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You are here: BAILII >> Databases >> England and Wales High Court (Patents Court) Decisions >> Illumina Cambridge Ltd v Latvia MGI Tech SIA & Ors [2021] EWHC 57 (Pat) (20 January 2021) URL: http://www.bailii.org/ew/cases/EWHC/Patents/2021/57.html Cite as: [2021] RPC 12, [2021] EWHC 57 (Pat) |
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Neutral Citation Number: [2021] EWHC 57 (Pat)
Case No: HP-2019-000052
IN THE HIGH COURT OF JUSTICE
BUSINESS AND PROPERTY COURTS OF ENGLAND AND WALES
INTELLECTUAL PROPERTY LIST (ChD)
PATENTS COURT
Royal Courts of Justice
The Rolls Building
7 Rolls Buildings
Fetter Lane
London EC4A 1NL
Date: 20/01/2021
Before:
THE HON. MR JUSTICE BIRSS
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Between :
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ILLUMINA CAMBRIDGE LIMITED |
Claimant |
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(1) LATVIA MGI TECH SIA (2) MGI TECH CO., LTD (3) MGI INTERNATIONAL SALES CO., LTD (4) MGI TECH HONG KONG CO., LTD (formerly BGI COMPLETE GENOMICS HONG KONG CO., LTD)
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Defendants |
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Iain Purvis QC, Piers Acland QC and Kathryn Pickard (instructed by Powell Gilbert LLP) for the Claimant
Thomas Mitcheson QC, Thomas Hinchliffe QC, Miles Copeland, Isabel Jamal and Alice Hart (instructed by Allen & Overy LLP) for the Defendants
Hearing dates: 9th - 13th, 16th-20th, 25th, 26th November and 9th December 2020
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Approved Judgment
Covid 19 Protocol: This judgment is to be handed down remotely by circulation to the parties’ representatives by email and release to Bailii. The date for handing down is deemed to be 20th January 2021
.............................
THE HON. MR JUSTICE BIRSS
Birss J:
Topic |
Paragraph |
Introduction and the issues | |
The witnesses | |
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The modified nucleotide patents 578, 289 and 433 | |
The skilled person | |
The common general knowledge | |
The specifications of the modified nucleotide patents | |
Claim construction | |
Obviousness | |
Priority | |
Insufficiency | |
Added matter - amendment | |
Infringement | |
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The 412 patent - ascorbate | |
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The 415 patent - labelled nucleotide | |
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Conclusions | |
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Annexes: |
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Lists of issues provided at closing: |
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Illumina MNP Issues |
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MGI MNP Issues |
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MGI FP Issues (412 and 415) (no list from Illumina) |
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Introduction
1. This is a patent action about DNA sequencing technology. The patentee (Illumina) holds patents which derive from work by Solexa, a spin out company from Cambridge University which Illumina bought in 2007. The defendants (MGI) are all companies in the Beijing Genomics Institute group. MGI seeks to sell DNA sequencing systems in the UK. Illumina contends that these systems infringe various of its patents. In general, MGI denies infringement of any valid claim and contends the patents are invalid. Following a launch last year, MGI gave undertakings limiting UK sales until this trial.
2. It is convenient to take three Illumina patents together. They are EP (UK) No. 1 530 578, EP (UK) No. 3 002 289 and EP (UK) No. 3 587 433. These three patents are divisionals. The first two are entitled “Modified Nucleotides for Polynucleotide Sequencing” and 433 is entitled “Modified Nucleotides”. They based on an application filed on 22nd August 2003. Although the earliest claimed priority is a US filing on 23rd August 2002, in this case Illumina relied on the second priority document with a priority date of 23rd December 2002. The three patents were granted on 13th March 2013, 22nd February 2018 and 22nd April 2020 respectively. The 578 patent was opposed at the EPO but those proceedings ended with the patent upheld as granted. Opposition proceedings relating to the 289 continue and the opposition period for 433 has not yet ended. These patents all relate to an azidomethyl group as a reversible chain terminator in sequencing by synthesis.
The modified nucleotide patents - issues
5. In terms of validity, MGI pleaded that the modified nucleotide patents are obvious over four pieces of prior art:
i) International patent application WO 91/06678 (Tsien) filed by SRI International and published on 16th May 1991;
ii) International patent application WO 02/29003 (Ju) filed by a group at Columbia University and published on 11th April 2002;
iii) A paper entitled “1-Alkythioalkylation of Nucleoside Hydroxyl Functions and Its Synthetic Applications: A New Versatile Method in Nucleoside Chemistry”, Zavgorodny et al., Tetrahedron Letters (1991) Vol. 32, No. 51, pp 7593-7596; and
iv) A paper entitled “S,X-acetals in nucleoside chemistry. III1. Synthesis of 2’- and 3’-O-azidomethyl derivatives of ribonucleosides”, Zavgordony et al., Nucleosides, Nucleotides and Nucleic Acids (2000) Vol. 19, Issue 10-12, pp1977-1991.
6. The written evidence covered all four citations, however shortly before trial MGI abandoned its case on Tsien and on Ju. By closing it became clear that there was no need to dwell on Zavgorodny 2000. MGI’s case can be made over Zavgorodny 1991 and if that does not succeed then the case over Zavgorodny 2000 would not succeed either.
8. Another validity question is whether particular claims of 578 and 433 are obvious for lack of technical contribution and/or insufficient. The issue is the same for both claims. Illumina advances an amendment which (it is not disputed) would cure that invalidity but does not agree those unamended claims are invalid and so the point falls to be decided. The relevant claims are 12 (as granted) of 578 (now claim 7 of claim set A) and claim 6 of 433 (as granted and in claim set C).
9. There were two added matter objections to the claim amendments. The one which remains live relates to claim 9 of 289 (claim set B). The one which was dropped was a challenge to claim 1 of 578 (claim set A). MGI dropped it after Illumina changed the amendments it was seeking to 578 by deleting granted claim 8. Both added matter issues are referred to at Illumina MNP Issue 6 but as explained only one is live.
10. Finally there is an insufficiency squeeze in relation to a number of the relevant claims of the modified nucleotide patents such that, if they are not obvious, they are insufficient, in part having regard to the recent Supreme Court decision in Regeneron v Kymab [2020] UKSC 27.
11. In terms of infringement, MGI has various systems alleged to infringe. One system is called StandardMPS and the other is called CoolMPS. Both use the azidomethyl group on the deoxyribose as a reversible chain terminator. In StandardMPS the four nucleobases carry a different fluorescent dye molecule covalently linked to the base via a linker. In CoolMPS the nucleobase is not covalently linked to a dye, rather detection uses four different antibody molecules, each linked to a different dye and each of which binds to a different nucleobase and the azidomethyl group. There are various detailed infringement issues, including allegations based on the doctrine of equivalents.
12. MGI also has two further azidomethyl based systems. They are the “two colour variant” and something called DNBSEQ E. In the two colour variant instead of four different dyes linked to the four nucleotides as in Standard MPS, only two dyes are used and detection occurs in two colours. Just as two binary bits can encode four numbers, so two dyes can distinguish four nucleotides by putting one dye on one nucleotide, the other dye on another nucleotide, both dyes on a third nucleotide, and no dye on the fourth nucleotide.
14. All four of StandardMPS, CoolMPS, the two colour variant and the DNBSEQ E are alleged to infringe some claims of the modified nucleotide patents. Some of those points are admitted and others are not. The very useful lists of issues provided in closing naturally only list the points which are in dispute, but to get a full picture one needs to see the admitted aspects as well. A useful summary of the whole position was provided by Illumina. I have adjusted the claim numbers in it. In summary the position is:
StandardMPS, the two colour variant and the DNBSEQ E variant
i) Claims 1, 7, 12, 20 and 24 of the 578 patent (claim set A) are alleged to be infringed by all three systems. MGI does not admit infringement of claim 20 (claim set A) by the two colour or DNBSEQ E variants. The other allegations are admitted.
ii) Claims 1, 4, 5 and 6 of the 289 patent (claim set B) are alleged to be infringed by all three systems. MGI does not admit infringement of claim 4 by the two colour variant kit or the DNBSEQ E variant kit. The other allegations are admitted.
iii) Claims 1 and 6 of the 433 patent (claim set C) are admitted to be infringed by all three systems.
Cool MPS
iv) It is alleged that the CoolMPS system infringes claims 1, 7, 12, 20 and 24 of the 578 patent (claim set A). Infringement of claims 1 and 24 (dependent on claim 1) (claim set A) is admitted. Infringement of claims 7, 12 and 20 of the 578 patent (claim set A) is in issue. The points on normal construction relate to cleavable linker, incorporation and base/blocking group attachment. The points on equivalents relate to cleavable linker and incorporation.
v) It is alleged that the CoolMPS system infringes claims 1, 4, 5 and 6 of the 289 patent (claim set B). Infringement of claims 1 and 5 of the 289 patent is admitted. Infringement of claims 4 and 6 of the 289 patent is in issue. The point relates to cleavable linker on both a normal construction and doctrine of equivalents.
vi) It is admitted that the CoolMPS system infringes claims 1 and 6 of the 433 patent (claim set C).
15. At the end of its list of issues MGI raised a point (MGI MNP Issue 12) about declarations under s71 of the 1977 Act. The point was not argued in any detail and Illumina objected to dealing with it in this way. I am not in a position to decide anything about it in this judgment. If the point is still live then the way forward must be for MGI to make an application for whatever order they are asking the court to make.
The fluorescence issues - the 412 and 415 patents
17. Illumina proposed a conditional amendment to claim 1. The amendment is advanced as a way to cure the added matter problem if, which Illumina denies, the added matter point succeeds. MGI does not contend the amendment per se is not allowable but argues that it does not cure the added matter. It makes no difference to infringement.
18. On infringement of the 412 patent, MGI admits that Standard MPS infringes claims 1 and 15. As I understand it that admission includes the two colour variant as well. Illumina does not assert infringement of the 412 patent by the DNBSEQ E variant. Illumina does assert that CoolMPS infringes claim 1 of the 412 patent both on a normal construction and by the doctrine of equivalents, and these arguments are denied by MGI.
19. For the 415 patent there is an unopposed application to amend down to claim 3 as granted. Infringement by StandardMPS of claim 1 as proposed to be amended was admitted. Illumina did not allege infringement by any of the other three systems.
20. The issues on the 415 patent all relate to invalidity. The prior art relied on is US Patent No. 4,900,686 (Arnost) published on 13th February 1990 and PCT Application No. WO 2004/018493 (Milton) published on 4th March 2004. The former (Arnost) relates to fluorescent dye compounds and the latter (Milton) relates to linkers. MGI advances a collocation argument based on these two documents. There is also an Agrevo / lack of technical contribution obviousness argument. There had been a point on insufficiency but it was dropped.
The trial
22. After the trial Illumina sent me an unsolicited note concerning Regeneron v Kymab. To forestall a proliferation of notes, I directed a short further hearing which took place (remotely) on 9th December to hear both sides on these issues.
The witnesses
23. Illumina called Professor Peter Leadlay as an expert to give evidence in relation to the modified nucleotide patents. Prof Leadlay is the Herchel Smith Professor of Biochemistry Emeritus at Cambridge, Fellow of the Royal Society and Fellow of the Royal Society of Chemistry. After studying chemistry at Oxford, Prof Leadlay held various academic positions at the ETH Zürich and at Oxford before moving to Cambridge in 1977 where he became Professor of Molecular Enzymology in 1998 and took the Herchel Smith Chair in 2006. Between 1993 and his retirement in 2018, Prof Leadlay directed the DNA Sequencing Facility in the Biochemistry Department at Cambridge.
24. MGI acknowledged that Prof Leadlay is a distinguished scientist and was good at explaining technical concepts (he was), but submitted that he was in a very unfortunate position of being asked to give evidence in relation to a field which was not his own and that as a result his evidence was of limited value to the court. I reject that submission. Prof Leadlay was the director of a major DNA sequencing laboratory at all material times. The fact he was not doing the day to day work himself does not disqualify him from speaking about it. As Prof Leadlay readily accepted, he was not trying to devise new sequencing machines. That does not disqualify him from giving evidence. Prof Leadlay’s experience and knowledge amply qualified him to assist the court on the issues relevant to the modified nucleotide patents. The fact the professor had not read the papers such as Metzker and Canard which MGI wanted to say were common general knowledge did not demonstrate he was not in the relevant field. For one thing that assumes the truth of a heavily disputed proposition MGI seeks to prove. It may amount to nothing more than a consequence of the fact he was not trying to develop new methods himself at the relevant date. It may serve as evidence contrary to MGI’s case. In any case the submission is another instance of the frequent fallacy in patent cases that the only experts qualified to comment have to have been working on the very problem the patent sets out to solve at the relevant time. That is wrong. The expert’s particular area of interest and work may well be a factor to take into account, depending on the circumstances, but it rarely justifies a submission of the kind advanced by MGI here.
25. MGI also submitted that Prof Leadlay’s attempt to “recreate” (as MGI put it) the common general knowledge was flawed, that he overreached himself and speculated to fill in gaps. I do not accept this characterisation of the witness at all. A particularly unfair submission is a criticism about evidence the professor gave in cross-examination about a conference in 1994. Never mind the fact that given a 2002 priority date nothing useful was likely to be gained from considering who may or may not have attended a single conference in 1994. The criticism is that Prof Leadlay “changed his tune” about who would have attended the conference when it was pointed out to him that the Metzker and Canard groups had presented at the conference. However Prof Leadlay did no such thing. I remember the oral evidence on this but I have taken the trouble to carefully re-read the whole of the relevant transcript. The professor’s evidence was consistent throughout. The fact he or his laboratory manager John Lester might have gone to it (but did not) is not inconsistent with his view that the skilled person, as the professor defined that person, would not have.
26. Another criticism is said to be the professor’s suggestion that the earliest Metzker and Canard work was not promising “even in 1994”, whereas he said the patent offered a breakthrough “even though” as MGI asserts “the data in each are comparable”. I will deal with the technical issues in context, but as a criticism of the witness this is also hopeless. The answers the professor gave to the question about 1994 were cogent and not inconsistent with his views about the patent(s) in suit.
27. The only other criticism of Prof Leadlay I will mention is that his evidence was said to be coloured by his own experience of thinking that Solexa were the first people to use reversible chain terminators in general. This is just another way of making the same point that Prof Leadlay had not read papers such as Metzker and Canard. It is not a reason to apply a general discount to his evidence. MGI also submit that the professor’s evidence was itself tainted with hindsight. It is certainly true that in principle hindsight can infect arguments advanced in favour of an inventive step, as well as arguments in favour of obviousness but if I find that has taken place I will deal with it in context.
28. None of MGI’s submissions about Prof Leadlay’s evidence lead me to think I should generally discount his evidence at all. On the contrary Prof Leadlay was a good witness, using his skill and knowledge to help the court understand the technical issues and decide this case. There are points of detail relating to particular pieces of evidence given by all the witnesses in this case, including Prof Leadlay. If they need to be addressed, they are best dealt with in context.
29. MGI called two expert witnesses in relation to the modified nucleotide patents. The first was Professor Dr. Andreas Marx, who is currently - and has been since 2004 - Professor of Organic Chemistry/Cellular Chemistry at the University of Konstanz in Germany. After studies in Chemistry at the Ruhr-Universität Bochum, Prof Marx obtained his D. Phil. at the University of Basel in organic/biological chemistry studying DNA polymerases and modified nucleotides. After a period in Japan at the Nagoya University, Prof Marx was a Group leader at the Kekulé-Institute of Organic Chemistry at the University of Bonn until 2004, where he completed the requisite qualification to become a professor in Germany specialising in organic chemistry and biochemistry.
31. The second of MGI’s witnesses in relation to the modified nucleotide patents was Professor Nicolas Winssinger, who is currently a professor in the Department of Organic Chemistry at the University of Geneva. Prof Winssinger studied science at Tufts University before doing doctoral and post-doctoral research at the Scripps Research Institute in San Diego, California. From 2002 - 2005, Prof Winssinger was an associate professor and director of the organic and bioorganic laboratory at the Institute of Science and Supramolecular Engineering at the Louis Pasteur University. Thereafter, Prof Winssinger was a full professor within the same institution, but at the University of Strasbourg, before he moved to the University of Geneva in 2012.
32. Although Illumina did not criticise Prof Winssinger for it, I was not impressed with the professor’s testimony in cross-examination. An issue relevant to obviousness was about the perceptions of the skilled person of the utility of Staudinger chemistry for reducing azides. Counsel put to Prof Winssinger that Staudinger was thought to be slow at the relevant temperatures and Prof Winssinger said he strongly disagreed. Counsel then put to the professor a scientific paper of his published in 2003 (Debaene and Winssinger) which involved the use of azides in the synthesis of peptide nucleic acids to mask the N terminus and used Staudinger chemistry for deprotection. The questions made the simple point that on the face of the paper, it seemed that in 2003 Prof Winssinger had regarded the Staudinger reduction as attractive due to its mildness, but as having impractically long reaction times. The professor did not accept that that was the right way to understand the paper. I am not concerned about whether the professor’s explanation of the context of the work in the paper in fact shows that the issue about timing it mentions is relevant in the present case or not. What troubled me was the blithe way Professor Winssinger treated something he had previously written (or at least was in his name). Chasing through the chemistry led to tests carried out on two azaylide compounds 10 and 11. They were part of the testing to fix the timing issue (or I think actually to resolve a knock on effect of the step taken to fix the timing issue, but it does not matter). The paper records (p4447 lower LH side) that he and his co-worker were “pleased to observe that compound 10 was completely consumed after 1 hr” but then stated that “it was interesting to note” that compound 11 (tributyl azaylide) “did not react under these conditions”. In other words, on the face of it, the fix was not so simple. One of the two compounds worked but “interestingly” (in his own words at the time) the other did not. In his answer (at T9/1044 lines 11-25) the professor did not face up to what had been written but instead sought to suggest it was not interesting at all but rather was just the result of the well established, text book, rules of organic chemistry. This was not the first argumentative answer from the professor but is the clearest example and shows a lack of objectivity on his part. He was arguing the case. He was not there seeking to give candid and objective evidence. To reject the entirety of his evidence would be a disproportionate response but I am doubtful I can place much weight on opinions expressed by Prof Winssinger which are not backed up by other evidence such as contemporaneous documents.
33. In relation to EP 412 and EP 415, Illumina called Professor Marc Greenberg. Since 2016 he has been the Vernon K Krieble Professor of Chemistry at the Johns Hopkins University. Prof Greenberg studied chemistry at New York University, before doing a PhD in chemistry at Yale. Prof Greenberg then did post-doctoral research as the American Cancer Society Postdoctoral Fellow at CalTech. In 1998, he moved to Colorado State University, where he became a professor in the Department of Chemistry in 1999. In 2002, Prof Greenberg moved to Johns Hopkins.
34. MGI called Professor Johnsson in relation to EP 412 and 415. Prof Johnsson is currently Director at the Max Planck Institute for Medical Research, Department of Chemical Biology in Heidelberg, a position he has held since 2017. Prof Johnsson studied chemistry at the ETH Zürich and subsequently undertook post-doctoral research in the USA (Berkeley) and Germany (Ruhr-Universität Bochum). From 1999 to 2017 Prof Johnsson held a number of academic positions at the Institute of Chemical Sciences and Engineering at the Swiss Federal Institute of Technology in Lausanne before he moved to the Max Planck Institute.
36. The parties also called three more professors as fact witnesses. Illumina called Professor John Mattick AO and Professor Michael Lovett. They were called to assist Illumina’s case that sequencing by synthesis using reversible chain terminators (RCT) was not common general knowledge, particularly at the earlier priority dates in this case (2002 and 2004). MGI called Prof George Church, largely to address the same point.
37. Prof Mattick is the SHARP Professor of RNA Biology at the University of New South Wales, Sydney. Prof Lovett is the Chair in Systems Biology at the National Heart and Lung Institute at Imperial College. Prof Church is Professor of Genetics at Harvard Medical School. MGI chose not to cross-examine Profs Mattick and Lovett. Prof Church was cross-examined. He was a good witness and Illumina did not criticise his evidence. I am grateful to all three of these professors for their evidence.
The witnesses not called, and questions not asked
38. At various stages each side made a point that the other side had access to an individual who, it was contended, could have given better evidence on a point than that party had advanced, and suggested I should draw a negative inference. This is a legitimate submission and can be very telling in a specific instance. However in the end both sides were able to make very much the same points, which were generic in nature. For example while Illumina appears to have access to Prof Burgess who could give more direct evidence about the work published in Metzker (for example) since it came from his group but was not called, so it turned out MGI has access to Dr Metzker himself but did not call him either. There was also a suggestion that Prof Church, some of whose papers were in the case, could have been called to say more by MGI or could have been asked about more by Illumina. It is relevant to bear in mind that the court always controls expert evidence and the Patents Court in particular is astute to restrict overlapping expert evidence and to encourage cross-examination which is focussed only on the major issues. This general approach to case management means that one cannot assume a party always felt free to call further experts or to ask further questions. In the end I have decided to decide this case as best I can based on the evidence that is here, of which there is a lot, rather than speculating about why there is not even more evidence.
The modified nucleotide patents - 578, 289 and 433
39. In order to make sense of what follows, it is necessary to understand some of the technical background and how MGI’s obviousness case is put.
51. This is sufficient technical background to understand how MGI puts it case on obviousness. As pleaded MGI relied on Tsien, Ju and two Zavgorodny papers. A vital difference between the Zavgorodny papers on one hand and the Tsien and Ju references on the other is that while Tsien and Ju are about sequencing by synthesis using reversible chain terminators, the Zavgorodny papers are not.
52. The Zavgorodny papers do describe an azidomethyl blocked nucleic acid molecule but they are not concerned with DNA sequencing at all (there are other reasons for using blocking groups). Whereas Tsien and Ju describe sequencing by synthesis using reversible chain terminators but do not include any reference to azidomethyl as a reversible chain terminator group. Now by the start of the trial MGI had abandoned the case over Tsien or Ju and concentrated on the case over Zavgorodny. However it is manifest that a skilled person who had never heard of the technique of sequencing by synthesis using reversible chain terminators, and who read either Zavgorodny paper in 2002, could not possibly think of the invention because nothing in either paper would prompt someone who had no knowledge of sequencing by synthesis to think of the technique at all.
53. MGI’s primary case is that the skilled person for the purposes of obviousness is or includes a team interested in or researching sequencing by synthesis using reversible chain terminators. MGI says that, based on this definition of the team, it follows that the skilled person will have sequencing by synthesis using reversible chain terminators in mind when reading the Zavgorodny reference. That does not necessarily mean the invention has to be obvious, but without it, MGI’s primary case would be untenable.
54. Illumina contends that MGI’s primary case is bound to fail because it is based on an illegitimate definition of the person skilled in the art, given the failure as Illumina sees it, of reversible chain terminators by the priority date. Illumina contends the true definition of the person skilled in the art in this case is a team interested in developing improved methods of sequencing, which would include improvements to Sanger sequencing. On Illumina’s case that team was unaware of sequencing by synthesis using reversible chain terminators. To that team (says Illumina) the invention is not obvious over Zavgorodny.
55. That leads to MGI’s alternative case, which is based on Illumina’s definition of the skilled team. It is said that sequencing by synthesis using reversible chain terminators would be part of the common general knowledge of that skilled team. They would have it firmly in mind if Zavgorodny had crossed their desk in 2002.
56. However the problem with this alternative case is that, for the skilled team as defined by Illumina, the idea of sequencing by synthesis using reversible chain terminators was not part of the common general knowledge. There is clear evidence (and I find) that real skilled people focussed on improvements to Sanger sequencing had never heard of it. (The fact that some such people may well have heard of it does not make it common general knowledge.)
The skilled person
58. Who is the person skilled in the art? Stated generally the law is clear that patents are directed to those likely to have a real and practical interest in the subject matter of the invention. This language is based on paragraph 81 on the judgment of Henry Carr J in Garmin v Philips [2019] EWHC 107 (Ch) in which the judge summarised the law in this area. The real practical interest in the subject matter includes devising the invention itself as well as putting it into practice and so, as was highlighted in Schlumberger v EMGS [2010] EWCA Civ 819, the concept of the person skilled in the art actually applies in two distinct circumstances. In a proper case they may be two different persons (or teams). One person skilled in the art is the person to whom the patent is addressed and whose attributes, skills and common general knowledge will be necessary to implement the patent. As Illumina submitted that person is always going to be the appropriate skilled team from the point of view of addressing sufficiency, since the patentee is entitled to put together his invention by combining any skill-sets he likes. As Pumfrey J said in Horne Engineering v Reliance Water Controls [2000] FSR 90 (quoted in Schlumberger at para 51)
“it is often possible to deduce the attributes which the skilled man must possess from the assumptions which the specification clearly makes about his abilities.”
60. One principle in Schlumberger was identified in paragraph 65:
“In the case of obviousness in view of the state of the art, a key question is generally “what problem was the patentee trying to solve?” That leads one in turn to consider the art in which the problem in fact lay. It is the notional team in that art which is the relevant team making up the person skilled in the art.”
62. Furthermore, blindly applying an approach based on the definition of the problem to be solved could lead to a very narrowly defined skilled person and that can create its own difficulties, which were well described by Peter Prescott QC in Folding Attic Stairs v The Loft Stairs Company Ltd [2009] EWHC 1221 (Pat). He showed why it could be wrong to frame the art in a narrow way. At paragraphs 33-34 he said:
“33. Common general knowledge is quite different. It is what people skilled in the art actually do know, or ought to know, provided that knowledge is regarded as sound. Common general knowledge is not a phrase used in the Patents Act or the European Patent Convention. It would be difficult to define the person skilled in the art in this case, or the common general knowledge, because so far as I know there is no recognised profession or calling of designing folding attic stairways. At the date of the patent nobody seems to have done it in the British Isles except the Claimant and perhaps one other company. There must have been one or more companies in America, I suppose. It is unfair to define an art too narrowly, or else you could imagine absurd cases e.g. “the art of designing two-hole blue Venezuelan razor blades”, to paraphrase the late Mr T.A. Blanco White. Then you could attribute the “common general knowledge” to that small band of persons who made those products and say that their knowledge was “common general knowledge” in “the art”. That would have the impermissible result that any prior user no matter how obscure could be deemed to be common general knowledge, which is certainly not the law.
34. However it does not make much difference in this case, because the amount of special knowledge that is required to understand the patent in suit is not great. I would identify the person skilled in the art as one who has practical experience as a manufacturing carpenter, assisted by a metal fabricator. At the date of the patent (1996) this person or team would be vaguely aware of folding stairways in general terms, at most. The actual construction of old Stira, while known to many customers, was not common general knowledge in the art, in my judgment.”
63. So while Folding Attic Stairs neatly explains one of the difficulties, given its facts the judge did not have to identify a principle to be applied to solve it. Furthermore, while a too narrow definition could be unfair to the inventors, it could be just as wrong and unfair to the public to define a team so widely that their common general knowledge is so dilute as to make something seem less obvious than it really was (see Pumfrey J in Mayne v Debiopharm [2006] EWHC 1123 (Pat) at paras 3-4).
“I think one can draw from [Dyson v Hoover] that the Court, in considering the skills of the notional “person skilled in the art” for the purposes of obviousness will have regard to the reality of the position at the time. What the combined skills (and mind-sets) of real research teams in the art is what matters when one is constructing the notional research team to whom the invention must be obvious if the Patent is to be found invalid on this ground.”
65. This was summarised in Medimmune v Novartis [2012] EWCA Civ 1234 at paragraph 76-77 as a principle that the court will have regard to the reality of the position at the time and the combined skills of real research teams in the art. In Medimmune the court found that “antibody engineering” was an established field by the priority date. There were 10 such real teams in the evidence and they were all likely to have a practical interest in the subject matter and to have the skills to implement it.
66. In the present case Illumina proposed, based on Medimmune, that a sensible test was to require something which could properly be called an established field at the priority date. Depending on the facts the field could be a research field as in Medimmune or a field of manufacture as in Folding Attic Stairs.
i) To start by asking what problem does the invention aim to solve?
ii) That leads one in turn to consider what the established field which existed was, in which the problem in fact can be located.
iii) It is the notional person or team in that established field which is the relevant team making up the person skilled in the art.
71. Finally I will say something about the evidence. There was a dispute at the outset of the trial about an aspect of MGI’s case relating to the definition of the skilled person. Part of MGI’s skeleton advanced a different skilled person from the one in Prof Marx’s evidence. Related to this, in his fifth report, the professor sought to clarify something he had said earlier on this topic which Illumina contended was in fact a shift, related to the same point. It is necessary for experts to explain who they think the skilled person is, not least in order to explain the basis on which they are giving their evidence. However while the expert and other evidence is critical to resolving a dispute about the identity of the skilled person, in the end the identity of that person is a matter for the court, applying the law to the facts to reach a conclusion.
Person skilled in the art– the facts
72. I start with the 2002 priority date and the modified nucleotide patents.
75. In his fifth report Prof Marx was asked by MGI to clarify what he meant by “methods including sequencing by synthesis". He said he did not think that teams involved in or interested in developing other methods of sequencing but not sequencing by synthesis would be interested in the teaching of the patents. This was not really a clarification. It was a shift in position. And while no doubt Prof Marx was unaware of this, it was obviously driven by a shift in thinking by MGI’s legal team as they decided to drop Tsien and Ju and concentrate on Zavgorodny.
77. The problem which the invention claimed in the modified nucleotide patents aims to solve can be stated in different ways. MGI contended that based on the disclosure of the patents, the problem the patentee was trying to solve was the identification of removeable protecting groups which could meet the requirements for use in methods of sequencing by synthesis; in other words, to find improved removable protecting groups to act as reversible chain terminators in sequencing by synthesis. Illumina’s formulation was not very different. It was the identification of a successful reversible blocking group for the 3' position for use in sequencing by synthesis. At this stage nothing turns on the differences between these formulations, nor does it follow that the skilled person, however defined, has that problem in mind. That latter question depends on the common general knowledge.
83. Although pyrosequencing was the most advanced alternative to Sanger at 2002, there were other techniques which were being considered in the years up to and including the priority date. One of those was the use of reversible chain terminators in what is now called sequencing by synthesis. MGI referred to a number of groups with an interest in reversible chain terminators, over and above Solexa itself.
84. There was a research group at Baylor College of Medicine (Richard Gibbs) and Texas A&M (Kevin Burgess). This group published five papers on reversible chain terminators from 1994 until 1999 including the Metzker 1994 paper in Nucleic Acids Research. Illumina submitted the work of this group had petered out by the priority date, and the evidence of a later, post priority grant application did not show that the group continued but rather was a consequence of the later developments. The evidence about this issue was thin. It is more likely than not that the focus of this group on reversible chain terminators after the 1999 did wane. I am not convinced the grant application showed that the work continued in the intervening years, rather it showed that workers with a real interest in the subject encountered a reason to get going again.
86. There was a group led by Prof Ju at Columbia University. Their work led to the Ju patent application cited as prior art by MGI in this case. It claimed priority from a US filing in 2000 and was published in April 2002. The abstract provides:
“This invention provides methods for attaching a nucleic acid to a solid surface and for sequencing nucleic acid by detecting the identity of each nucleotide analogue after the nucleotide analogue is incorporated into a growing strand of DNA in a polymerase reaction. The invention also provides nucleotide analogues which comprise unique labels attached to the nucleotide analogue through a cleavable linker, and a cleavable chemical group to cap the -OH group at the 3' -position of the deoxyribose.”
88. The company Genovoxx based in Lübeck filed a patent application (WO 02/088382) claiming priority from 2001 and published in November 2002. It relates to sequencing by synthesis using reversible chain terminators. Prof Church (see below) had been in contact with that group after the priority date. Illumina positively rely on Genovoxx’s work as pointing in a quite different direction from the invention in issue and I will address that below. The point at this stage is that this group was clearly active in this area at the time.
89. Other companies who applied for patents relating to sequencing by synthesis using reversible chain terminators before the priority date were Medical Biosystems Ltd based in Totnes (application published in 1999); Caliper Technologies Corp of Mountain View, California (application published in 2000); ASM Scientific Inc. of Cambridge, Mass. (application published in 2000), Illumina itself prior to acquiring Solexa (application published in 2000); Amersham Pharmacia Biotech (application published in 2001); and Agilent Technologies Inc. of Palo Alto (application filed May 2002, post published).
90. There is no need to go into further detail about any of these other companies at this stage. As with Genovoxx, Illumina points out that the approaches some of these companies appeared to be taking is in a different direction from the invention in issue but as I have already said, that is not germane at this stage. It is also important not to read too much into the fact that a company has filed a patent application. It does not, for example, prove that that company has done any active “wet chemistry”. Nevertheless in the context of the other evidence in my judgment the totality of these patent applications support the point MGI seeks to make.
97. MGI referred to a number of documents from proceedings in other jurisdictions (including the EPO) relating to this European patent, or patents in the same family, in which Illumina had characterised the skilled person in a manner similar to the way MGI put its case here and not as Illumina submitted to me. Illumina were free in this jurisdiction to try and prove something different from that in other jurisdictions, with different evidence. However I have found that attempt fails.
The common general knowledge
101. The classic statement of the law on common general knowledge is in General Tire v Firestone [1972] RPC 457 at p. 482. More recently, the Court of Appeal in Idenix v Gilead [2016] EWCA Civ 1089 at para 72, citing General Tire, summarised the correct approach to common general knowledge as follows:
“It follows that the common general knowledge is all that knowledge which is generally regarded as a good basis for further action by the bulk of those who are engaged in a particular field. It is that knowledge which those working in that field will bring to bear when they are reading or learn of a piece of prior art. It is not necessary that those persons have that knowledge in their minds, however. The common general knowledge includes material that they know exists and which they would refer to as a matter of course if they cannot remember it and which they understand is generally regarded as sufficiently reliable to use as a foundation for further work”.
102. A point arises on the principles. The reference to a “good basis for further action” does not mean only things which work can be common general knowledge. The common general knowledge of a skilled person will often be as much about knowing what does not work as it is about knowing what does. Both are examples of a “good basis for further action” in that they are ideas which are worth acting upon. In a similar vein, in Merck v Ono [2015] EWHC 2973 (Pat) at para 24, I held that the common general knowledge includes contradictions as long as the information was sufficiently well known to be common general knowledge. So the fact a given technique was something which had been proposed for some years, tried out by a number of groups, but not (yet) shown to work, would not in and of itself preclude information about that technique being held to be part of the common general knowledge. A technique like that which was sufficiently well known could be common general knowledge.
Common general knowledge - the facts
Metzker 1994
Canard 1994
112. There was also a Canard 1995 paper but it was not concerned with reversible chain terminators.
Later papers (1999)
Other kinds of sequencing by synthesis
The evidence as a whole about the state of reversible chain terminator in the common general knowledge
119. MGI emphasised that in cross-examination Prof Leadlay explained that Metzker 1994 was showing a single cycle, which he described as very, very preliminary work, and said the same comment applies to Sarfati (T2/19911-24). MGI pointed to the text in Canard 1994 that explained that “our results show that it is possible to reach high incorporation levels required to perform several cycles in a row” and submitted that Prof Leadlay accepted that Metzker 1994 “sets the stage” and that Canard demonstrated the proof of principle.
120. I accept MGIs submissions but only up to a point. They are more reflective of the view of someone reading these papers in 1994 than they would be by 2002, by which time no further significant steps forward had occurred. By 2002 a more accurate characterisation of the view of the skilled person, as Illumina submitted, was that neither Metzker nor Canard had achieved anything more than an initial incorporation in 1994, and their later efforts up to 1999 had not succeeded.
121. What was the common general knowledge about the problems which had to be solved? MGI’s characterisation of the “problem to be solved” was the identification of a reversible chain terminator which could meet the requirements for use in sequencing by synthesis. A critical question is whether that problem or something like it was part of the common general knowledge of the skilled person. The reason this is critical is that the evidence of Prof Marx that the invention was obvious was based on an approach made clear in his evidence and cross-examination. His approach was that the skilled person looks at Zavgorodny with the specific aim in mind of finding a blocking group he might be able to use in a reversible chain terminator sequencing process. Moreover the questions put to Prof Leadlay were on essentially the same premise (that the skilled person came to the cited art interested in taking forward sequencing by synthesis with a new reversible chain terminator).
122. Illumina submitted that the idea of pursuing new chemical groups as reversible chain terminators on the 3' end of the nucleotide in sequencing by synthesis was not representative of the common general knowledge at 2002. I agree. My reasons are as follows.
Organic chemistry
The specifications of the modified nucleotide patents
131. As Illumina did in its opening skeleton, I will address the specification of the 289 patent. In fact there are some extra passages in the specification of the 578 patent but nothing turns on them at this stage.
i) This allows for accurate sequencing by adding nucleotides in multiple cycles as each nucleotide residue is sequenced one at a time, thus preventing an uncontrolled series of incorporations occurring.
ii) The incorporated nucleotide is read using an appropriate label attached thereto before removal of the label moiety and the subsequent next round of sequencing. In order to ensure only a single incorporation occurs, a structural modification ("blocking group") of the sequencing nucleotides is required to ensure a single nucleotide incorporation but which then prevents any further nucleotide incorporation into the polynucleotide chain.
iii) The blocking group must then be removable, under reaction conditions which do not interfere with the integrity of the DNA being sequenced.
iv) The sequencing cycle can then continue with the incorporation of the next blocked, labelled nucleotide.
v) In order to be of practical use, the entire process should consist of high yielding, highly specific chemical and enzymatic steps to facilitate multiple cycles of sequencing.
i) exhibit long term stability;
ii) be efficiently incorporated by the polymerase enzyme;
iii) cause total blocking of secondary or further incorporation; and
iv) have the ability to be removed under mild conditions that do not cause damage to the polynucleotide structure, preferably under aqueous conditions.
“Nucleotides bearing this blocking group at the 3' position have been synthesised, shown to be successfully incorporated by DNA polymerases, block efficiently and may be subsequently removed under neutral, aqueous conditions using water soluble phosphines or thiols allowing further extension”
149. However while I have accepted part of Prof Marx’s evidence here at a technical level, I was not persuaded by his view that the contents of the patent did not did not represent an important or significant development. To characterise the patent as MGI sometimes did in argument as just showing one more cycle (three) compared to two cycles shown in the prior priority date papers is not realistic and not how it would be viewed by the skilled person.
150. Counsel for Illumina put to Prof Marx that this experimental data was a significant technical advance in the field of reversible chain termination sequencing. Prof Marx did not accept that because of the quality of the data as summarised above. He was prepared to accept that the third cycle of incorporation of the T nucleotide was a step which had not been shown before but he would not accept it was an important or significant development. This was the least persuasive part of Prof Marx’s testimony and on this topic I preferred the evidence of Prof Leadlay. Prof Leadlay’s view was as follows. The data shows that modified nucleotides with a 3' azidomethyl blocking group may be used for controlled, one at a time, incorporation of nucleotides into a polynucleotide. The 3' azidomethyl modified nucleotides were incorporated by the polymerase, resulting in chain termination. The blocking group and fluorescent label are capable of being removed using a water-soluble phosphine to regenerate the 3' hydroxyl, allowing further rounds of incorporation of 3' blocked nucleotides in a stepwise manner. I accept this evidence.
Claim construction
The claims of the 578 patent
159. MGI also draw attention to the point that in the form as granted this claim (claim 2 claim set A) had a counterpart in claim 8 as granted. Whereas what is now claim 2 (claim set A) relates to the detectable label being attached by the linker to the base, the counterpart granted claim 8 required the detectable label to be attached by the linker to the blocking group.
The claims of the 289 patent
174. The other notable claim of 289 is claim 9 of claim set B (claim 13 as granted). This claim defines part of the method claimed in earlier claims such as claim 6 by reference to removing the blocking group using a water soluble phosphine. By amendment Illumina seek to add the words “under neutral, aqueous conditions”. MGI contends this amendment adds matter.
The claims of the 433 patent
178. An important difference between claim 6 of 433 and the corresponding claim of 578 is that the latter is limited to a modified nucleotide in which the detectable label is linked to the base by a linker, whereas claim 6 of 433 contains no such limitation. Thus although MGI deny infringement of claim 7 of claim set A of 578 by Cool MPS because it uses antibody detection, MGI admits infringement of claim 6 of 433 because the nucleotide which is to be incorporated is only defined by reference to its having the right base, sugar and 3' azidomethyl blocking group.
Obviousness
180. The approach the court should take to testing the question of obviousness is well settled, based on the questions posed by Oliver LJ in Windsurfing v Tabur Marine [1985] RPC 59 at pp71 - 74 and reviewed by the Court of Appeal in Pozzoli v BDMO [2007] FSR 37 at paras 14 - 23, as follows:
(1) Identify:
(a) the notional person skilled in the art; and
(b) the relevant common general knowledge;
(2) Identify the inventive concept of the claim in question or if that cannot readily be done, construe it;
(3) Identify what, if any, differences exist between the matter cited as forming part of the state of the art and the inventive concept of the claim or the claim as construed;
(4) Viewed without any knowledge of the alleged invention as claimed, do those differences constitute steps which would have been obvious to the person skilled in the art or do they require any degree of invention?
“… The notional skilled person is assumed to have read and understood the contents of the prior art. However that does not mean that all prior art will be considered equally interesting. The notional skilled person is assumed to be interested in the field of technology covered by the patent in suit, but he is not assumed to know or suspect in advance of reading it that any particular piece of prior art has the answer to a problem he faces or is relevant to it. He comes to the prior art without any preconceptions and, in particular, without any expectation that it offers him a solution to any problem he has in mind. Some pieces of prior art will be much more interesting than others. … ”
Zavgorodny 1991
186. The Zavgorodny figure is:
188. The last paragraph of Zavgorodny is as follows:
“The compounds discussed above are useful specifically blocked synthons. For example, alkylthioalkyl groups can be removed with methyl iodide, mercury(II) and silver(I) salts, tritylium tetrafluoroborate, or bromine/water treatment. O-Methoxymethyl substituted nucleosides may be deblocked according to Nishino, and acetoxymethyl and 2-cyanoethoxymethyl groups undergo elimination under alkaline conditions. Azidomethyl group is of special interest, since it can be removed under very specific and mild conditions, viz. with triphenylphosphine in aqueous pyridine at 20 ºC.”
Differences over Zavgorodny
194. At one stage MGI had an alternative case that the molecule of claim 1 was obvious over Zavgorodny irrespective of sequencing by synthesis because it would be obvious as a candidate antiviral. That case was dropped before trial.
Is it obvious?
202. The conditions needed to remove the blocking group obviously matter in the abstract, but the reference to removal under specific and mild conditions here does not assist MGI very much. If the skilled person had thought that it was the removal conditions which were a particular problem and were the reason why sequencing by synthesis using reversible chain terminators had stalled as a concept, then it might be different, but that is not the case.
203. The skilled person would understand the reference to specific and mild conditions as a reference to the circumstances of Zavgorodny itself rather than a suggestion about the properties of this group in conditions required for DNA synthesis. On the other hand as a matter of the common general knowledge of the organic chemist member of the team, if they did get this far, they would think that they would be able to select conditions using their own skill which would be likely to remove such an azide group from a nucleotide without being likely to cause difficulties for DNA. That is why the “pyridine point” raised by Illumina is a bad point. It is true that the skilled person would be unlikely to want to use the particular removal conditions referred to in Zavgorodny (triphenyl phosphine in aqueous pyridine). That is because pyridine is known to denature DNA. But the skilled person would be well aware of that and as I have said, would be aware of suitable aqueous conditions using phosphines which would be expected to remove an azide without being such as to denature DNA.
205. I reject the submission of MGI’s that because an azidomethyl group is small, that would support a prospect of successful incorporation. On the contrary, the evidence as at 2002 does not allow that conclusion to be drawn. Azidomethyl is larger than a number of the groups tested in Metzker some of which failed completely (O-acyl), and others of which only worked inconsistently (O-methyl - which worked with the A base only using reverse transcriptase and with the T base only with some DNA polymerases). I accept Prof Leadlay’s summary of the relevance of size which he gave in cross-examination: too big is bad but small is not necessarily beautiful.
211. Illumina sought to go further and suggest that the true position was positively against reasonable yield and speed. This was in Prof Leadlay’s evidence on the basis that the skilled person thinking of O-azidomethyl as a blocking group would look it up in Greene & Wuts and find a 1988 paper by Loubinoux which reported only unpromising 60%-80% yields and long reaction times. Prof Leadlay was not challenged on this but I was not persuaded the skilled person would undertake such a paper chase.
212. MGI also sought to go further in the opposite way by seeking to establish a positive case that the expectation would be of reasonable yields and speed. This was by reference to the work of Bertozzi. However again I was not persuaded that the skilled person would think any useful analogy could be drawn between that work and an attempt to use an azidomethyl blocking group in sequencing by synthesis. However even if it was, I was also not convinced the exercise produces a clear result in MGI’s favour. Looking at the Bertozzi work as a whole, as the skilled person would, if they got that far, see that there is evidence of a need for long times (6 hours) to produce optimal yield.
ICOS factors
213. MGI contended that the factors summarised in ICOS all point in favour of a finding of obviousness. The points are:
i) Obvious to try - I reject MGI’s submission that there was a sufficient likelihood of success to warrant trying incorporation of the azidomethyl with a range of standard polymerases. There would be no such expectation.
ii) Routine work - The work actually involved in testing a range of polymerases or testing deprotection is not difficult to do.
iii) Cost - Cost is not a relevant factor in this case.
iv) Value judgments - This is not a case about multiple value judgments. However deciding to try out azidomethyl in a sequencing by synthesis test does not follow from Zavgorodny.
v) Multiple paths of research - does not apply here.
vi) Motive - I reject MGI’s submission that this points in favour of obviousness. On the contrary it points against for the reasons already addressed.
vii) Unexpected result - A 3'-O-azidomethyl blocking group has the useful features promised by the patent in paragraph [0004 and [0005]. That was not predictable from the prior art.
viii) Step by step analysis - This is not a major factor in the present case.
ix) Added benefit - This is not a bonus effect case.
The deposition of Dr Liu
214. Under a Civil Evidence Act notice MGI relied on a passage in a deposition of Dr Xiaohai Liu of Solexa in USA proceedings between Illumina and the Trustees of Columbia University. Dr Liu is one of the named inventors on the modified nucleotide patents. The deposition was in 2013. In the deposition Dr Liu was shown Zavgorodny 1991. The testimony MGI relies on is an answer Dr Liu gave when he was shown the passage about azidomethyl being of special interest which is quoted above. The questioner put to him that that passage would suggest that an azidomethyl group might be something to try as a protecting group for SBS. His answer was: “That’s a perfectly valid argument. Yeah, I agree with you. You probably thinking about it; use it, yes.”
Inventive step - conclusion
216. Standing back, for the reasons explained above claim 1 of 578 is not obvious over Zavgorodny 1991. I reject MGI’s case on lack of inventive step. As mentioned at the outset, if the claim is not obvious over Zavgorodny 1991 then it is not obvious over Zavgorodny 2000 either.
Secondary evidence
218. Illumina relied on secondary evidence at least to some extent, submitting as follows. Azide chemistry was not unknown, azides were even known as blocking groups and azidomethyl was not an unknown chemical group. There were a number of disparate instances of papers in which protecting groups for reversible chain terminator sequencing have been suggested (including Tsien, Ju, some of the patent applications in 2000-2002, Metzker and Canard). Nevertheless none of them even suggest azidomethyl and Illumina pointed out that Prof Marx accepted he could not explain why not.
219. Illumina also referred to post published material in the form of a 2005 paper from the Ju group by Ruparel and a 2004 paper from Prof Church’s group by Shendure. The Ruparel paper (passage quoted below) supports the idea that in fact finding as successful reversible blocking group for the 3' end was a formidable challenge (as Prof Marx accepted) and it seems that the Ju group adopted the azidomethyl approach after learning of its use by the inventors. In relation to other blocking groups Ruparel states:
“Significant efforts have been dedicated for evaluating a wide variety of 3’ modified nucleotides to be used as terminators for various DNA polymerases and reverse transcriptases, but none of the functional groups tested have had established methods to regenerate a free 3-OH.”
Obviousness - lack of technical contribution
223. The claims to a method of controlling incorporation, which are claim 7 (claim set A) of the 578 patent and claim 6 (as granted) of the 433 patent, are both defined in such a way that the method is defined as applicable in a synthesis or a sequencing reaction. MGI contended that insofar as the claims covered the method in “a synthesis reaction not being a sequencing by synthesis reaction”, then the claim had no technical benefit over the common general knowledge or prior art and so the claims are invalid for lack of inventive step on the Agrevo basis. The same argument was put under the heading of insufficiency. Illumina denied the invalidity but offered an amendment to delete synthesis, which would cure it. This point is MGI MNP issue 3.
224. MGI’s case, as put in paragraph 341 of its written closing, is:
“[…] One [point] relates in essence to the patentee’s failure to limit his claims to the use of azidomethyl in methods in which its reversible nature is of utility, i.e. SBS methods. Instead the patentee has claimed greedily, attempting to throw the claims wider to cover the use of azidomethyl in methods of synthesis and Sanger sequencing. In both cases the claims cover embodiments in which the use of azidomethyl simply represents an alternative chain terminator, whose selection is not justified by any useful technical property. […]”
225. MGI submitted that there were well-known methods of DNA synthesis such as PCR and phosphoramidite synthesis reactions in which while one could use an azidomethyl group, it would serve no useful purpose. Therefore the selection of an azidomethyl blocked nucleotide for use in such methods is not justified by any useful technical property and so the claim is broader than that which is justified by the patentee’s contribution to the art. MGI referred to the (unchallenged) evidence of Prof Marx that the skilled person would not think that nucleotides with 3’O-azidomethyl groups would be useful in either the PCR or phosphoramidite method. MGI contended that in Prof Leadlay’s written evidence he had said that he saw no reason why the skilled person would seek to use the claimed nucleotides in such methods. In response Illumina relied on evidence given by Prof Leadlay that there was utility in using nucleotides with 3’O-azidomethyl groups other than in a RCT sequencing by synthesis reaction. He explained it could be used in Sanger sequencing as a chain terminator.
226. I accept Prof Marx’s view that the skilled person would not think there was any utility in using those nucleotides in either the PCR or phosphoramidite method. However based on Prof Leadlay, I also find that nucleotides with 3’O-azidomethyl groups could be used as chain terminators in a Sanger sequencing reaction. However this latter point made by Prof Leadlay relates to the limb of the claim related to sequencing and does not meet the point made by MGI based on Prof Marx’s evidence, which relates to the different, synthesis, limb of the claim.
228. I will therefore allow the amendment to delete synthesis from the two claims.
229. A second point on claim 6 of 433 also arises. It does not relate to claim 7 (claim set A) of 578. The point is that claim 6 of EP 433 is not limited by an express requirement that the modified nucleotide had to be linked to a detectable label. MGI says that exceeds the technical contribution and leads to invalidity (Agrevo or insufficiency conditional on non-obviousness of claim 1). Note that it is the absence of that limitation which means the claim is infringed by the antibody based Cool MPS technique. This is MGI MNP Issue 4.
230. MGI relies on the evidence of Prof Marx that there were no sequencing methods known at the priority date (2002) which used reversibly terminated nucleotides but with no detectable label attached to the nucleotide. Therefore it is said that the claim is broader than is justified by its contribution to the art.
Priority
234. Barnes discloses an azidomethyl group amongst a list of possible blocking groups to use as a reversible chain terminator at the 3' O position on a nucleotide in sequencing by synthesis. It is in figure 3 (top right) when R4 and R5 are H. Prof Marx’s evidence was that it would be obvious to follow that up. I agree that it would be. I think MGI sought to draw a parallel between the reasons why they said azidomethyl was obvious over Barnes and the obviousness case over Zavgorodny. There is no such parallel. The situations are quite different. Barnes discloses the idea of carrying out a method of sequencing by synthesis using reversible chain terminators. Figure 3 is provided as setting out some examples of suitable protecting groups for use in that very context (see p5 para [0062]). The document would be understood to be suggesting that those groups, including azidomethyl, had suitable properties for use in that very reaction system. The reader of Barnes would see it as suggesting that azidomethyl, as well as others, would be likely to be incorporated and removed in a useful manner as a reversible chain terminator for sequencing by synthesis. The fact that other groups are obvious over Barnes too does not make it inventive to choose azidomethyl as the way forward.
235. Turning to priority, the legal test was not in dispute. Illumina referred to Icescape v Ice-World [2018] EWCA Civ 2219 at paragraphs 38-42. The priority document must contain sufficient material to constitute an enabling disclosure of the claims in issue and in determining the question the Court will consider the position through the eyes of the skilled person who reads the priority document with their common general knowledge.
236. MGI’s point is that the gels which form part of the granted patent specification are not in the second priority document and, it asserts, the document contains no data which purports to be the results of an actual experiment. The argument is run as an attempt at a squeeze as compared to the obviousness case over Zavgorodny. I will come back to that at the end.
237. The first point is that Illumina submitted and I accept that there is textual support in the document for all the relevant claims (1, 12 or 24 of claim set A of 578). In other words, in summary, the idea of carrying out sequencing by synthesis using 3' O-azidomethyl blocked nucleotides, in particular, as reversible chain terminators is disclosed in the second priority document. For what it is worth azidomethyl is not simply an entry in a list. Example 1 of the second priority document relates expressly to using an azidomethyl group to protect the 3' OH.
238. MGI contends that the second priority document contains no data to support the claimed utility. Even in its own terms that is not the whole story. Example 1 on page 23 of the document specifically provides:
Nucleotides bearing this blocking group [O-azidomethyl] at the 3' position have been shown to be successfully incorporated by a number of different polymerases, block efficiently and may be subsequently removed under neutral, aqueous conditions using water soluble phosphines or thiols allowing further extension:
“clearly discloses (whereas Zavgorodny 1991 and Zavgorodny 2000 do not) the utility of 3'-O-azidomethyl blocked nucleotides as reversible chain terminators in a sequencing by synthesis method. For example, [the document] discloses on page 23 that such modified nucleotides have been shown to be successfully incorporated by a number of different polymerases, block efficiently, and may subsequently be completely removed with 100% yield under neutral, aqueous conditions using water soluble phosphines or thiols, allowing further extension of the oligonucleotide chain.”
242. There is no squeeze relating to Zavgorodny and no inconsistency between this conclusion and the finding of non-obviousness. That deals with MGI MNP Issues 6 and 7.
Insufficiency
243. MGI contended that if, contrary to their primary case, claims 7 and 12 of the 578 patent (claim set A) are not obvious over Zavgorodny then those claims are insufficient. There are two issues.
244. The first one relates to read length. The point is that claim 12 (for example) claims a method for determining the sequence of a target single stranded nucleotide wherein at least one incorporation (my emphasis) is of a nucleotide defined in previous claims such as claim 2, in other words an azidomethyl 3' blocked nucleotide in which the base is linked to a detectable label by a linker. MGI says that this claim is open ended in terms of the length of the nucleotide to be sequenced and submits that the data in the patent only present results for a limited number of cycles, as shown in figures 5 and 6. Therefore, it is said, the monopoly claimed exceeds the technical contribution and the specification does not enable the skilled person to perform a sequencing method across the breadth of the claim without undue burden. The same point is made about claim 7 of claim set A in its amended form (limited to a sequencing reaction). The issue can be decided by reference to claim 12. Claim 7 will stand or fall with it.
245. The argument as explained in the previous paragraph works as a free standing objection. In fact all of MGI’s insufficiency arguments were pleaded as squeezes with obviousness. The way MGI puts the read length argument as a squeeze is clearest in the opening skeleton (para 198). The submission is that the modified nucleotide patents do not disclose anything to suggest to the skilled person that they could achieve read lengths longer than that they would expect could be achieved on the basis of Zavgorodny, even in respect of the exemplified embodiment, let alone across the scope of the claims. The reason MGI put it as a squeeze is I think because it has not sought to call evidence directly to show how difficult it may or may not be, starting from the patent, to carrying out sequencing. Rather it relies on Prof Marx’s evidence about the quality of the data in the patent itself.
246. This first issue is meant to be MGI MNP Issue 5. Although issue 5 is drafted more broadly, the only specific point raised is the read lengths question. MGI MNP Issue 5 also refers to claim 1 but no such point was pleaded nor was it advanced in the closing. I will not allow it to be raised now.
247. The second issue is the submission that claim 12 “covers methods of sequencing using nucleotides, linkers and labels that would not enable the skilled person to perform a sequencing method across the breadth of the claim without undue burden”. This way of putting it is MGI MNP issue 2. It is put in a more specific way in MGI’s opening skeleton at paragraph 199. There it is said that the claim covers nucleotides which could be modified in ways which would prevent their incorporation and covers linkers for which the conditions required for cleavage would damage DNA. I will call this the impractical linkers point, recognising it is not in fact so limited.
248. For both arguments MGI relied on Regeneron v Kymab. Aside from relying on the principles in that case, part of MGI’s point was to suggest that these insufficiencies were examples of the problem which arose in Regeneron of a claim covering later developed successful techniques which techniques could not have been arrived at just with the patent (and the common general knowledge) but needed further steps too to make them work. MGI submitted that the fact that today it is possible to read substantial lengths of sequence using azidomethyl 3' blocker nucleotides with suitable linkers, polymerases and labels etc. does not mean that the patent is enabling.
249. Illumina did not agree with these submissions, arguing that they failed on the facts and involved a mis-application of Regeneron. I will start with Regeneron.
250. MGI focussed on the propositions that Lord Briggs derived from his review of the authorities. The propositions make frequent reference to product claims, but the targets of MGI’s insufficiency attacks to which it contends Regeneron is applicable are process claims. Illumina did not agree that the principles could be transposed in the way MGI contended for. To resolve this I will turn to the context in which these principles were enunciated.
“i) The requirement of sufficiency imposed by article 83 of the EPC exists to ensure that the extent of the monopoly conferred by the patent corresponds with the extent of the contribution which it makes to the art.
ii) In the case of a product claim, the contribution to the art is the ability of the skilled person to make the product itself, rather than (if different) the invention.
iii) Patentees are free to choose how widely to frame the range of products for which they claim protection. But they need to ensure that they make no broader claim than is enabled by their disclosure.
iv) The disclosure required of the patentee is such as will, coupled with the common general knowledge existing as at the priority date, be sufficient to enable the skilled person to make substantially all the types or embodiments of products within the scope of the claim. That is what, in the context of a product claim, enablement means.
v) A claim which seeks to protect products which cannot be made by the skilled person using the disclosure in the patent will, subject to de minimis or wholly irrelevant exceptions, be bound to exceed the contribution to the art made by the patent, measured as it must be at the priority date.
vi) This does not mean that the patentee has to demonstrate in the disclosure that every embodiment within the scope of the claim has been tried, tested and proved to have been enabled to be made. Patentees may rely, if they can, upon a principle of general application if it would appear reasonably likely to enable the whole range of products within the scope of the claim to be made. But they take the risk, if challenged, that the supposed general principle will be proved at trial not in fact to enable a significant, relevant, part of the claimed range to be made, as at the priority date.
vii) Nor will a claim which in substance passes the sufficiency test be defeated by dividing the product claim into a range denominated by some wholly irrelevant factor, such as the length of a mouse’s tail. The requirement to show enablement across the whole scope of the claim applies only across a relevant range. Put broadly, the range will be relevant if it is denominated by reference to a variable which significantly affects the value or utility of the product in achieving the purpose for which it is to be made.
viii) Enablement across the scope of a product claim is not established merely by showing that all products within the relevant range will, if and when they can be made, deliver the same general benefit intended to be generated by the invention, regardless how valuable and ground-breaking that invention may prove to be.”
iv) The disclosure required of the patentee is such as will, coupled with the common general knowledge existing as at the priority date, be sufficient to enable the skilled person to perform substantially all the types or embodiments [ ] within the scope of the claim. That is what, [ ], enablement means.
258. One can therefore put Lord Briggs’ principles (v) to (vii) in general terms as follows:
v) A claim which seeks to protect products or processes which cannot be performed by the skilled person using the disclosure in the patent will, subject to de minimis or wholly irrelevant exceptions, be bound to exceed the contribution to the art made by the patent, measured as it must be at the priority date.
vi) This does not mean that the patentee has to demonstrate in the disclosure that every embodiment within the scope of the claim has been tried, tested and proved to have been enabled […]. Patentees may rely, if they can, upon a principle of general application if it would appear reasonably likely to enable the whole range […] within the scope of the claim to be performed. But they take the risk, if challenged, that the supposed general principle will be proved at trial not in fact to enable a significant, relevant, part of the claimed range to be performed, as at the priority date.
vii) Nor will a claim which in substance passes the sufficiency test be defeated by dividing the […] claim into a range denominated by some wholly irrelevant factor, such as the length of a mouse’s tail. The requirement to show enablement across the whole scope of the claim applies only across a relevant range. Put broadly, the range will be relevant if it is denominated by reference to a variable which significantly affects the value or utility of the product or process in achieving the purpose for which it is to be performed.
262. Illumina pointed to the references to undue burden in the way both of MGI’s issues are advanced (see e.g. Grounds of Invalidity para 3(d)) and submitted that nothing in Regeneron was concerned with that. Illumina also referred to Mentor v Hollister [1991] FSR 577 and [1992] RPC 1. In that case the claim required an adhesive to be used to adhere the sheath to the penis. Many adhesives would not have worked but the skilled person could readily select one which would work using reasonable trial and experiment, so the claim was held to be sufficient. Illumina submitted that the patentee is entitled to expect the skilled person to utilise reasonable trial and experiment to implement the claim, including by selecting appropriate examples of individual elements of the claim
263. MGI submitted that Mentor was decided before Biogen and to the extent it is inconsistent with Regeneron it has been overruled. MGI also submitted that it is settled law that claims cannot be limited simply to those embodiments which work, citing the contact lens case Novartis v Johnson & Johnson [2010] EWCA 1039.
264. Related to this was a disagreement between the parties about the impact of the German BGH decision Dipeptidyl-Peptidase-Inhibitoren (X ZB 8/12) (“the DPI case”). The case was referred to by Lord Briggs at paragraph 45 as taking the matter no further than Genentech/ Polypeptide Expression (T292/85) or Nabisco/ Micro-organisms (T361/87). Illumina said that unlike Regeneron which was about a claim to products which cannot be made, the DPI case was about a single method of treatment which could be carried out by choosing from a range of “input substances”. MGI said the DPI case was doubted by the EPO in Trustees of Princeton/ OLED (T0544/12) at paragraph 4.9.5.
267. What Novartis v Johnson & Johnson is not authority for is the idea that just because the patent left it to the skilled person to select a particular starting material for themselves from a class defined in functional terms, either directly or by carrying out anything which could be called a test, that necessarily made the claim insufficient. Quite the contrary. This is made clear in paragraph 89. There Jacob LJ is contemplating what would have happened if success had been easy to predict. The consequence would have been that the claim was not insufficient. On the facts of that case it would have been obvious but that is another matter. I know MGI say that this present case has the same squeeze. It may or may not but the important thing is not to misread the authorities. The law as laid down in Novartis v Johnson & Johnson is not as simple as saying that claims cannot ever be limited to those embodiments which work. Such claims may or may not pose an undue burden on the skilled person. If they do they will be insufficient. If they do not, then not.
… it may be admissible to recite a group of substances in a generalised form, even if not all substances that belong to this group are suitable for the purpose of the invention, provided the skilled person is easily able to determine the suitability of the individual substances by experiments …
279. In summary, the principles I derive from these authorities are:
i) When examining any aspect of claim scope for the purposes of the enablement it is necessary to distinguish between ranges relevant in the Regeneron sense and other ranges.
ii) For ranges relevant in the Regeneron sense, to be sufficient, there must be enablement across the whole scope of the claim within that relevant range (subject to de minimis exceptions) at the relevant date. If a type or embodiment within such a range is not enabled at that date then the fact it could be made later, as a result of further developments not enabled by the patent, even though it never could have been made without the invention, will not save the claim from insufficiency.
iii) Not all claims will necessarily contain a range relevant in the Regeneron sense but if they do, then this principle applies to that range.
iv) An example of an other range, not relevant in the Regeneron sense, will be a descriptive feature in a claim (whether structural or functional) which can cover a variety of things, but for which that variety does not significantly affect the value or utility of the claimed product or process in achieving its relevant purpose. The relevant purpose is judged in all the circumstances, starting from the terms of the claim itself but also, where appropriate, by reference to the essence or core of the invention.
v) For a claim feature which amounts to a range in this other sense, the skilled person must still be able to make a suitable selection, without undue burden, in order for the claim to be sufficiently disclosed. However provided that is so at the relevant date, such a claim feature will not be insufficient simply because it is capable of also covering within its scope things which had not been invented at that relevant date.
vi) When examining enablement of any kind, the test is always about what the skilled person is able to do without undue burden. The patentee is entitled to expect that the skilled person, in seeking to make the invention work, will exercise that skill. If need be that exercise will involve testing and experiments, as long as it is not unduly burdensome.
280. Turning to the facts, I will address impractical linkers first.
Impractical Linkers
289. I wondered if (as Illumina submitted) there was a simpler answer to this Regeneron point in that the ranges encompassed are all to be construed implicitly as limited only to those components which are suitable (“suitable nucleotides” etc.), however I do not believe that would be an answer, since it does not face up to the fact that the claim also covers later invented suitable types.
290. However just because the claims are not invalid based on the Regeneron principle is not the end of the analysis. Part of MGI’s case, based as it is on a squeeze on inventive step, is that the need to select suitable types presents an undue burden for the skilled person. I reject that. On the facts I have found the skilled person can select suitable types of the various components without difficulty. The exercise of skill and some routine testing may be needed but I am not satisfied any burden of undertaking that work is undue. I reject this limb of the insufficiency.
Read length
292. The first question is whether in claim 12 a read length from a single base up to whatever upper limit one chooses, is a relevant range in the Regeneron sense. MGI submitted that it was, Illumina in effect submitted that it was not. One of Illumina’s submissions was that the claim was to a method (singular) for determining a sequence rather than to a range of methods.
296. At this point I will track back to obviousness because MGI contends this is a squeeze and so if I reach the answer I have reached, then that could only be because the claim should have been obvious. I do not agree with that, for the following reasons.
297. MGI is right that this conclusion highlights that all that needed to be obvious to invalidate claim 12 was to sequence a single one nucleotide using the 3' azidomethyl blocked nucleotide (with linker etc.). (And note that there is a bit more to claim 12 and claim 7 than incorporation - about blocking a subsequent nucleotide in claim 7 and removal of a label before incorporation of another nucleotide in claim 12, but nothing turns on those points.) The problem for MGI is that this dimension to the arguments on inventive step does not help MGI on the facts. The conclusion rejecting insufficiency is not inconsistent with the finding of non-obviousness.
298. What MGI is really trying to say is that because (say) Metzker 1994 did show the sequencing of one nucleotide, it follows that there is no real technical advance in this case because the claim only requires the sequencing of one nucleotide. Or similarly, that it is not open to hold (as I have) that the common general knowledge of the skilled person was that the technique of sequencing by synthesis using reversible chain terminators may well be something which could not be made to work, among other reasons because it was not reliably repeatable, because all that one needs to do to make the claimed invention work is sequence one nucleotide, and that was feasible based on Metzker. Neither point is right. There is a technical advance for the reasons already referred to. Essentially, the azidomethyl blocking group does meet the stringent requirements referred to in the patent. As for the common general knowledge, the state of the common general knowledge is a matter of fact unaffected by the scope of the claim. The fact that armed with the patent the skilled person only has to sequence one nucleotide to satisfy claim 12 does not mean the common general knowledge changes. Nor does it, in fact, alter the reasons why an azidomethyl blocking group was not obvious over Zavgorodny.
299. Given that Regeneron is a new development of the law of insufficiency I will also briefly consider what the situation would be if a read length of more than one was a relevant range in the Regeneron sense. I am quite satisfied on the evidence I have heard that the skilled person armed with the patent, willing to make the invention work, would be able carry out repeatable sequencing by synthesis using a 3'–O–azidomethyl blocking group. They would be able to run the sequencing process for substantially more cycles that the few shown in the gels in the patent. It would require the optimisation work described by Prof Leadlay and I have accepted his evidence. There would be tests to perform and a lot of work but none of it would represent an undue burden. The professor was not asked where a limit might be and MGI did not set out to establish that. MGI’s sole case on the evidence was based on Prof Marx’s criticisms of the quality of the data in the patent but as I have explained already, I do not accept them. Nor do I accept that those concerns indicate that the skilled person would be hampered in being able to put the sequencing technique disclosed in the patent into practice.
300. The legal burden of proof to establish insufficiency is on MGI. No evidential burden has shifted. There is no evidence which would allow me to make a finding on the balance of probabilities that the limit of what the skilled person is enabled to do, without an undue burden, is anything less than what they would reasonably regard as what had been promised by the patent, or claimed if, contrary to my finding, claim 12 does represent a range of read lengths in the Regeneron sense.
301. I reject MGI’s case based on insufficiency.
Added matter - amendment
302. No amendment will be allowed if it has the result that the matter disclosed extends beyond that disclosed in the application for the patent as filed. The leading case on added matter is Nokia v IPCom [2012] EWCA Civ 567. At paras 45-60, Kitchen LJ reviewed the law on added matter. At para 60 he described the key question as “whether the amendment presents the skilled person with new information about the invention which is not directly and unambiguously apparent from the original disclosure. If it does then the amendment is not permissible”.
303. The issue relates to claim 9 (claim set B) of 289 (claim 13 as granted). Claim 9 adds to the sequencing method claims of 289 (claim 6 of claim set B et al) a requirement to remove the blocking group using a water soluble phosphine. Illumina seek to amend that claim to add the words “under neutral, aqueous conditions”. MGI says this amendment adds matter. The reason why is a bit of a paper chase. It is true (as Illumina points out) that there is textual support for the amendment at p43 ln 10 of the application as filed (this happens to be the same text about removing the azidomethyl group which has been quoted above from the priority document P2). The same passage also seems to have become para [0103] as granted in 289. However MGI says that in the application as filed there was also a limiting definition of an aqueous solution. It was at p5 ln 26-34. The definition places a lower limit on the amount of water in the liquid of at least 20%. This definition has not been carried forward into the granted patent. Therefore, it is said by MGI, whereas in the application as filed “aqueous conditions” would be understood to be at least 20% water, as amended the claim will add matter because it uses the general phrase and could be understood to envisage aqueous conditions with less than 20% water.
304. Neither party devoted much effort to this point but it still needs to be decided. No evidence has been drawn to my attention which is said to have a bearing on the issue. I say this because I believe some evidence was required. While the definition passage which MGI relies on is indeed not in the specification of 289 as granted, that passage is in the specification of 578 (at paragraph [0015]), which of course is also based on the same application as filed. Its context (as it is in the application as filed) it is part of a section (from paragraph [0014] as granted of 578) which is addressing what is said to be a method of deprotection using a water soluble transition metal catalyst. Perhaps that is not relevant to the claimed method (I do not know but there are notably fewer references to transition metal complexes in 289) but it would then explain why the passage was deleted (presumably without objection from the examiner) when the 289 specification was drawn up. Furthermore if MGI’s objection to the claim amendment was a good one, then that removal from 289 of that passage discussing transition metal catalysts has had the consequence that the other passage which refers to aqueous conditions to deprotect the azidomethyl (now at [0103] of 289) adds matter for the very reason MGI objects to the amendment. In other words if the argument is right the specification itself adds matter irrespective of the claim amendment. Of course that does not mean the argument is necessarily wrong but it puts it in context.
306. Thus the amendment is formally allowable. However as far as I am aware the purpose of the amendment has not been drawn to the court’s attention. The pleaded reasons are entirely generic and opaque. I guess part of the reason for the amendment is so that the claim is in the same form as a set of claims before the EPO in the continuing opposition proceedings. That all very well (and is the right thing to do) but the court ought not be in doubt about what the consequence would have been if the amendment was not formally allowable. Presumably there is somewhere an attack on validity to which this is an answer. No amendment should be permitted without the patentee explaining with reasonable specificity what the purpose of the amendment is. I will allow Illumina the opportunity at the hearing to determine the form of order to explain what the purpose is, and if that is done satisfactorily then I will allow the amendment.
Infringement
307. As explained in the introductory section above, infringement of a number of claims is admitted. This section is only concerned with the infringement issues where a point has to be decided. To recap, they are (i) whether Cool MPS falls within claim 12 of 578 (Claim set A) [MGI MNP Issue 10] and (ii) whether either the two colour variant of Standard MPS or the DNBSEQ E method fall within the kit claims, claim 20 of 578 (claim set A) or claim 4 of 289 (claim set B) [MGI MNP Issue 9].
308. Illumina advances its case of infringement both on a normal construction and (for issue (i) about Cool MPS) by the doctrine of equivalents. Following the Supreme Court’s decision in Actavis v Eli Lilly [2017] UKSC 48, the correct approach to infringement by equivalents is to ask three questions (see [66] of Lord Neuberger’s judgment in Actavis):
(i) Notwithstanding that it is not within the literal meaning of the relevant claim(s) of the patent, does the variant achieve substantially the same result in substantially the same way as the invention, ie. the inventive concept revealed by the patent?
(ii) Would it be obvious to the person skilled in the art, reading the patent at the priority date, but knowing that the variant achieves substantially the same result as the invention, that it does so in substantially the same way as the invention?
(iii) Would such a reader of the patent have concluded that the patentee none the less intended that strict compliance with the literal meaning of the relevant claim(s) of the patent was an essential requirement of the invention?
309. To establish infringement the answers have to be yes, yes and no.
(i) whether Cool MPS falls with claim 12 of 578 (Claim set A) [MGI MNP Issue 10]
313. Thus MGI says that the nucleotide in the state it is incorporated into the chain does not have a linker or label attached to it. Therefore there is no incorporation of the required thing in the claim. By contrast Illumina says that if one considers the state of the system when detection takes place, the antibody has bound to the nucleotide and that whole conjugate structure has been incorporated. In that conjugate structure the nucleotide is linked by the antibody to a label. Therefore since the required thing in the claim has been incorporated, the claim is satisfied. Illumina also says that if this is not a literal infringement it is equivalent and infringes that way.
314. MGI’s second point is that even if that composite structure is to be regarded as incorporated, there is no infringement because the claims require the cleavable linker to be covalent in nature and to be linked only to the base. As regards the first aspect, there is no dispute that antibody binding is not covalent and so, if MGI is right on construction, then there is no literal infringement. However Illumina disagrees with that construction, submitting the claim is not limited to covalent linkers, and also again relies on equivalence even if there is no literal infringement. The other point arises because the antibody binds to more parts of the molecular structure than the base. The issue is a pure point of claim construction. There is no equivalents aspect.
315. I will start with both aspects of the linker issue.
Cleavable linker
317. MGI’s case is that all the linkers in the specification are covalent in nature and so, the skilled reader would see that what the patent meant by the term was a covalently bonded chemical group. I agree with MGI that all the examples given in the specification are covalent (e.g. the last two sentences of [0023], and the linkers in [0079]-[0090] (using the numbering in 289)). However I do not agree that that leads to the conclusion that the skilled reader would think that a characteristic about the nature of the chemical bonding had to be read into the term. The skilled reader would understand the expression “linker” as a general one and one which is defined functionally. It is anything which links. No doubt, as the skilled reader would see from the patent, the examples the patentee could think of when the patent was written were indeed covalent but the reader can also see that the patentee has used the broadest language available to define that which links the label to the base. There is no basis for assuming the patentee used language in a manner intended to exclude anything which in fact makes a suitable link between the base and the label.
318. There was a point about the passage in the specification about multi-component linkers and biotin (paragraph [0066] of 289). Illumina suggested it referred to non-covalent structures like biotin. However there is a bit more to it than that. Here the patent is indeed contemplating what it calls multi-component labels, and in those instances the detection of the label moiety occurs by non-covalent binding of a detector molecule to a label molecule. One example given is using a streptavidin molecule to bind to a biotin label. However there is nothing here to suggest that the mode of attachment of the biotin label moiety to the base is any different from any other teaching in the patent. This paragraph of the patent does not assist Illumina (nor does the reference in this paragraph to antibody detection at the end of it, which would be understood in the same way).
319. MGI relied heavily on the passage at paragraph [0076] (of 289) which states that cleavable linkers are known in the art and says that conventional chemistry can be applied to attach a linker to a base. This does not help. Prof Leadlay’s view (to the extent it is relevant) was that this would be understood very often to be covalent attachment but did not absolutely exclude other ways of doing it. I accept that.
322. The question of equivalents does not therefore arise however I will consider it on the hypothesis that, on the contrary, the term cleavable linker does require a covalent bond. MGI suggested that the skilled reader would take it that the patentee was aware of and contemplated antibody detection but did not claim it. I do not agree that that is a fair way of putting it. MGI here is relying on the same paragraph [0066] (of 289) which refers to biotin and antibody detection. As MGI was at pains to point out when considering normal construction, this paragraph is not concerned with alternatives to the conventional kinds of linkers described elsewhere. The non-covalent interactions here, between the streptavidin detector and biotin label or between the antibody detector and dinitrophenol label, are not examples of non-covalent linkers. Therefore they would be within the claim even if it was limited to covalent linkers.
323. Conversely the reference to antibody detection in that paragraph does not assist Illumina either for the same reason. It is different.
324. MGI also suggested that the skilled person would think strict compliance with the literal meaning of the expression (construed to mean covalent) was essential because the skilled person would know that if they wanted to use an antibody detection technique like Cool MPS they would need to raise the antibodies themselves. I do not buy that. There is nothing in the specification which would lead the skilled to think that the reason for limiting the linkers to covalent linkers was anything to do with that sort of consideration. As for the common general knowledge, as between Prof Leadlay’s evidence that the team could be confident of raising a suitable antibody and Prof Greenberg’s view that antibodies for DNA lesions did not work well, I prefer Prof Leadlay on this. I do not accept MGI’s suggestion that Prof Leadlay’s evidence was bombastic. Prof Greenberg was not an expert on the relevant antibody literature.
Incorporation of a nucleotide [of claim 3]
326. To recap, in Cool MPS at the moment in time when the unlabelled 3'-O-azidomethyl blocked nucleotide joins the chain complementary to the target sequence it is not a molecule of claim 3. Therefore MGI says there is no incorporation of the required molecule. By contrast at the moment in time when the fluorescent detection takes place, the relevant nucleotide is a molecule within claim 3, because the base is linked to a detectable label via a cleavable linker. Therefore Illumina says the claimed molecule has been incorporated, albeit in two steps. Which is the right way of looking at it?
328. MGI says the claim refers to incorporation of labelled nucleotides (e.g. paragraph [0004]). So it does but I do not agree that that resolves the distinction between the two parties’ cases.
329. MGI also points to passages (e.g. [0028]) which describe the thing being acted on by the polymerase as the blocked and labelled nucleotide (my emphasis). MGI also submits that the patent explains that the linker should be long enough so as to hold the label far enough away so as not to interfere with the polymerase enzyme (paragraph [0088] of 289). These points are right and they reflect the specifics of the methods exemplified in the patent. The question is whether they justify reading a limitation into the claim. They would be stronger if the claim as expressly stated that the process of incorporation had to be completed by the polymerase alone, but the claims say no such thing. The polymerase itself is not even mentioned in either claim 7 or claim 12 (claim set A).
330. MGI also points out that the patent indicates that it is desirable that the cleavable linker should not interfere with subsequent incorporation of a labelled nucleotide (paragraph [0068] of 289). However, although I do not think it matters, in case it does I do not accept that MGI has established that there is no risk of interference with the subsequent nucleotide in the sequencing effort using Cool MPS. That is because the Cool MPS process contains a step which only makes sense if there is an appreciable risk that some antibodies remain bound even after the washing step to remove them. That step is a step to cleave the covalent linkage between the fluorescent label and the antibody.
332. MGI points out that claim 12 (claim set A) is a method claim not a product claim, which is right of course. MGI submits that what matters, as a matter of process, is what the polymerase enzyme incorporates into the growing complementary polynucleotide. I do not accept it is that simple. When one focusses on the process steps required by the claim, there are three steps in the overall method, and they are all important. They are (i) the incorporation of a nucleotide of claim 3, (ii) the determination of the identity of the incorporated nucleotide of claim 3, and (iii) the removal of the blocking group and the label before the incorporation of the next complementary nucleotide. The overall method is a way of determining the sequence of a target single stranded polynucleotide by monitoring the sequential incorporation of complementary nucleotides.
334. As before I will consider equivalents in case I am wrong. MGI submitted that one should not approach the third Actavis question on the footing that the skilled person must assume that the patentee knew about the proposed variant. I think that must be right in the sense that one does not make an assumption of any kind (unlike the second question), but I doubt anything turns on it.
335. On the hypothesis that the normal construction of the claim requires a single incorporation step of the molecule in the form of claim 3 by the action of the polymerase, MGI’s major submission is that there is no disclosure or contemplation in the patent of an alternative to that approach, and referred to three technical issues associated with that. One is the paragraph [0066] multicomponent label point. That is addressed above and adds nothing. Second is the suggestion, put to Prof Leadlay, that the patent, by referring to attachment of the label to the base or the blocking group, is inviting the reader to think other positions are less favourable. Prof Leadlay accepted that was a reasonable possibility and I accept that evidence. However I do not agree that it means that the patent can be read as actually ruling out those attachments or other kinds of attachment.
337. MGI’s argument was that the skilled person would presume that if the patentee had thought of a way of avoiding scarring by not having any sort of attachment to the incorporated nucleotide (and thereby no scarring), then the patentee would have mentioned it and so the fact that it is not mentioned proves the patentee did not think of it.
338. I think the position is simpler than these submissions seek to make it. I agree with MGI that the patentee does not describe an antibody detection method like the Cool MPS method, nor does it describe the idea of a two step incorporation. However I do not agree that this answers the third Actavis question in MGI’s favour. Indeed if the patent had disclosed a two step method but had a claim which on a literal construction excluded it, then that would be a much stronger case for answering the third question in MGI’s favour.
(ii) whether either the two colour variant of Standard MPS or the DNBSEQ E method fall within the kit claims, claim 20 of 578 (claim set A) or claim 4 of 289 (claim set B) [MGI MNP Issue 9].
343. Claim 20 of 578 (claim set A) provides for “A kit, comprising, a plurality of different nucleotides wherein said plurality of different nucleotides are as defined in [claim 3]”. Claim 3 relates to a 3'–O–azidomethyl blocked nucleotide with a detectable label linked to the base by a cleavable linker. MGI contends that claim 20 is not infringed because the claim should be understood as requiring all the nucleotides present to satisfy claim 3 (i.e. have a detectable label) whereas in the two MGI systems only three of the four types do that. I reject that as a ground for non-infringement. As Illumina submits, claim 20 used the word “comprising” which would be understood to mean includes but is not limited to. In other words provided there is a plurality of types of nucleotide which satisfy claim 3 (and there will be three types in either system), it follows that the claim is satisfied. The fact that there is also a fourth type of blocked nucleotide which is unlabelled does not matter.
EP 1 828 412 - ascorbate
348. The invention concerns using ascorbic acid or a salt thereof in the buffer used at the detection step in sequencing by synthesis, in order to mitigate photodamage to DNA. MGI says it is obvious over the prior art Buechler. Before going further it is convenient to deal now with two issues of principle arising from the relationship between Buechler and the common general knowledge. One of the submissions is that the content of Buechler (see below) adds little or nothing to the common general knowledge. Arising from that Illumina submitted it was relevant to consider the obviousness case over Buechler as amounting to an attack based on common general knowledge alone. This was said to have two consequences. First Illumina referred to the caution in Apimed v Brightwake [2012] EWCA Civ 5 at para 54, citing Abbott v Evysio [2008] EWHC 800 (Pat), about hindsight combinations of common general knowledge unencumbered by detail which might point the other way. However that point has no relevance to this argument because as a prior art document, Buechler is necessarily not a combination of ideas driven by hindsight knowledge of the invention in issue in this case. Nor does Buechler include or leave out any detail driven by those sorts of hindsight considerations.
349. The second point is a better point at the level of principle. If Buechler does not add significantly to the common general knowledge then evidence addressed to the rhetorical question - if it was obvious why was it not done before? - could be relevant. Illumina contended that there was evidence that those working in the sequencing by synthesis field at the time, before the relevant date, and therefore without knowledge of the invention, were not concerned about photodamage. Illumina based this submission on certain prior published scientific papers. These papers had not been relied on by Prof Greenberg but counsel put them to Prof Johnsson in cross-examination. When I deal with the common general knowledge, it will be convenient to address these papers at the same time. They are not necessarily common general knowledge as such but they illuminate the common general knowledge thinking and motivations of the skilled person and so it makes sense to approach the matter in that way.
350. The relevant common general knowledge is as follows.
353. It was well known that reactive oxygen species form as fluorophores are put into an excited state by the relevant illumination. These species can include singlet oxygen (which is a highly reactive oxygen molecule O2 in an excited state), hydroxyl radicals, peroxides and superoxide radical anions. There are two main processes called Type I and Type II. The Type I pathway produces free radicals which can react with other things - one effect is to lead to the production of reactive oxygen species such as superoxide, hydroxide and peroxide radicals. Type II only produces singlet oxygen. Singlet oxygen can in turn lead to the production of further reactive oxygen species.
The scientific papers
Use of antioxidants in papers on sequencing by synthesis
360. The three papers relied on by Illumina are Mitra et al Anal Biochem 320 (2003) pp55-65; Braslavsky et al PNAS April 1, 2003 Vol 100 pp3960-3964 and Seo et al PNAS April 13, 2004 Vol 101 pp5488-5493. These papers came from three well respected sources - respectively Prof Church’s group at Harvard, Prof Quake’s group at Caltech, and the group led by Jingyue Ju at Columbia University.
361. The Mitra (2003) paper is another paper concerning Prof Church’s idea for polonies and sequencing using FISSEQ (a 1999 Mitra & Church paper about the same technique is referred to above in relation to the modified nucleotide patents). To recap, this is a kind of sequencing by synthesis, but it does not use reversible chain terminators. Instead fluorescent labelled nucleotides are added a single kind of nucleotide at a time and then fluorescent detection is used to see if the known kind of nucleotide has incorporated. The technique illuminates fluorophores on labelled DNA primers and on nucleotides.
362. As Illumina points out, the wash buffers disclosed in this paper do not include any oxygen scavengers. One might infer from that that the authors did not perceive a risk of photodamage (or photobleaching) to be sufficient to be worth addressing.
363. Nevertheless the authors did observe a decrease in intensity over time. One of the possible causes of that problem which was identified in the paper itself was “incomplete extension”. Prof Johnsson explained that that would cover incomplete extension due to photodamage. The fact that a later paper showed that the group did not end up finding incomplete extension when they developed the method further does not matter. This leads to another piece of speculation, one might ask whether the absence of an express reference to photodamage in the original paper was because there was in fact no risk in their conditions anyway or was it because there was a risk but they did not realise it? Further, and not a major point, MGI are entitled to note that the original paper did recognise a potential problem, which was something which could have been caused by photodamage, although they did not spell that out and one is again left to speculate.
364. The Braslavsky (2003) paper relates to a single molecule sequencing by synthesis method in which Cy3 labelled nucleotides are used both in their own right and as fluorescence resonance energy transfer (FRET) donors for Cy5 labelled nucleotides. The science is quite involved and the detail is not necessary to understand the points. What matters is that the technique involves multiple rounds of illumination to cause fluorescence and includes a deliberate photobleaching of some of the fluorophores. Photobleaching necessarily involves creating reactive oxygen species, since that is how it occurs. Whether the experiment worked as a sequencing method or not is not really the issue. The important point for Illumina is said to be an absence of concern about photodamage to the DNA.
365. The trouble with Illumina’s case is that the authors did employ an oxygen scavenging system, which in fact included an antioxidant (although that latter point only emerged in closing - which is not MGI’s fault given the way the papers were put without supporting evidence from Prof Greenberg). The authors added the oxygen scavenging system to protect the Cy3 dye which was subjected to repeated illumination. The dye was required to fluoresce on its own or act as a donor in the FRET system, but as I say that detail does not matter. Illumina are entitled to point out that the paper does not say in terms that a concern about photodamage was a reason for the oxygen scavenging system. But as Prof Johnsson pointed out, the oxygen scavenger system would have the effect of reducing photodamage too. Illumina submits that Prof Johnsson agreed it was difficult to infer that the authors were concerned about photodamage. I do not accept that submission (based on one answer in a passage) fairly summarises the professor’s view as a whole. Prof Johnsson knew that he was being asked to speculate about the authors motives. His view was that photobleaching and photodamage go hand in hand, that there was a clear possibility of photodamage occurring and that the system the authors used would act to reduce both. He was agreeing that their prime motivation was to protect against photobleaching, because they were doing that deliberately, but that is as far as his evidence went.
Other scientific papers
368. Prof Greenberg referred to a paper by Nazarenko (2002) concerning a self-quenching PCR probe. The paper describes multiple cycles of illumination and is another example in which authors might have included an antioxidant had they been concerned about the risk of photodamage to DNA, but appear not to have done, although there is a possible ambiguity, as Prof Johnsson pointed, about stabilizers.
369. Prof Johnsson referred to two papers on single molecule fluorescence: Kapanidis & Weiss and Rothwell. In both of them the authors used ascorbate and other agents to protect against photobleaching. As Illumina are entitled to point out, these papers do not state in terms that a risk of photodamage is a motive.
370. Papers from the field of photodynamic therapy and the use of photosensitisers provide evidence which shows that fluorophores can induce photodamage by generating reactive oxygen species. However I agree with Illumina that such material does not amount to evidence which bears on the assessment of risk by a skilled person thinking about sequencing by synthesis using fluorescently labelled nucleotides at the priority date. That is because for sequencing by synthesis the skilled person would wish to use bright photostable dyes with high quantum yields for fluorescence and low triplet yields. Although photosensitisers would also be desirably photostable, they are also chosen for their high triplet yield and high singlet oxygen yield. Papers mentioned in Prof Johnsson’s report which fall into this class are Boutrine (1996) from Claude Hélène’s group at Inserm and the De Rosa review paper (2002). It is about photosensitisers.
The papers - conclusions
371. Taking the evidence of the three sequencing by synthesis papers in particular, in my judgment they do not support a finding which assists Illumina. The material is not a reliable basis from which one could infer that real teams working in sequencing by synthesis itself did not think photodamage to the DNA was a sufficient risk so as not to take any steps to mitigate it. The Mitra paper is Illumina’s best paper for that submission but it was very early work and it is not clear whether the risk of photodamage in those circumstances has ever turned out to be a material problem anyway in those conditions. The Braslavsky paper does not support any inference in Illumina’s favour. The authors added an oxygen scavenging system for their own reasons. It would have protected against photodamage too. Also the Seo paper does not support Illumina’s case because the authors did in fact use a system which scavenged radicals. Some kind of photobleaching or photodamage may or may not be the reason why they did this.
374. Illumina’s submission overall is that the skilled person would choose to use bright and photostable fluorophores in sequencing by synthesis and in that context there was nothing in the common general knowledge to alert the skilled person to the risk of photodamage. That was said to be because bright and photostable fluorophores necessarily reduce the extent to which reactive oxygen species are created and so reduce and risk of photodamage. Prof Johnsson did not accept it was that simple. His view was that the skilled person using a fluorescent system was always aware of that risk. By which he meant an appreciable risk.
375. There was evidence about the intensity of illumination required. One needs to take care with figures expressed in watts because the intensity also depends on the area illuminated and is governed by an inverse square law. No quantitative conclusion can be expressed based on the common general knowledge. Nevertheless the evidence did support a qualitative conclusion. The skilled person at the priority date thinking of using fluorescent detection in a sequencing by synthesis context would regard the illumination likely to be required as relatively intense, albeit applied for short periods. That would have a bearing on their views about risk.
The specification of the 412 patent
380. It bears spelling out that the purpose of the buffer is to prevent photodamage to the DNA strand rather than photobleaching to the fluorophores. Every time the fluorophores are illuminated (once per cycle) a fresh lot of reactive oxygen species will be generated which can then go on to react with other molecules. However at every cycle of this process the old fluorophores are washed away and fresh fluorophores are added in the form of fresh labelled nucleotides. Therefore an individual fluorophore molecule does not experience more than one cycle of illumination. However the DNA strand remains in place all the time and so, as the complementary strand grows and the cycles repeat, the DNA will have been present for an increasing number of illumination events, each generating some reactive oxygen species. Note that this explanation follows from what is in the patent, it does not mean that the skilled person, without hindsight, would necessarily see this or think it through in this way. A common slip in patent cases is to equate the fact that the invention can be explained after the event with obviousness. They are not the same.
Claim construction / infringement
381. Claim 1 as proposed to be amended is in this form:
1. A method of sequencing at least two nucleotides of a template nucleic acid by successive cycles of sequencing-by-synthesis comprising repeating the steps of:
a) incorporating one or more fluorescently labelled nucleotides into a strand of nucleic acid complementary to said template nucleic acid; and
b) determining the identity of one or more of the incorporated nucleotide(s), wherein the steps of determining the identity of the incorporated nucleotide(s) is carried out in a buffer which comprises ascorbic acid, or a salt thereof.
[amendment emphasised]
383. Step (a) of the method refers to the incorporation of a fluorescently labelled nucleotide into the complementary DNA strand. Step (b) relates to the imaging step. That is the occasion when the ascorbate needs to be in the buffer because that is when the illumination takes place.
385. In terms of infringement - there is no dispute that MGI uses ascorbate in its relevant buffer. Therefore (save for the E variant) Standard MPS infringes claim 1 and this is admitted. The only issue of infringement of claim 1 relates to Cool MPS. The use of antibodies as the way of labelling the incorporated nucleotide raises an analogous infringement issue to the issue about incorporation which arises for the modified nucleotide patents. Illumina contends there is literal infringement but if not infringement by equivalents.
388. MGI relied on two further points in support of its case on normal construction. I mention them in case this goes further. One was the same kind of point made for the modified nucleotide patents, namely that the examples in the specification are all cases in which the nucleotide acted on by the polymerase has the label already linked to it. In the case on the modified nucleotide patents this did not help. If it were not for the narrow express definition in the 412 patent it would not help here either, but along side that definition it is supportive.
389. The other was the submission that there was said to be no technical reason why the claim would be understood to cover methods where the fluorophore was added after the nucleotide was incorporated. Prof Greenberg’s view was that how the labelling was achieved was immaterial to the second (detection) step (which he called imaging). MGI contended (closing para 189) that the skilled person would understand that there were technical reasons why labelling with the fluorophore after incorporation may affect photodamage.
390. In fact the evidence MGI relied on for this was a paragraph in a confidential annex to Prof Johnsson’s third report in which he explained that there were various potential benefits from doing the labelling using an antibody, as in Cool MPS, rather than having the fluorophore linked covalently to the nucleotide. It does not matter what the particular potential benefits are and since it was in a confidential bit of the report I will not spell them out save to say that one was that the risk of photodamage might be reduced. This evidence does not support MGI’s case on normal construction. In my judgment Prof Greenberg’s evidence referred to above represents the thinking of the skilled person reading the patent. It would support a wide meaning, like the one in the modified nucleotide patents, were it not for the expressly narrower definition in the specification of 412. [After the draft judgment was circulated I was told that MGI no longer maintained the confidentiality of the annex.]
391. Therefore I find there is no infringement on a normal construction.
392. Turning to equivalence, as with the modified nucleotide patents, it is common ground that the first two Actavis questions are answered in Illumina’s favour. The issue is the third question.
393. MGI is right that all the examples in the 412 patent have the nucleotides directly linked to a fluorophore and the specification does not mention the idea of an alternative based on subsequent labelling in general nor the use of antibodies to do that in particular. However these are not strong points in MGI’s favour on the third question.
394. MGI made the same point here which it did for the modified nucleotide patents, that if the idea underlying Cool MPS (using antibody labelling) had been suggested then the skilled person would think it was difficult to raise antibodies. I have preferred Prof Leadlay’s view to the contrary over Prof Johnsson’s view on that score. In the 412 case MGI also referred to what was similar evidence from Prof Marx, that to make it work would require significant research. The fact that MGI called similar evidence from two experts does not improve it. I do not doubt that the work would be significant but I still prefer Prof Leadlay’s evidence. In my judgment the team would be confident it could be done. Therefore this line of thinking does not assist MGI on the third Actavis question.
395. Finally MGI repeated the point that the antibody method “could affect” the extent of photodamage. As explained already, this evidence (in an annex to Johnsson 3) is in fact that the method potentially could reduce photodamage. That is not a reason which supports MGI’s case on equivalents at all. I remind myself that this issue arises because MGI’s Cool MPS antibody method contains ascorbate in the buffer. Using that additive, to reduce the risk of photodamage, is the essence of the invention of the 412 patent and claimed in claim 1.
396. Despite these unconvincing arguments from MGI, in fact I believe the answer to the third Actavis question should be in MGI’s favour for a much simpler reason. The reason why skilled person would think that strict compliance with the normal construction of “incorporation” was essential is because the specification has gone out of its way to define that term in a clear and simple way. It is not necessary for the skilled person to speculate about why the patentee may have done that, the fact is that it has been done. The Cool MPS system is in fact an immaterial variant to the invention claimed in claim 1, but the patent is deliberately drafted in such a way as to exclude it.
397. Claim 15 is in this form:
A kit for use in a method according to any one of claims 1 to 14 comprising:
one or more fluorescently labelled nucleotides, wherein the fluorescent label is linked to the nucleotides via a cleavable linker;
an enzyme capable of catalysing incorporation of said nucleotides into a nucleic acid strand complementary to a nucleic acid template to be sequenced;
and a buffer comprising ascorbic acid or a salt thereof, or a supply of ascorbic acid or a salt thereof.
398. There is no dispute that (again save for the E variant) Standard MPS infringes this claim, and this is admitted. Illumina does not contend that CoolMPS infringes this claim either literally or by the doctrine of equivalents.
Obviousness
Buechler
404. However of more significance is the point emphasised by Illumina about the conditions (time and illumination) that Buechler is focussed on. The experiments are mostly focussed on storage of material over periods of hours or days, comparing the effect of storage in the dark with storage in ambient room light. The one example which does not involve storage is example 10 but again here the test is between the assay conducted in the dark (dim green light) against the assay conducted under white room light and the illumination being examined was ambient room light.
405. Illumina also pointed out that Buechler (mostly) used phthalocyanins as the fluorophore molecules. Illumina emphasised the point that some phthalocyanins are used for their appreciable yield of singlet oxygen in photodynamic therapy. I do not accept that this represents a reason why the skilled person who was thinking about a particular assay (in this case some kind of sequencing by synthesis assay) would discount what is described in Buechler as something of no relevance. They would see Buechler as making a general point, supported by experiments in specific circumstances.
Is claim 1 obvious?
408. What would the skilled person think having read Buechler? I do not accept that much is gained for Illumina by the difference in conditions. The skilled person would not approach matters on the basis of trying to reason out relative risk by comparing the conditions used in the experiments in Buechler with those in a sequencing by synthesis experiment. It is manifest that the conditions are quite different in terms of time and illumination intensity. That is not how the skilled person would think. What the skilled person would see in Buechler was a teaching that in the context of bioassays using fluorescent conjugates, there was photodamage to biological molecules in an in vitro context. That included a risk of damage to nucleic acids. They would understand the mechanism which caused this - that illumination of a fluorophore can generate reactive oxygen species which in turn can cause photodamage to other molecules like DNA.
409. MGI submitted it would reinforce the skilled person’s common general knowledge of the risk of photodamage. I agree. That is how it would strike them.
410. An important point, emphasised by Prof Johnsson, is that ascorbate was a stable, soluble and readily available additive which the skilled person would be familiar with and would have no concern about any negative downstream effects. This materially assists MGI’s case. Since, as they were, the mitigation steps were very well known and have no serious drawbacks associated with them, this case is not about a problem where the solution requires any effort to find, is hard to do or comes with significant downsides. The skilled person would not add an additive for no reason, but if they thought there was any appreciable risk that reactive oxygen species might have a relevant effect in this particular context, it would be obvious to add ascorbate.
411. Illumina submitted that the skilled team would use bright and photostable dyes, but as Prof Greenberg agreed, the reason for doing this was to minimise the generation of reactive oxygen species that could bleach the dye and damage the DNA. The professor accepted that having a photostable dye and using a stabiliser like ascorbate were both ways of getting to the same end, which was to minimise photobleaching and photodamage.
412. Standing back, in my judgment the invention is obvious to a skilled person in the light of Buechler. The skilled person would know there was an appreciable risk of photodamage to the DNA given that it will be in the presence of fluorophores and repeated, relatively intense, illumination. One way in which a skilled person could mitigate that risk to some extent would be to select a dye regarded as very bright and photostable but it was equally obvious to choose a moderately bright and photostable dye. Either way it would be obvious to add ascorbate to the relevant buffers in a sequencing by synthesis reaction. The skilled person would have no doubt that whatever conditions and materials were chosen, some reactive oxygen species would be generated. Ascorbate is a well known antioxidant, known to mitigate the inevitable risk.
Alternative cases
413. An alternative case which Illumina perceived MGI to be advancing was that it was obvious to add ascorbate to mitigate a risk of photobleaching of the dye itself. I did not detect such a case but if it was suggested I would not accept it. A skilled person thinking about that would appreciate that any given set of dye molecules only experience one round of illumination.
414. An alternative case which MGI did advance was the submission that even if the skilled person did not think of adding ascorbate at the start, when they ran their experiments they would encounter a fading of the signal in successive cycles (just as reported in the patent at paragraph [0005]). It would be obvious that the cause was photobleaching of the DNA and obvious to apply Buechler at that point and thereby add an antioxidant such as ascorbate. This was Prof Johnsson’s evidence and MGI submitted that it was not challenged in cross-examination.
415. First as a matter of principle, this kind of argument is open to MGI. The fact that it works in a notional way in that experiments which take some time to set up and run before the problem is noticed are treated as taking place at the priority date, is not a valid objection to it (see Merck v Teva [2011] EWCA Civ 382 paragraphs 36-37).
417. I find that even if it was not obvious to decide to add ascorbate to the buffers before carrying out any sequencing by synthesis tests in the first place, the skilled person who took that approach would, acting without any inventive step, encounter a problem of fading and would, without invention, find that it was caused by photodamage by adding ascorbate. The claims are obvious based on MGI’s alternative case too.
Added matter and amendment
418. The law on added matter was set out above in the relevant section for the modified nucleotide patents. The added matter argument here is an intermediate generalisation point directed to something missing from claim 1 as granted (and dependent kit claim 15). Claim 1 is set out above. What is absent from it is essentially any reference to the character of the illumination needed to cause the label to fluoresce (such as being intense). The allegation is that the application as filed (published as WO 2006/064199) only discloses the method of claim 1 together with the requirement that the detection step includes repeated or prolonged exposure to intense illumination. MGI refer to p3 ln3-8 and ln12-18 of the specification in the application and also to claim 1 as filed (at p50 ln3-8). As a matter of the words in the document, MGI is correct. The argument then goes that the difference between the disclosure in the application and the claim as granted is not trivial because although in sequencing by synthesis one generally would use intense illumination, Prof Johnsson explained that that is not necessarily the case. The precise intensity required will depend on the equipment used and the time of illumination and, he said, “I do not think that intense light would strictly be necessary”. Thus argues MGI the application discloses the invention as applicable to a sub-set of sequencing by synthesis processes, namely those which include exposure to intense illumination, whereas the teaching of the granted patent is that the ascorbate containing buffer can be applied to all sequencing by synthesis processes. This is said to be new information and added matter.
420. Is MGI right? In my judgment the answer is no. The reason why not is because no new information is provided in the granted patent as compared to what was disclosed to the skilled person imbued with the common general knowledge by the application as filed.
421. I am not persuaded that the skilled person would read the references to intense illumination in the application as filed as a disclosure that the invention was directed to a sub-set of sequencing by synthesis processes. Rather, if they thought about it at all, they would read it as reflective of a shared assumption made by the reader and the inventors that sequencing by synthesis did involve illumination which they would regard as relatively intense. Or putting it another way, while I have no difficulty with Prof Johnsson’s view that the degree of intensity of illumination will vary, I am not convinced that his evidence can be taken to mean that the skilled reader of the application as filed would ever have in mind an idea that there is such a thing as sequencing by synthesis using illumination which would not be fairly regarded as “intense”, particularly given the qualitative nature of the expression itself. I accept Prof Greenberg’s view that the skilled person would understand the reference to “intense illumination” to be a description of the type of illumination they would expect to be required to achieve fluorescence imaging in sequencing by synthesis.
422. Moreover I am not persuaded that the skilled person reading the granted patent as a whole (including the claim) would detect any suggestion that the invention was being taught as applicable not only to an “intense” sub-class of sequencing by synthesis techniques but also to a “non-intense” subclass of sequencing by synthesis too. The teaching about intense illumination in the specification of the application is still present in the granted patent, at paragraphs [0007] and [0008]. The fact the expression is not in claim 1 (or claim 15) would not lead the reader to reason that therefore there is a positive teaching that the invention could be used in other circumstances. If a truly non-intensely illuminated form of sequencing by synthesis was part of the common general knowledge at the relevant time then I suppose the argument might be more tenable, but there was no such evidence.
423. I reject the added matter case.
EP 2 021 415 - labelled nucleotide
The common general knowledge
The patent and claim construction
441. Note the azide group roughly in the middle. It makes the linker cleavable.
A nucleotide labelled with a compound according to the formula:
451. There is no issue about infringement. MGI accepts that it has made, used and sold a compound within what is now claim 1 in its RCT sequencing systems in issue in this case.
452. The issue is validity over Milton and Arnost and an insufficiency squeeze. Milton is a patent from the Solexa group. Essentially MGI’s case is as follows. Milton discloses the idea of using labelled nucleotides with cleavable detectable fluorescent labels in a sequencing by synthesis process. In particular it discloses a nucleotide labelled with a fluorescent dye called Cy3 which has been conjugated to the nucleotide using a linker which is in fact linker LN3 in the 415 patent and is part of the molecule claimed in the 415 patent. Milton teaches that this is a useful product in sequencing by synthesis. On the other hand Arnost (a patent from the Polaroid company published in 1990) discloses fluorescent dyes for making in labelled conjugates for use in biological diagnostic assays. Compound XVI of Arnost is in fact Dye 2 of the 415 patent. Indeed Arnost teaches derivatisation of the dye moieties, albeit the linker arm used in the 415 patent is not disclosed.
453. MGI then argues that in the light of this prior art claim 1 is a mere collocation along the lines of Sabaf v MFI [2004] UKHL 45 and as recognised in some European Patent Office decisions and in the EPO Guidelines for Examination. MGI argues that in the claimed molecule the nucleotide, the linker and the dye each act independently of one another. They each perform the function for which they were already known in the art (or was obvious). However the whole is not greater than the sum of the parts. There is no synergy in this combination. And so no inventive step.
454. Importantly MGI does not say, and has no evidence that, it would have been obvious for a skilled person given Milton to use the dye XVI disclosed in Arnost. One can well understand why such a case would not have succeeded. It is hard to imagine, absent hindsight, that the skilled person would ever alight on dye XVI of Arnost having read Milton. There is no evidence that the application of the common general knowledge by a skilled person reading Milton would lead to the Arnost document at all. Notably dye XVI of Arnost (aka Dye 2 of the 415 patent) was not a commercially available rhodamine dye at the priority date.
455. MGI’s submission is that it does not have to prove that it would have been obvious for a skilled person given Milton to use the dye disclosed in Arnost. The reason why not is because the combination of the nucleotide plus linker of Milton with the dye of Arnost has no extra technical effect or benefit, over and above the known effects of those components acting independently.
456. As an alternative MGI argues that the claim makes no technical contribution to the art and is invalid as Agrevo obvious for that reason. The Milton prior art teaches that a fluorescent dye labelled nucleotide with this linker will be useful in sequencing by synthesis, and no further contribution to the art is made by the 415 patent showing that a particular dye used with that linker/nucleotide combination is useful in sequencing by synthesis.
457. Illumina does not agree. Its case is that the compound of claim 1 is a useful compound, that its utility derives from the compound as a whole and cannot be parsed down to be nothing more than the sum of the parts. Therefore the collocation argument fails. Illumina also submits that the successful use of the compound taught in the 415 patent’s 20 cycle sequencing reaction with a 1% error rate represents a technical advance over Milton and an answer to MGI’s alternative case.
458. Illumina also points out that despite the researches of its legal team, there is no case in which the collocation principle has been applied to a case about a chemical molecule. The submission is that this is not an accident. It is because the argument cannot succeed when applied to that sort of invention.
The law
461. The leading case is Sabaf. Lord Hoffmann gave the single judgment. At trial Laddie J had found the claim was invalid, applying the “law of collocation”, much along the lines argued in the present case by MGI. Laddie J made reference to Lord Tomlin in British Celanese v Courtaulds (1935) 52 RPC 171 and to the EPO Guidelines. The Court of Appeal overturned that decision because they found the law to be that it was impermissible to combine two prior art disclosures unless it was obvious to combine them. Lord Hoffmann held that the Court of Appeal’s approach was contrary to both English and EPO law (paragraphs 19-24). He summarised the applicable principles in two ways. First in paragraph 24 he approached the matter on the basis that there may be two inventions in a single patent claim, holding that:
“24. […] I quite agree that there is no law of collocation in the sense of a qualification of, or gloss upon, or exception to, the test for obviousness stated in s.3 of the Act. But before you can apply s.3 and ask whether the invention involves an inventive step, you first have to decide what the invention is. In particular, you have to decide whether you are dealing with one invention or two or more inventions. Two inventions do not become one invention because they are included in the same hardware. A compact motor car may contain many inventions, each operating independently of each other but all designed to contribute to the overall goal of having a compact car. That does not make the car a single invention.”
462. Then, after dealing with s14 of the 1977 Act, Lord Hoffmann said this:
“26. The EPO guidelines say that “the invention claimed must normally be considered as a whole”. But equally, one must not try to consider as a whole what are in fact two separate inventions. What the Guidelines do is to state the principle upon which you decide whether you are dealing with a single invention or not. If the two integers interact upon each other, if there is synergy between them, they constitute a single invention having a combined effect and one applies s.3 to the idea of combining them. If each integer “performs its own proper function independently of any of the others”, then each is for the purposes of s.3 a separate invention and it has to be applied to each one separately. […]”
465. Illumina drew attention to a passage in the extract from Lord Tomlin’s speech in British Celanese which is cited in Sabaf. Lord Tomlin’s way of characterising the first case I have mentioned above was to as one in which the prior art features, when placed together, “have some working inter-relation producing a new or improved result”. MGI suggested this was wrong in the light of Sabaf. I do not believe it is, provided it is understood in the context of what Lord Hoffmann said. The new or improved result has to be the result of the relationship between the parts of the combination.
466. Although the parties did not refer to it, I derive two further points relating to this from Kitchin J’s judgment in Abbott Laboratories v Evysio [2008] EWHC 800 (Pat) at para 182-185.
468. In paragraph 185 in expressing his conclusion that the claim in that case was not simply a collocation of elements which perform their own functions independently of each other, Kitchin J referred to the fact that there was an interaction between the elements which the designer of the relevant product must take into consideration. Therefore each element cannot be regarded as an individual invention for obviousness purposes. I agree that this is a material consideration.
Inventive step
Milton
471. I agree with MGI that Milton discloses the idea of using labelled nucleotides with cleavable detectable fluorescent labels in a sequencing by synthesis process. The idea of using 3' blocked bases A G C and T in an RCT form of sequencing by synthesis is disclosed (see the passage from p1 - p3 and in particular at p2 ln 8-10). The essential idea disclosed is to conjugate a suitable fluorophore, via a suitable cleavable linker, to a suitably functionalised nucleotide. A suitable functionalised nucleotide is shown at p38.
479. However, at the risk of repetition, there is no case that it would be obvious for that skilled person in those circumstances to alight on dye XVI of Arnost at all. The reference to rhodamines does not take the skilled person to Arnost on any view. At one stage MGI appeared to suggest that the olanzapine case Dr Reddy’s v Eli Lilly [2009] EWCA Civ 1362 was relevant on the basis that dye XVI could be regarded as a selection from the general class of dyes disclosed in Milton by the word “rhodamine” on p18. That is wrong for two reasons. First, the term rhodamine is not a disclosure of every individual molecule which could be called a rhodamine dye, just as connecting means does not, as a matter of disclosure, disclose a nail. The latter may (or may not) be obvious from the former but that is another matter. Dye XVI is not disclosed by p18 of Milton at all. Second, p18 in fact only refers to commercially available dyes, and there is no evidence dye XVI was one of those at the priority date. Therefore Dr Reddy’s v Eli Lilly is not relevant.
Arnost
486. One of the molecules described is molecule XVI. It is in example III. It is:
490. In terms of obviousness, I am quite sure it was obvious for a skilled person at the priority date concerned with labelling biological molecules, given Arnost, to take molecule XVI forward as a candidate fluorophore. They would assume it had spectral properties in the range taught by Arnost and nothing in their common general knowledge would indicate otherwise. Nevertheless I was not persuaded by MGI’s attempt to say that a comparison with known Atto dyes would make molecule XVI even more obvious but that does not matter.
Lack of technical contribution
496. Although this is MGI’s alternative case, it is convenient to deal with it first. The argument is run over Milton. The question is whether the claimed molecule makes a technical contribution over Milton. The submission is that the specific rhodamine dye claimed in the 415 patent within the molecule of claim 1 does not provide any technical advance over Milton’s teaching to use rhodamines in general. The dye in the claim has no beneficial properties over rhodamines in general. It is an arbitrary dye. These are MGI’s submissions.
500. A striking point is that despite the narrow scope of this claim, MGI infringes it. MGI is using the claimed molecule. I have not taken it into account although it might be said to be at least some evidence from which one would be entitled to infer that the molecule is useful. MGI’s counsel in closing made some submissions about how the use of the molecule came to have happened and what MGI were doing about it, but they were not supported by evidence and in any case do not take away from the fact that MGI are using the claimed molecule in their commercial sequencing by synthesis systems.
Milton and Arnost side by side - collocation
502. Claim 1 can be seen as a combination of two aspects:
i) the 4 carbon linker form of dye XVI; and
ii) a derivatised nucleotide plus linker LN3.
504. MGI point to the fact that the 415 patent is written on the basis that the claimed molecule is made up of building blocks - dye, linker, nucleotide etc. That is true but while it gives some support to the argument, in the end it is not determinative. Almost all inventions can be described as being made up of parts but that is not an admission by the patentee that the parts form a mere collocation.
510. As a matter of fact the claimed thing is a single molecule. The evidence is clear that these two aspects of that molecule are capable of interacting with one another. There is a potential for interaction between these aspects which the skilled person must always take into consideration. The fact the interaction would be one which is unhelpful does not mean it is not relevant. Moreover in this, essentially empirical, field the skilled person will not know whether or not there is in fact an interaction until a test is done. In fact the tests are not burdensome, but they would need to be done. In that sense this is a long way from Sabaf because there is no basis in that case for thinking there might be an interaction and then looking to find out. The two aspects in Sabaf simply do not interact with one another. The skilled person did not have to test them to find out. A vice in MGI’s case is that it seeks to mix together considerations about things being obvious to try with the collocation principle.
513. To establish that this claim is obvious it would be necessary to show that it was indeed obvious to make the single entire molecule for the purposes of testing it. I can see that if that indeed had been obvious, then the obvious to try test might be satisfied in MGI’s favour, but it was not and the point does not arise.
Conclusion
515. EP (UK) 1 530 578 with claims as amended in the form of claim set A is valid. All four of the MGI systems known as Standard MPS, Cool MPS, the two colour variant and DNBSEQ E infringe each of claims 1, 7, 12, 20, and 24 (claim set A) of that patent.
516. EP (UK) 3 002 289 with claims as amended in the form of claim set B is valid. All four of Standard MPS, Cool MPS, the two colour variant and DNBSEQ E infringe each of claims 1, 5 and 6 of that patent. In relation to claim 4, it is infringed by Standard MPS and Cool MPS but not by the two colour variant or DNBSEQ E. The amendment to claim 9 is allowable but Illumina needs to explain what the amendment is for.
520. I do not address the s71 point in this judgment.
Annexes - claim sets of the modified nucleotide patents
Claim set A - Claims of 578 as proposed to be amended
[The amendments are shown in green and red. Red shows the changes in the first set of amendments as compared to the granted claims, green shows the further changes. The only conditional amendment is to claim 12 as granted (7 as amended). The rest is unconditional and unopposed.]
1. A modified nucleotide molecule comprising a purine or pyrimidine base and a ribose or deoxyribose sugar moiety having a removable 3’-OH blocking group covalently attached thereto, such that the 3’ carbon atom has attached a group of the structure
-O-Z
wherein Z is any of -C(R’)2-N(R")2’C(R’)2-N(H)R", and -C(R’)2-N3, wherein
each R" is or is part of a removable protecting group; each R’ is independently a hydrogen atom, an alkyl, substituted alkyl, arylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, acyl, cyano, alkoxy, aryloxy, heteroaryloxy or amido group, or a detectable label attached through a linking group; or (R’)2 represents an alkylidene group of formula =C(R’’’)2 wherein each R’’’ may be the same or different and is selected from the group comprising hydrogen and halogen atoms and alkyl groups; and wherein said molecule may be reacted to yield an intermediate in which each R" is exchanged for H, which intermediate dissociates under aqueous conditions to afford a molecule with a free 3’OH an azidomethyl group.
2. A molecule according to claim 1 wherein R’ is an alkyl or substituted alkyl.
3. A molecule according to claim 1 or claim 2 wherein - Z is of formula -C(R’)-N3.
4. A molecule according to any one of claims 1 to 3 wherein Z is an azidomethyl group.
5. A molecule according to claim 1 or claim 2 wherein R" is a benzyl or substituted benzyl group.
62. A molecule according to any preceding claim 1 wherein said base is linked to a detectable label via a cleavable linker or a non-cleavable linker.
73. A molecule according to claim 62 wherein said linker is cleavable.
84. A molecule according to any one of claims 1 to 5 wherein a detectable label is linked to the molecule through the blocking group by a cleavable or non-cleavable linker.
954. A molecule according to any one of claims 62 to 843 wherein said detectable label is a fluorophore.
1065. A molecule according to any one of claims 62 to 954 wherein said linker is acid labile, photolabile or contains a disulfide linkage.
1176. A modified nucleotide molecule as claimed in any one of claims 1 to 1065 which comprises one or more 32P atoms in its phosphate portion.
1287. A method of controlling the incorporation of a nucleotide as defined in any one of claims 62 to 1065 and complementary to a second nucleotide in a target single- stranded polynucleotide in a synthesis or sequencing reaction comprising incorporating into the growing complementary polynucleotide said nucleotide, the incorporation of said nucleotide preventing or blocking introduction of subsequent nucleoside or nucleotide molecules into said growing complementary polynucleotide.
1398. The method of claim 1287, wherein the incorporation of said first nucleotide is accomplished by a terminal transferase or polymerase or a reverse transcriptase.
14109. The method of claim 1398 wherein the polymerase is a Thermococcus sp
151110. The method of claim 14109 wherein the Thermococcus sp is 9°N or a single mutant or double mutant thereof.
161211. The method of claim 151110 wherein the double mutant is -Y409V A485L.
171312. A method for determining the sequence of a target single-stranded polynucleotide, comprising monitoring the sequential incorporation of complementary nucleotides, wherein at least one incorporation is of a nucleotide as defined in any one of claims 62 to 1065 and wherein the identity of the nucleotide incorporated is determined by detecting the label linked to the base, and the blocking group and said label are removed prior to introduction of the next complementary nucleotide.
181413. The method according to claim 171312 wherein the label of the nucleotide and the blocking group are removed in a single chemical treatment step.
191514. The method according to claim 171312, comprising:
(a) providing a plurality of different nucleotides wherein said plurality of different nucleotides are either as defined in any one of claims 62 to 1065 and wherein the detectable label linked to each type of nucleotide can be distinguished upon detection from the detectable label used for other types of nucleotides;
(b) incorporating the nucleotide into the complement of the target single-stranded polynucleotide;
(c) detecting the label of the nucleotide of (b), thereby determining the type of nucleotide incorporated;
(d) removing the label of the nucleotide of (b) and the blocking group; and (e) optionally repeating steps (b)-(d) one or more times;
thereby determining the sequence of a target single-stranded polynucleotide.
201615. The method according to claim 191514, wherein each of the nucleotides are brought into contact with the target sequentially, with removal of non-incorporated nucleotides prior to addition of the next nucleotide, and wherein detection and removal of the label and the blocking group is carried out either after addition of each nucleotide, or after addition of all four nucleotides.
211716. The method according to claim 191514, wherein each of the nucleotides are brought into contact with the target together simultaneously, and non-incorporated nucleotides are removed prior to detection and subsequent to removal of the label and the blocking group.
221817. The method according to claim 191514, comprising a first step and a second step, wherein in the first step, a first composition comprising two of the four nucleotides is brought into contact with the target and non-incorporated nucleotides are removed prior to detection and subsequent to removal of the label, and wherein in the second step, a second composition comprising the two nucleotides not included in the first composition is brought into contact with the target, and non-incorporated nucleotides are removed prior to detection and subsequent tc removal of the label and blocking group, and wherein the first and second steps are optionally repeated one or more times.
231918. The method according to claim 191514, comprising a first step and a second step, wherein in the first step, a composition comprising one of the four nucleotides is brought into contact with the target, and non-incorporated nucleotides are removed prior to detection and subsequent tc removal of the label and blocking group and
wherein in the second step, a second composition comprising the three nucleotides not included in the first composition is brought into contact with the target, and non- incorporated nucleotides are removed prior to detection and subsequent to removal of the label and blocking group and wherein the first step and the second step are optionally repeated one or more times.
242019. The method according to claim 191514, comprising a first step and a second step, wherein in the first step, a first composition comprising three of the four nucleotides is brought into contact with the target, and non-incorporated nucleotides are removed prior to detection and subsequent to removal of the label and blocking group and wherein in the second step, a composition comprising the nucleotide not included in the first composition is brought into contact with the target, and non-incorporated nucleotides are removed prior to detection and subsequent to removal of the label and blocking group and wherein the first step and the second step are optionally repeated one or more times.
252120. A kit, comprising:
(a) a plurality of different nucleotides wherein said plurality of different nucleotides are either as defined in any one of claims 62 to 1065; and
(b) packaging materials therefor.
262221. A kit according to claim 252120, wherein the detectable label in each nucleotide can be distinguished upon detection from the detectable label used for any of the other three types of nucleotide.
272322. The kit of claim 252120 or 262221, further comprising an enzyme and buffers appropriate for the action of the enzyme.
282423. Use of a nucleotide as defined in any one of claims 1 to 1176 in a Sanger or a Sanger- type sequencing method.
292524. An oligonucleotide comprising a modified nucleotide of claims 1-1176.
302625. A nucleotide triphosphate comprising a modified nucleotide of claims 1-1176.
Claim set B - 289 as proposed to be amended unconditinally
[The amendments are in red]
1. A modified nucleotide triphosphate molecule comprising a purine or pyrimidine base and a deoxyribose sugar moiety having a 3’-azidomethyl group.
2. A molecule according to claim 1 wherein said base is linked to a detectable label via a cleavable linker or a non cleavable linker.
3. A molecule according to claim 2 wherein said linker is cleavable.
43. A molecule according to claims 2 or 3 wherein said detectable label is a fluorophore.
5. A molecule according to claims 3 or 4 wherein said linker contains a phosphine cleavable azide.
64. A kit comprising:
(a) four modified nucleotide triphosphate molecules, each comprising a purine or pyrimidine base and a deoxyribose sugar moiety having a 3’-azidomethyl group where each nucleotide has a base that is linked to a detectable label via a cleavable linker and where the detectable label linked to each nucleotide can be distinguished upon detection from the detectable label used for the other three nucleotides; and
(b) packaging materials therefore.
7. A kit according to claim 6 further containing a polymerase.
8. The kit according to claim 7 wherein the polymerase is a Thermococcus sp.
95. A polynucleotide molecule comprising a modified nucleotide comprising a purine or pyrimidine base and a deoxyribose sugar moiety having a 3’-azidomethyl group.
106. A method for determining the sequence of a target single-stranded polynucleotide, comprising monitoring the sequential incorporation of complementary nucleotides, wherein at least one incorporation is of a nucleotide comprising a purine or pyrimidine base and a deoxyribose sugar moiety having a 3’-azidomethyl group where the nucleotide has a base that is linked to a detectable label via a cleavable linker and wherein the identity of the nucleotide is determined by detecting the label linked to the base and the blocking group and label are removed prior to introduction of the next complementary nucleotide.
117. The method of claim 106 wherein the label of the nucleotide and the blocking group are removed in a single chemical treatment step.
128. The method of claims 106 or 117, the method comprising:
(a) providing a plurality of different nucleotides wherein each nucleotide of said plurality of different nucleotides has a 3’-azidomethyl group and a base that is linked to a detectable label via a cleavable linker, wherein the detectable label linked to each type of nucleotide can be distinguished upon detection from the detectable label used for other types of nucleotides;
(b) incorporating the nucleotide into the complement of the target single-stranded polynucleotide;
(c) detecting the label of the nucleotide of (b), thereby determining the type of nucleotide incorporated;
(d) removing the label of the nucleotide of (b) and the blocking group; and
(e) optionally repeating steps (b)-(d) one or more times;
thereby determining the sequence of a target single-stranded polynucleotide.
139. The method of any one of claims 106 to 128 wherein the blocking group is removed using a water soluble phosphine under neutral, aqueous conditions.
14. The method of claim 13 wherein the phosphine is a derivatised trialkyl phosphine.
15. The method of claim 14 wherein the phosphine is derivatised with one or more functionalities selected from the group comprising amino, hydroxyl, carboxyl and sulfonate groups.
Claims set C - 433 claims as proposed to be amended
[The amendments are in red]
1. A kit comprising four modified nucleotide triphosphate molecules, each comprising a purine or pyrimidine base and a deoxyribose sugar moiety wherein the 3' carbon atom of the sugar moiety has attached a group of the structure
-O-Z
wherein Z is of the formula -CH2N3.
2. The kit according to claim 1, comprising the nucleotides A, T, C and G.
3. The kit according to claim 1 or claim 2, further comprising a terminal transferase, polymerase or reverse transcriptase.
4. The kit according to claim 3, comprising a polymerase.
5. The kit according to claim 4, wherein the polymerase is a Thermococcus sp.
6. A method of controlling the incorporation of a nucleotide complementary to a second nucleotide in a target single stranded polynucleotide in a synthesis or sequencing reaction, the method comprising incorporating into a growing complementary polynucleotide a nucleotide comprising a purine or pyrimidine base and a deoxyribose sugar moiety wherein the 3' carbon atom of the sugar moiety has attached a group of the structure-
-O-Z
wherein Z is of the formula -CH2N3,
the incorporation of said nucleotide preventing or blocking introduction of subsequent nucleotide molecules into said growing complementary polynucleotide.
7. The method according to claim 6, wherein four different nucleotides are brought into contact with the target single stranded polynucleotide simultaneously.
8. The method according to claim 6 or claim 7, wherein the 3' -O-CH2N3 is removed from the deoxyribose sugar moiety prior to introduction of the next complementary nucleotide to generate a 3' hydroxyl group.
9. The method of claim 8, wherein the 3'-O-CH2N3 group is removed using a water- soluble phosphine.
10. The method of claim 9, wherein the water-soluble phosphine is a derivatised trialkyl phosphine.
11. The method of claim 10, wherein the derivatised trialkyl phosphine is derivatised with one or more functionalities selected from the group comprising amino, hydroxyl, carboxyl and sultanate groups.
Lists of issues:
The claim numbering in these lists of issues has been adjusted to correspond to the claim sets in this judgment.
Illumina MNP Issues
1) The identity of the Skilled Team;
2) Whether sequencing using reversible chain terminators (RCTs) was common general knowledge at the priority date;
3) Whether claims 1, 12 & 24 of EP 578 (claim set A) are obvious in light of:
a) Zavgorodny 1991; or b) Zavgorodny 2000;
4) Whether an insufficiency squeeze operates against Zavgorodny 1991 or 2000;
5) Whether claim 7 of EP 578 (claim set A) and claim 6 of EP 433 (claim set C) are invalid for Agrevo-obviousness / insufficiency;
6) Whether the proposed amendments to claim 1 of EP 578 (claim set A) and claim 9 of EP 289 (claim set B) are bad for added matter;
7) Whether the Modified Nucleotide Patents are entitled to claim priority from GB 0230037;
8) Whether claims 7 and 12 of EP 578 (claim set A) and claim 6 of EP 289 (claim set B) are infringed by CoolMPS and whether claim 20 of EP 578 (claim set A) and claim 4 of EP 289 (claim set B) are infringed by the StandardMPS 2 colour and E variant kits.
MGI MNP Issues
2. If the answer to issue 1 is no, is claim 12 of EP 578 (claim set A) insufficient on the basis that it covers methods of sequencing using nucleotides, linkers and labels that would not enable the skilled person to perform a sequencing method across the breadth of the claim without undue burden?
3. Are claim 6 of EP 433 (claim set C) and claim 7 of EP 578 (claim set A) obvious for lack of technical contribution, and/or if the answer to issue 1 is no are they insufficient, because they cover a method of controlling the incorporation of a nucleotide having a 3’O-azidomethyl group in a synthesis reaction (not being a sequencing by synthesis reaction)?
4. Is claim 6 of EP 433 (claim set C) obvious for lack of technical contribution, and/or if the answer to issue 1 is no, is it insufficient, because it covers methods of controlling the incorporation of a nucleotide in a sequencing by synthesis reaction in which the nucleotide is neither linked to nor comprises a detectable label?
5. If the answer to issue 1 is no, are each of claims 1, 12 and/or 24 of EP 578 (claim set A) insufficient due to lack of enablement/lack of technical contribution?
6. Are each of claims 1, 12 and/or 24 of EP 578 (claim set A) entitled to claim priority from priority document P2?
7. If the answer to issue 6 is no, are each of claims 1, 12 and/or 24 (claim set A) obvious over Barnes?
8. Is claim 9 of EP 289 (claim set B) as proposed to be unconditionally amended invalid for added matter?
9. Does the StandardMPS two colour variant and/or DNBSEQ E variant fall within the scope of claim 20 of EP 578 (claim set A) and/or claim 4 of EP 289 (claim set B) properly construed?
10. Does CoolMPS fall within the scope of claim 12 of EP 578 (claim set A) properly construed?
11. If the answer to issue 10 above is no, does CoolMPS infringe claim 12 of EP 578 (claim set A) by equivalence?
12. [Miscellaneous issue in relation to s71 Patents Act 1977]
MGI FP issues (412 and 415)
EP 412
1. Is claim 1 obvious over Buechler?
2. Is claim 1 invalid for added matter?
3. If the answer to issue 2 is yes, does the amendment save claim 1?
4. Does CoolMPS fall within the scope of claim 1 properly construed?
5. If the answer to issue 4 is no, does CoolMPS infringe claim 1 by equivalence?
EP 415
1. Is claim 1 a collocation of two inventions - namely derivatised Dye 2 (as shown at Figure II at [0094] of EP 415) and the azide linker (as synthesised in Example 4 of EP 415) attached to a nucleotide?
2. If so:
a. Is the derivatised Dye 2 obvious over Arnost?
b. Is the azide linker disclosed in or obvious over Milton?
3. Starting from Milton, is there any technical contribution in using derivatised Dye 2 with the azide linker disclosed in Milton?