of success that it would be incorporated into the complementary strand of DNA and that it could then be removed to obtain a reasonable yield and at a reasonable speed.

Entitlement to priority of the Modified Nucleotide Patents

As for issue ii) on priority, Arnold LJ held that there was no squeeze between the priority attack and obviousness attack. MGI had alleged that if the Modified Nucleotide Patents were not obvious over Zavgorodny then they were not entitled to claim priority from the priority application. The allegation being that the priority application would have left the skilled team no better informed than Zavgorodny. Arnold LJ disagreed with MGI, holding that the priority application was an advance on Zavgorodny largely because Zavgorodny contained no indication that an azidomethyl blocking group should be used in sequencing by synthesis. The priority application made such a proposal, stating that nucleotides containing the group had been reversibly incorporated into the DNA complementary strand and also provided experimental conditions for the reversal step.

Arnold LJ also considered whether the priority application made it plausible that the claimed nucleotides in the Modified Nucleotide Patents had the claimed utility and therefore whether the Modified Nucleotide Patents were entitled to priority on that basis. Although MGI had not clearly run an implausibility argument, Arnold LJ agreed with the first instance judge that on the “unchallenged evidence” the priority document did make it plausible that the claimed compounds would work. The unchallenged evidence in issue was an example in the priority application showing one cycle of reversible chain blocking. The example made it plausible that an azidomethyl group would work and the Modified Nucleotide Patents just provided further support.

MGI’s appeal in relation to the Modified Nucleotide Patents was therefore dismissed. Additionally, although Illumina’s main case on priority was that the first instance judge’s findings were correct, in the alternative it put forward an argument that plausibility was not required for priority as a matter of law. Although Arnold LJ did not need to decide this point, he noted that Illumina had not filed a respondent’s notice raising its alternative argument and that it should have done so. The reason being that Civil Procedure Rule 52.13(2)(b) requires a respondent to file a respondent’s notice if they wish to ask the appeal court to uphold the lower court for reasons different from or additional to those given by the lower court. Although on the facts of the case Arnold LJ said he would have given permission for a respondent’s notice to be filed in any event, and ultimately the point did not need deciding, it had the potential to be a costly oversight.

EP 415 a collocation of non-inventive features?

On issue iii) on EP 415, Arnold LJ held that the class of compounds claimed in EP 415 were not a mere collocation of obvious features. MGI had alleged that the two elements of claim 1, the claimed linker and claimed dye, were two known obvious features that together achieved no synergistic effect or interacted in a non-obvious way. Although each of the features taken alone were obvious, EP 415 claimed a single invention (the whole compound) that made a technical contribution to the art that the prior art did not. Arnold LJ agreed with the findings of the first instance judge that a nucleotide with the claimed linker could interact adversely with the claimed dye and that the skilled team could not know whether this would occur without testing. EP 415 demonstrated that there was no adverse reaction and that the claimed compounds were useful for sequencing by synthesis. Showing that there was no adverse reaction was enough to render EP 415 inventive and therefore valid.

Nugee LJ and Warby LJ agreed with Arnold LJ’s findings.


[1] [2021] EWHC 57 (Pat)

[2] [2021] EWCA Civ 1924