Illumina Cambridge Limited v Latvia MGI Tech Sia

This is an appeal by the Appellants (“MGI”) from an order of Birss J (as he then was) dated 18 February 2021 declaring, for the reasons given in his judgment dated 20 January 2021 [2021] EWHC 57 (Pat), that four patents owned by the Respondent (“Illumina”) were, as amended, valid and had been infringed by MGI. The judge also held that a fifth patent was invalid, but there is no appeal by Illumina against his order for revocation of that patent.

The four patents which are the subject of the appeal fall into two groups:

European Patent (UK) No. 1 530 578, European Patent (UK) No. 3 002 289 and European Patent (UK) No. 3 587 433 (“the Modified Nucleotide Patents”). These three patents are divisionals. The first two are entitled “Modified Nucleotides for Polynucleotide Sequencing” and the third is entitled “Modified Nucleotides”. They are based on an application filed on 22 August 2003. Although the earliest claimed priority is from a US application filed on 23 August 2002, Illumina only sought to maintain priority from the second priority document, a British application filed on 23 December 2002 (“P2”). It is common ground that the issues in relation to the Modified Nucleotide Patents may be determined by reference to the second of the three patents (“289”).

EP (UK) No 2 021 415 entitled “Dye Compounds and the Use of Their Labelled Conjugates” (“the 415 Patent”). The application for this patent was filed on 16 May 2007 claiming priority from a US application filed on 18 May 2006.

The patents describe and claim inventions in the field of DNA sequencing, more specifically a technique known as “sequencing by synthesis”. The inventions described and claimed in the Modified Nucleotide Patents are concerned with using an azidomethyl group (-CH₂N₃) as a reversible chain terminator in sequencing by synthesis. The 415 Patent describes and claims a class of molecules useful in sequencing by synthesis consisting of three moieties: a nucleotide, a particular cleavable linker and a particular fluorescent dye.

The judge was faced with a considerable number of issues. On the appeal, only three of those issues are still live, namely:

Are the Modified Nucleotide Patents obvious over S. Zavgorodny et al, “1-Alkythioalkylation of Nucleoside Hydroxyl Functions and Its Synthetic Applications: A New Versatile Method in Nucleoside Chemistry”, Tetrahedron Letters, 32 (15), 7593-7596 (1991) (“Zavgorodny”)?

Are the Modified Nucleotide Patents entitled to priority from P2? It is common ground that, if the Modified Nucleotide Patents are not entitled to priority from P2, then they are obvious over Illumina’s US Patent Application No. 2003/0104437 (“Barnes”), which was published on 5 June 2003.

Is the 415 Patent obvious as a collocation of non-inventive features?

There was a substantial dispute before the judge as to the identity and attributes of the person or team skilled in the art to whom the Modified Nucleotide Patents were addressed. The judge found at [96] and [98] that they were addressed to a team working on research into sequencing by synthesis with two members. One member would have a background in molecular biology or genetics, with a focus on DNA sequencing in particular, the other member would have a background in organic chemistry. They would both have a post-graduate degree, probably a PhD but perhaps a Masters, and some years’ research experience.

There was also a substantial dispute as to the skilled team’s common general knowledge. Before turning to the judge’s findings, it may assist comprehension if I give a couple of paragraphs of explanation based on the primer agreed between the parties for trial.

The structure of DNA. DNA consists of two complementary strands that wind around one another to form a double helix. The strands of DNA are made up of a string of individual nucleotides, which are composed of deoxyribose (a 5-carbon sugar), a nitrogenous base, and a phosphate group, as shown below. There are four different nucleotides in DNA, which differ from each other by their nitrogenous bases: adenine (A), cytosine (C), guanine (G), and thymine (T). Adenine and guanine are “purine” bases, whereas cytosine and thymine are “pyrimidine” bases.

The nucleotides in each strand are linked by their phosphate group, which connects the 5' carbon atom (the atom in the -CH₂- group external to the ring) of one deoxyribose to the 3' carbon atom (the atom with a hydroxyl (-OH) substituent) of the deoxyribose of the next nucleotide, to form a sugar-phosphate backbone as shown below. The two complementary strands assemble together by pairing of the nitrogenous bases mediated by complementary hydrogen bonds, such that C pairs with G and A pairs with T.

Sanger sequencing. In the 1970s two ways of sequencing DNA were devised, each named after their inventors: Maxam-Gilbert sequencing and Sanger sequencing. Maxam-Gilbert sequencing was based on cutting the DNA strands using reagents which break the sequence at known places and analysing the results to deduce the original sequence. Sanger sequencing supplanted Maxam-Gilbert sequencing, and automated machines running Sanger sequencing were used in the human genome project in the 1990s.

The judge explained Sanger sequencing as follows:

Sequencing by synthesis. Sanger sequencing had certain drawbacks. The judge found that, by December 2002, there were a number of teams researching alternatives to Sanger sequencing. These included techniques which one would now call sequencing by synthesis. Only one such technique had been demonstrated to work, a technique called pyrosequencing. The details of pyrosequencing do not matter for present purposes. It suffices to say that it was different to sequencing by synthesis using reversible chain termination.

Reversible chain termination. As the judge explained, well before 2002, some in the art had the idea of trying to do a variant of Sanger sequencing, but with a chain terminator which was reversible. Such terminators are also referred to as blocking groups, protecting groups and protective groups. The idea was that, if the blocking of the 3' hydroxyl group could be reversed after the identity of the added nucleotide had been confirmed, then the next nucleotide in the chain could then be added and the process repeated.

Two research groups led this field. The first was a group led by Richard Gibbs (Baylor College of Medicine) and Kevin Burgess (Texas A & M University). This group published five papers on reversible chain termination in the period from 1994 to 1999, including Michael Metzker et al, “Termination of DNA synthesis by novel 3'-modified deoxyribonucleoside 5'-triphosphates”, Nucleic Acids Research, 22(2), 4259-4267 (1994) (“Metzker 1994”). The second was a group at the Pasteur Institute in Paris led by Bruno Canard and Robert Sarfati. This group published six papers from 1994 to 1999, including Canard and Sarfati, “DNA polymerase fluorescent substrates with reversible 3′-tags”, Gene, 148(1), 1-6 (1994) (“Canard 1994”). Neither group had published anything on this topic between 1999 and 23 December 2002.

The judge’s findings as to the state of the skilled team’s common general knowledge concerning reversible chain termination began at [104] as follows:

The judge considered Metzker 1994 at [106]-[110]. In summary, he found that it disclosed a single cycle of incorporation of a 3'-O-protected nucleotide in which the protective group was a 2-nitrobenzyl group, deprotection and re-initiation of DNA synthesis in which a natural dNTP was incorporated. The judge considered Canard 1994 at [111], and found that it also disclosed a single cycle of incorporation of a 3'-O-protected nucleotide using a different protective group.

The judge’s findings as to the common general knowledge continued as follows:

Synthetic organic chemistry. The judge found that the skilled team’s common general knowledge included two aspects of synthetic organic chemistry:

As noted above, it is common ground that 289 may be taken as representative of the Modified Nucleotide Patents. The specification of 289 is a moderately lengthy and detailed one running to 147 paragraphs, but much of the detail is unimportant for present purposes.

The specification explains at [0001] that the invention relates to modified nucleotides having a removable protecting group, their use in polynucleotide sequencing methods and a method for chemical deprotection of the protecting group.

It describes the concept of sequencing by synthesis at [0004]:

It identifies what is required of a blocking group for this purpose at [0005]:

It identifies the problem addressed by the invention at [0006]:

At [0007] Metzker 1994 is acknowledged, but it is said that “the 3'allyl blocked compound was not used to demonstrate a complete cycle of termination, deprotection and reinitiation of DNA synthesis”. At [0011] it is said that Metzker 1994 does not “actually teach[…] the deprotection of 3'-allylated hydroxyl group in the context of a sequencing protocol”. The specification goes on:

The specification introduces the invention at [0013]:

At [0015] there is a consistory paragraph identifying a first aspect of the invention as a modified nucleotide or nucleoside molecule 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 defined as encompassing a substantial range of substituents. This consistory paragraph does not correspond to claim 1, which is much narrower.

At [0016]-[0019] there are consistory paragraphs identifying further aspects of the invention: a method of controlling the incorporation of a nucleotide molecule complementary to the nucleotide in a target single-stranded polynucleotide in a synthesis or sequencing reaction; a method for determining the sequence of a target single-stranded polynucleotide; and a kit comprising a plurality of different individual nucleotides of the invention and packaging.

At [0020]-[0024] details are given of the nucleotide itself and of the proposal to use a linker to link the base to a detectable label. Further details of suitable labels and linkers are given in a passage from [0063] to [0090]. The preferred detectable labels are fluorophores, which can be detected by fluorescence.

In [0050] the specification states that one example of -O-Z is where Z is azidomethyl. Removal of azido groups is discussed in [0051].

From [0102] to [0147] the specification describes a series of examples of the invention in which azidomethyl is the blocking group. This passage begins with the statement at [0103]:

At [0104] to [0139] the synthesis of modified nucleotides with a 3'-OH azidomethyl blocking group, linked to a fluorescent dye via a linker moiety, is described. Syntheses of modified versions of all four of G, C, A and T with the triphosphate and a 3'-O-azidomethyl group are detailed. Compounds 6, 18, 24, and 32 are used in experiments. These are dTTP, dCTP, dGTP and dATP respectively.

Experiments showing blocking, incorporation and deblocking using the modified nucleotides are described in [0140]-[0147] with the results shown in Figures 5 and 6. The specification states in [0147] that two cycles of incorporation with compounds 18 (C), 24 (G) and 32 (A) and six cycles of incorporation with compound 6 (T) can be seen.

The experiments used radiolabelled “hairpin” primers, attached to beads, into which the modified nucleotides were incorporated. There were three stages: (a) incorporation of the modified nucleotide; (b) a chase by native unmodified nucleotides to check that incorporation of the modified nucleotide and thereby blocking of further incorporation had occurred; and (c) deblocking of the modified nucleotide to remove the blocking group and fluorescent label. This is shown in a diagram produced by Prof Leadlay:

At each stage, beads were removed from the reaction and the DNA was released from the beads onto a gel to allow analysis of the reaction products. The position of the bands on the gel corresponds to the size of the DNA: larger molecules move more slowly and are therefore visualised higher up the gel than smaller ones. The radiolabel on the hairpin permits the bands to be visualised.

Fig. 5 shows the results for compounds 24, 18 and 32 (G, C and A). Prof Leadlay provided an annotated version of the figure which the judge accepted as showing how it would be understood by the skilled team:

The hairpin band (to the left of each set) shows the position of the hairpin primer (prior to any incorporation) on the gel. Moving from left to right, the bands show the position of the DNA following the first cycle of incorporation; chase and deblocking phases and then the second cycle. The higher position of the band indicates a larger DNA molecule and hence shows that incorporation has occurred. Similarly, the lower position of the band indicates a smaller DNA molecule, and hence shows that de-blocking (and removal of the fluorescent label) has occurred.

The judge found that the first cycle for compounds 18 and 32 shows complete incorporation and de-blocking of the modified nucleotides. The first cycle for compound 24 shows that there was also incorporation and de-blocking, but it was not complete as there is a faint band at the same position as the hairpin primer band in lane 1, indicating that some hairpin primers remained into which no nucleotide had been incorporated.

Fig. 6 shows the results for compound 6 (T). Again, Prof Leadlay provided an annotated version which the judge accepted:

As with Fig. 5, the lanes from left to right represent: hairpin primer followed by the first and then subsequent rounds of incorporation, chase and de-blocking. The results for the first three cycles show clearly that a modified nucleotide incorporates into the polynucleotide at each cycle and is then successfully de-blocked.

It can be seen that, in general, in both sets of gels the bands widen as one goes from left to right. Little can be made out relating to the second cycles in Fig. 5 and the fourth, fifth and sixth cycles in Fig. 6.

Having considered the evidence of the experts concerning the interpretation of the gels, the judge found at [148] that:

The judge went on at [150] to accept Prof Leadlay’s evidence which the judge summarised as follows:

The judge concluded his review of the specification by finding that:

It is only necessary for the purposes of the appeal to refer to claims 1 and 6 of 289. Claim 1 is as follows:

Claim 6 as amended (claim 10 as granted) is as follows:

As the judge noted at [164], claim 12 (as amended, claim 17 as granted) of 578, to which claim 6 of 289 is equivalent, requires “at least one” incorporation. He went on at [292]-[301] to dismiss a case of insufficiency advanced by MGI based on the fact that the claim only requires one incorporation and has no upper limit to the number of incorporations. There is no appeal by MGI on the issue of insufficiency, but as will appear the judge rejected an argument that a conclusion that there was no insufficiency would be inconsistent with a finding of non-obviousness and MGI rely upon what he said in that context.

Zavgorodny describes a method for synthesising certain substituted nucleosides. A nucleoside differs from a nucleotide in that it lacks the 5' phosphate groups. In other words, a nucleoside is just the base and the deoxyribose (or ribose). Nucleosides had a number of applications at all material times, including as antiviral and anticancer agents. The disclosure is summarised in the abstract as follows:

Zavgorodny’s syntheses are summarised in the single figure in the paper, which is reproduced below.

The synthetic scheme involves starting with a 5' blocked nucleoside and generating a 3'-O-methylthiomethyl nucleoside. That product is compound 1 in the scheme (second from the left at the top). The 5' hydroxyl position is blocked by a benzyl group (“Bz”). Zavgorodny treats the specific methylthiomethyl group used in the experiments as representative of the wider class of alkylthioalkyl groups.

From the 3'–O-methylthiomethyl compound 1 various further routes are taken to generate a selection of nucleosides O-substituted at the 2', 3' and 5' positions. One of the methods used is to block the 3'-hydroxyl with an azidomethyl group. That is depicted in Zavgorodny’s figure as compound 5 (in which the 5' end is no longer blocked) where “X” is N₃. Compound 5 is a deoxyribonucleoside.

The last paragraph of Zavgorodny states (footnotes omitted):

The judge held at [189] that the first sentence reflected the focus of Zavgorodny as a paper about synthetic chemistry:

The judge went on to consider the significance of the final sentence:

The judge identified the difference between the claims and Zavgorodny at [193]:

The law. The judge briefly outlined the applicable principles at [179]-[182]. He set out the structured approach to the assessment of obviousness re-stated by Jacob LJ in Pozzoli SpA v BDMO SA [2007] EWCA Civ 588, [2007] FSR 37 at [23] and referred to Lord Hodge’s review of the law in Actavis Group PTC EHF v ICOS Corp [2019] UKSC 15, [2019] RPC 9. He also cited a passage from the judgment of Laddie J in Inhale Therapeutic Systems Inc v Quadrant Healthcare plc [2002] RPC 21 at [47] which it is worth setting out slightly more fully:

The judge’s reasoning. The judge began by observing at [195]:

The judge proceeded to reject MGI’s case that the claims were obvious in the light of Zavgorodny for four separate reasons. His first reason was as follows:

The judge’s second reason was as follows:

The judge gave his third reason at [204]:

The judge’s fourth reason was as follows:

By way of a cross-check, the judge concluded his assessment at [213] with a summary of the position with respect to each of the nine factors listed by Lord Hodge in Actavis v ICOS at [65]-[73], including the following:

As noted above, the judge returned to the question of obviousness when considering insufficiency. In that context he said this:

The appeal. Obviousness involves a multi-factorial evaluation and therefore this Court is not justified in intervening in the absence of an error of law or principle on the part of the judge: see Actavis v ICOS at [78]-[81]. This is particularly so given that the decision was one of an experienced specialist patents judge after hearing extensive oral evidence from experts in the field.

MGI contend that the Modified Nucleotide Patents cannot be both non-obvious over Zavgorodny and entitled to priority from P2. At trial MGI’s primary case was that the Patents were obvious, and, as explained in more detail below, priority was run as a squeeze. Given the judge’s conclusion on obviousness, MGI’s primary case on the appeal is that the judge’s reasoning on priority is inconsistent with his reasoning on obviousness and that he ought to have concluded that the Patents were not entitled to priority. In the alternative, MGI argue that, if the judge was right on priority, then he was wrong on obviousness. Given the way the case was put at trial, I consider that the correct course is first to consider whether the judge made any error in his assessment of obviousness. I shall address the allegation of inconsistency when I come to consider priority.

MGI do not suggest that the judge misdirected himself as to the law. Nor do they challenge his findings of fact as to the common general knowledge, his analysis of the disclosure of Zavgorodny or his identification of the difference between the claims and Zavgorodny. MGI argue that the judge should have concluded that the skilled team would have (i) appreciated the relevance of Zavgorodny to their research, (ii) been interested in the 3'-OH azidomethyl blocking group and (iii) tried incorporating a 3'-O-azidomethyl nucleotide into a chain and deblocking it in what the judge accepted were routine tests, and that the judge can only have reached the opposite conclusions on the basis of hindsight. The problem with this argument is that it merely amounts to a challenge to the judge’s evaluation of these points without identifying any error of principle on his part. Nevertheless, I will consider the main submissions made in support of it.

First, counsel for MGI took issue with the judge’s characterisation of his cross-examination of Prof Leadlay at [121] and [195] as being essentially on the premise that the skilled person came to Zavgorodny interested in taking forward sequencing by synthesis with a new reversible chain terminator. Counsel was able to demonstrate by reference to the transcript that he had not explicitly asked any questions on that basis. The judge clearly took the view, however, that that was the underlying premise of the line of questioning. Given that the judge had the advantage of witnessing the cross-examination, it is not possible for this Court to conclude that he was not entitled to take that view. I would go further, however. Having read the transcript, I agree with the judge’s view that the cross-examination was based on the unexpressed assumption that what the skilled team would be looking for was a new reversible chain terminator i.e. a new blocking group. In any event, this submission goes nowhere given that MGI do not challenge the judge’s findings as to common general knowledge.

Secondly, counsel for MGI submitted that the judge’s first reason for concluding that the claims were not obvious over Zavgorodny, namely that the skilled team would not have considered that Zavgorodny was relevant to their research, was inconsistent with his findings as to common general knowledge. I do not accept this. The judge made a clear finding at [126] that the skilled team was aware of the concept of using reversible chain termination and knew that this had not yet succeeded in practice, but did not have any specific problem in mind. The judge repeated this finding at [198], and it formed the foundation for his conclusion in [199] that it was only with hindsight that Zavgorodny could be seen to be relevant to research into sequencing by synthesis. Counsel for MGI argued that, not having any specific problem in mind, the skilled team would be receptive to the advantageous new blocking group disclosed by Zavgorodny. This simply does not follow, however. The skilled team would only be interested in a new blocking group if they thought that problems with existing blocking groups were the reason for the failure of previous groups to make the idea of reversible chain termination work in practice, but that was not the case.

Thirdly, counsel for MGI submitted that the judge wrongly treated Zavgorodny in effect as being from a different technical field, particularly given that the judge accepted at [200] that it did not matter than Zavgorodny was concerned with nucleosides rather than nucleotides. Again, I do not accept this. Zavgorodny is not concerned with sequencing by synthesis, it is concerned with synthetic methods. Thus it is not from the same technical field as the claimed invention. While Zavgorodny is from a neighbouring technical field, the judge was entirely justified in characterising it as simply an addition to the organic chemist’s toolbox.

Fourthly, counsel for MGI submitted that Prof Leadlay had accepted that, on the assumption that (as the judge found) the skilled team knows about sequencing by synthesis using reversible chain terminators, Zavgorodny’s statement that an azidomethyl blocking group could be removed “under very specific and mild conditions” would be of interest to the skilled team, and therefore the judge’s first and second reasons were both wrong. This point overlaps with the first point: as discussed, the judge interpreted the premise of the cross-examination differently and I agree with him. In any event, I do not accept counsel’s characterisation of Prof Leadlay’s evidence. While he did not say that, having read Zavgorodny, the skilled team would, as the judge put it, “put it down and move on”, his evidence was that the skilled team would note that Zavgorodny refers to “a number of other products which are known, established, well-characterised hydroxyl blocking groups” which would be likely to impress the team as much as azidomethyl. He went on to say that he did not think that the skilled team would be “motivated to use [azidomethyl] for sequencing, because there is simply not enough information to allow [them] to see that this matches the stringent requirements for such a blocking group” in sequencing. Later on, he said that Zavgorodny taught how to make six or seven blocking groups, most of which were “more attractive, on the basis of the conditions for their removal being better understood, and they would be taken forward, in my view, in preference to azidomethyl”. He went on to say that the team would be motivated to look again at “groups that had been established as having some of the features of the desired blocking group, and that includes O-nitrobenzyl”. The cross-examination culminated in the following exchange:

Fifthly, counsel for MGI submitted that the judge’s third and fourth reasons, both of which go to the question of whether the skilled team would have had a reasonable expectation of success if they were to try using an azidomethyl blocking group in sequencing by synthesis, were wrong. The third reason was said to be inconsistent with the judge’s findings as to common general knowledge and with his findings on priority, while the fourth reason was said to be inconsistent with the claims and the disclosure of the Modified Nucleotide Patents. MGI accept that the skilled team would need to do experiments to find out whether a 3'-O-azidomethyl blocked nucleotide was incorporated by polymerase and could be deblocked without denaturing DNA, but say that such experiments were routine and the skilled team could select suitable polymerases, linkers, cleavage conditions and detectable labels without difficulty.

The first of these points is a bad one. Nothing in [204] is inconsistent with the judge’s findings as to common general knowledge. The passages in the judgment relied upon in support of the submission are [151] (quoted in paragraph 42 above) and [285] (“there will be polymerases that do not work but the skilled person, given the information in the patent and the common general knowledge, will be able to select suitable polymerases without difficulty”). Both are concerned with the ability of the skilled team to put the teaching of the specification of the Modified Nucleotide Patents into practice. There is no inconsistency between saying a skilled team who had not read the Patents would not know whether a 3'-O-azidomethyl blocked nucleotide would be incorporated by DNA polymerase and saying that a skilled team who had read the Patents, which show that it is incorporated, would be able to optimise the method, and find other suitable polymerases, through routine work.

The second point is more conveniently addressed in the context of priority, and I will return to it below.

As for the third point, counsel for MGI pointed out the claims do not require a reasonable yield and reasonable speed, all they require is one cycle of incorporation and de-blocking. The judge was well aware of this, however, as can be seen from what he said at [191] and [297]-[298]. This does not detract from his conclusion at [204] that the skilled team would have no reason to think that there was a reasonable prospect of getting a reasonable yield and speed, and therefore a 3'-O-azidomethyl group was not obvious to try.

Finally, counsel for MGI argued that the judge had failed correctly to characterise the problem solved by the invention and the narrow technical contribution made by it. Again, this argument is more conveniently addressed in the context of priority.

I therefore conclude that the judge did not make any error in finding that the Modified Nucleotide Patents were not obvious in the light of Zavgorodny.

P2 is a considerably shorter document than 289. The general disclosure is similar to that of 289, and in particular it clearly discloses the use of an azidomethyl 3'-OH blocking group in sequencing by synthesis. The text contained in [0004] of 289 is to be found at page 21 line 36 to page 2 line 22 and the text contained in [0005] is to be found at page 9 line 28 to page 10 line 14 apart from the first five words (and those words are arguably implicit from the context provided by the preceding paragraph). P2 contains none of the experimental detail to be found in 289 at [104]-[147], however. Rather, it contains three examples which are described in less detail.

Example 1 is described on page 23 as follows:

It can be seen that the paragraph above the synthetic scheme is identical to [103] of 289 save that the latter contains the additional word “synthesised” in the second line.

It is not necessary to set out Examples 2 and 3 in detail, but it should be noted that Example 2 describes a different 3'-OH blocking group and states:

The judge accepted at [237] that there was textual support in P2 for all the relevant claims. This does not appear to have been in issue before him, and it was common ground in this Court.

The judge went on:

The law. In order for a claimed invention to be entitled to priority from an earlier application, it must, in the words of section 5(2)(a) of the Patents Act 1977, be “supported by matter disclosed” in that earlier application. Article 87(1) of the European Patent Convention expresses the requirement as being that priority can only be accorded in respect of “the same invention” as one in the earlier application. Section 5 is one of the sections which is declared to be intended to have the same effect as the corresponding provision of the EPC: see section 130(7). Both section 5 and Article 87 EPC give effect to Article 4 of the Paris Convention for the Protection of Intellectual Property.

In case G 2/98 [2001] OJ EPO 413 the Enlarged Board of Appeal of the European Patent Office expressed the test for priority as follows:

Jacob LJ explained this test in Unilin Beheer NV v Berry Floor NV [2004] EWCA Civ 1021, [2005] FSR 6 at [48] as follows:

It can be seen that Jacob LJ’s formulation has two aspects: disclosure (does the priority document give the skilled person essentially the same information as the claimed invention?) and enablement (does the priority document enable the skilled person to perform the claimed invention?)

So far as the first aspect is concerned, Kitchin J (as he then was) added in Abbott Laboratories Ltd v Evysio Medical Devices plc [2008] EWHC 800 (Pat), [2008] RPC 23 at [228]:

Floyd LJ explained this further in HTC Corp v Gemalto SA [2014] EWCA Civ 1335, [2015] RPC 17 at [65]:

So far as the second aspect is concerned, it is settled that the test of enablement is the same in the context of priority as in the context of sufficiency of disclosure: see Asahi Kasei Kogyo KK’s Application [1991] RPC 486 and Biogen Inc v Medeva plc [1997] RPC 1 at 46-49.

In Hospira UK Ltd v Genentech Inc [2014] EWHC 1094 (Pat) Birss J held as follows:

The decision in Hospira v Genentech was affirmed on appeal [2015] EWCA Civ 57, but priority was not in issue on the appeal. Birss J followed his statement of the law in Merck Sharp & Dohme Ltd v Ono Pharmaceutical Co. Ltd [2015] EWHC 2973 (Pat), [2016] RPC 10 at [127], but neither side contended to the contrary. It was also followed by Henry Carr J in Hospira UK Ltd v Cubist Pharmaceuticals LLC [2016] EWHC 1285 (Pat), [2017] RPC 10 at [114(v)], but the plausibility of the priority documents was not in issue in that case.

Illumina does not challenge the accuracy of Birss J’s statement that “the test for priority includes the requirement for plausibility in a case like [Hospira v Genentech]”, which was a medical use case, but it disputes that plausibility is always required for priority. I shall return to this point below.

Illumina does not dispute that, if plausibility is required, the criterion for plausibility is that stated by Lord Sumption in Warner-Lambert Co LLC v Generics (UK) Ltd [2018] UKSC 56, [2019] Bus LR 360 at [36]: “the specification must disclose some reason for supposing that the implied assertion of efficacy in the claim is true”. As Lord Sumption went on to explain at [37], a bare assertion is not enough. Definite proof is not required, however. Nor is experimental data necessarily required if the specification contains reasoning which would cause the skilled person to think that there was a reasonable prospect that the assertion would prove to be true.

The final point on the law concerns the burden of proof. The legal burden lies upon the patentee to justify its claim to priority, but as Laddie J explained in Evans Medical Ltd’s Patent [1998] RPC 517 at 533 the evidential burden may shift to the party attacking the validity of the patent:

The judge’s reasoning. The judge recorded at [235] that the legal test for priority was not in dispute before him, and referred to Icescape v Ice-World. He went on to hold that the claims of the Modified Nucleotide Patents were entitled to priority from P2 for the following reasons:

Although he did not expressly say so, it appears from this reasoning that the judge proceeded on the basis that, as a matter of law, plausibility was required for priority.

Illumina’s alternative case. In addition to supporting the judge’s decision on the facts, Illumina contend in the alternative that the judge was wrong to proceed on the basis that plausibility was required for priority as a matter of law. Although, for reasons that will appear, it is not necessary to decide whether this contention is correct, it is convenient to consider it before turning to MGI’s appeal because it illuminates the arguments on the appeal.

Illumina did not file a respondent’s notice raising this contention. Counsel for Illumina submitted that no respondent’s notice was required because the judge had made no decision adverse to Illumina so far as priority was concerned. I disagree. A respondent who wishes to ask the appeal court to uphold the decision of the lower court for reasons different from or additional to those given by the lower court must file a respondent’s notice: CPR rule 52.13(2)(b). Given that (i) the point is a pure question of law, (ii) the argument was clearly raised in Illumina’s skeleton argument, (iii) MGI raised no objection when they received the skeleton argument and (iv) MGI were able fully to respond to the argument in oral submissions, however, I would if necessary give Illumina permission to file a respondent’s notice raising this point.

In its skeleton argument Illumina contended that plausibility was only required for medical use claims, and that in other kinds of case all that was required for priority was disclosure and enablement. In the course of argument, however, counsel for Illumina retreated somewhat from this position. He accepted that plausibility was required not merely for medical use claims, but also in other kinds of case involving what he called “predictive claiming”, where the applicant was predicting that a class of products and/or methods would have utility across the breadth of the class.

As I understood the revised submission, this would include a case such as Idenix Pharmaceutics Inc v Gilead Sciences Inc. In that case the claims were on their face pure compound claims defining a class of compounds by means of a Markush formula. It was common ground, however, that the validity of the claims should be assessed on the basis that they were to be interpreted as claims to compounds which had anti-Flaviviridae activity: see [2014] EWHC 3916 (Pat) at [306] and [2016] EWCA Civ 1089 at [5], [104]. It is clear that the reason why the patentee conceded that interpretation was that it realised that, otherwise, the claimed inventions would not be inventive because they made no technical contribution to the art, applying the reasoning in T 939/92 AGREVO/Triazoles [1996] EPOR 171 (although in the event they were held uninventive on that ground anyway, because it was not plausible that substantially all of the compounds had such activity).

It may be noted that I stated at first instance in that case at [178] that:

When asked about this, counsel for Illumina’s initial response was to submit that this reasoning did not apply to priority. I do not understand why there should be any difference between priority and added matter in this respect, however, given that the legal tests are largely, if not entirely, the same: see Unwired Planet International Ltd v Huawei Technologies Co Ltd [2015] EWHC 3366 (Pat) at [106]-[107] (Birss J). So too is the underlying rationale of preventing patentees from obtaining an unwarranted advantage by subsequently adding subject-matter not disclosed in the priority document (priority) or in the application as filed (added matter): compare Birss J in Hospira v Genentech at [149] (priority) with Jacob LJ in Vector Corp v Glatt Air Techniques Ltd [2007] EWCA Civ 805, [2008] RPC 10 at [5]-[8] (added matter). This is another way in which the law gives effect to the fundamental principle articulated by the Technical Board of Appeal in T 409/91 EXXON/Fuel oils [1994] OJ EPO 653 at [3.4], cited with approval by Lord Hoffmann in Biogen v Medeva at 49 and by Lord Sumption in Warner-Lambert v Generics at [17], that “the patent monopoly should be justified by the actual technical contribution to the art”. As I understood his later submissions, counsel for Illumina accepted this in cases of “predictive claiming”.

Counsel for Illumina submitted that the Modified Nucleotide Patents did not involve “predictive claiming”, and hence plausibility was not required. I disagree with the premise of this submission. Claim 1 of 289 is to a class of chemical compounds (the breadth of which was not explored either at trial or on the appeal), and claim 6 is to a method involving that class of compounds. As can be seen from the judge’s reasoning on obviousness, the judge proceeded on the basis that the invention did not lie in merely identifying this class of compounds, but in identifying their utility in sequencing by synthesis, and hence in the claimed method. That was why claim 1 and claim 6 stood or fell together so far as obviousness was concerned. Neither in P2 nor in the granted Patents did Illumina demonstrate that all, or substantially all, of the claimed compounds had the claimed utility. Rather, it relied upon a limited amount of evidence as supporting the proposition that all, or substantially all, of the claimed compounds had such utility.

MGI’s appeal. In order to put the arguments on the appeal into context, it is important first to explain how MGI put their case on priority at first instance. As mentioned above, priority was run as a squeeze on obviousness: MGI argued that, if the claimed inventions were not obvious over Zavgorodny, then they were not entitled to priority over P2 because, MGI submitted, the skilled team would have been no better informed from a technical perspective after reading P2 than after reading Zavgorodny.

MGI did not plead in their Grounds of Invalidity that P2 did not make it plausible that the claimed compounds would have the utility claimed for them in 289. Nor did MGI lead any evidence from Prof Marx to that effect or put any such case to Prof Leadlay in cross-examination.

Still less did MGI plead or lead any evidence from Prof Marx or put to Prof Leadlay that the skilled team would think that Example 1 in P2 was a “prophetic” or “armchair” example, i.e. not a record of an experiment that had actually been performed, but rather a prediction of what would happen if it was carried out. The nearest MGI got to this was a statement in paragraph 12 of Prof Marx’s third report that the skilled person would view the statement that a 100% yield in the deblocking step was achieved “with a degree of scepticism as it is very rare for any reaction to proceed to 100% completion”. When this was put to Prof Leadlay, he disagreed on the ground that it is not uncommon for deblocking reactions to proceed to completion.

Despite this, MGI submitted in its written closing submissions that “the disclosure [in Example 1] appears entirely theoretical and no evidence is provided that any worked example has been accomplished”.

In these circumstances, I consider that the judge was not merely entitled, but correct, to find at [239] that Example 1 was to be taken at face value as “a statement that experiments have been done and that they were successful in various specific ways”. As Warby LJ pointed out during the course of argument, this finding is supported not merely by the wording of Example 1 and by the unchallenged evidence of Prof Leadlay quoted by the judge, but also by the statement in Example 2 quoted in paragraph 78 above.

MGI nevertheless contend that the judge fell into error in concluding that P2 made it plausible that the claimed compounds had the utility claimed for them. In support of this contention counsel for MGI made two main submissions. Before turning to those I should explain that he accepted that the judge was entitled to interpret the claims in the manner I have discussed in paragraph 101 above.

First, counsel for MGI pointed to the judge’s statement in [241] that it would not matter if Example 1 was a prophetic example because that would not render the disclosure any less plausible, and submitted that this demonstrated that the judge must have applied the wrong test. Counsel for Illumina accepted that this was a difficult passage to understand, and that if taken literally it would be contrary to common sense let alone legal principle. He submitted that the judge could not possibly have intended to contradict his own finding just two paragraphs beforehand at [239], and that what the judge must have meant was that any doubts the skilled team might have had would not have been sufficient to make them conclude that the experiment had not been performed. I accept this submission.

Secondly, counsel for MGI submitted that the judge’s reasoning on priority was inconsistent with his reasoning with respect to obviousness in that the latter was predicated upon the Patents having made a major technical contribution to the art, whereas the former involved P2 having made a very minor technical contribution.

The principal foundation for this submission was the judge’s findings at [148]-[152] (see paragraphs 40-42 above), and in particular his finding that the skilled team reading 289 as a whole and taking into account the experimental results in Figs. 5 and 6 would accept as plausible the proposition that a nucleotide with a 3'-O-azidomethyl blocking group satisfied the objectives set out in [0004] and [0005]. In addition, counsel for MGI relied upon the judge’s statements at [213(vii)] that a 3'-O-azidomethyl blocking group has the useful features promised by 289 in those paragraphs (see paragraph 60 above) and at [298] that the azidomethyl blocking group does meet the stringent requirements referred to in the patent (see paragraph 61 above). Thus, he submitted, the judge had assessed obviousness on the basis that the problem solved, and the technical contribution made, by the claimed inventions was the provision of a blocking group which plausibly met all of the “stringent requirements” in [0005] and thus enabled multiple cycles of incorporation and deblocking to be achieved as envisaged in [0004].

By contrast, as counsel for MGI emphasised, P2 does not include Figs. 5 and 6. Even if the skilled team took Example 1 entirely at face value, he submitted, at best all this showed was that a single cycle of blocking, incorporation and deblocking could be achieved. That was no more than Metzker 1994 and Canard 1994 had achieved. Thus the problem solved, and the technical contribution made, by P2 could only be the provision of an alternative blocking group to the groups used by those workers. If that was the case, the claimed inventions were obvious. Given the conclusion that the claimed inventions were not obvious, however, the correct conclusion in relation to priority was that P2 did not make it plausible that a 3'-O-azidomethyl blocking group achieved the benefits promised in 289 at [0004]-[0005].

Despite the skill with which these submissions were developed by counsel for MGI, I do not accept them. My reasons are as follows.

First, I agree with the judge there is no squeeze between obviousness and priority in this case. Contrary to MGI’s case, the skilled team is better informed from a technical perspective after reading P2 than after reading Zavgorodny. Zavgorodny contains no hint that a 3'-O-azidomethyl blocking group should be used in sequencing by synthesis, whereas P2 not merely proposes this, but also states that nucleotides with this group have been successfully incorporated by a number of different polymerases, block efficiently and may be subsequently removed under neutral, aqueous conditions allowing further extension. Furthermore, it gives the experimental conditions for the unblocking step and states that it proceeds to completion. As discussed above, the skilled team would conclude from this that it was plausible that the claimed compounds had the utility claimed for them.

Secondly, although MGI pleaded a case of AgrEvo obviousness against the Modified Nucleotide Patents, the case MGI ran at trial against the claims which are now in issue was a conventional case of obviousness over Zavgorodny. It is fair to say that, in that context, MGI argued that the technical contribution of the Patents was just the identification of an alternative blocking group. The judge did not accept that contention, but the reason why the judge rejected MGI’s case was not merely because of his assessment of the technical contribution made by the Patents, but more fundamentally because Zavgorodny did not point the skilled team towards the claimed inventions.

Thirdly, even in closing submissions, MGI did not argue, or at least did not clearly argue, that the Modified Nucleotide Patents were not entitled to priority because P2 did not make it plausible that the claimed compounds would have the claimed utility. The nearest MGI got to this was to submit in its written closing submissions that Prof Leadlay did not “provide any comment as to whether the skilled person would view the disclosure of P2 as plausible”; but when pressed by the judge during oral closing submissions as to “what the ground of loss of priority is”, counsel for MGI’s answer was “lack of enablement”.

Fourthly, even if that argument had been more clearly advanced, I consider that the judge would have been correct to reject it. Given Prof Leadlay’s unchallenged evidence quoted by the judge at [239], the judge was entitled to find, as he did at [240], that Example 1 made it plausible that a 3'-O-azidomethyl blocking group “will work”, that is to say, will satisfy the requirements described in the passages corresponding to [0004]-[0005] in 289 (see paragraph 75 above). It is true that, unlike 289, P2 does not include any experimental data showing more than one cycle of incorporation and deblocking, but it is clear from the judge’s findings as to common general knowledge and his remarks in the context of insufficiency that such data was not essential to render this plausible. Thus the data in the granted Patents simply made it more plausible.

For the reasons given above I would dismiss MGI’s appeals with respect to the Modified Nucleotide Patents.

The judge found at [424] that the 415 Patent was addressed to a skilled team consisting of three members, namely the two members of the team to whom the Modified Nucleotides Patent are addressed with the addition of a fluorescence chemist.

The judge set out his findings as to the skilled team’s common general knowledge at [425]-[435]. For present purposes the following slightly abbreviated account will suffice.

Various classes of fluorescent dye were known at the priority date, including xanthenes, which have a three-ring structure. Rhodamines are a sub-class of xanthenes in which amino groups are added to the xanthene core. Rhodamines were known to be useful for biological applications for a number of reasons. A well-known rhodamine was tetramethyl rhodamine:

In addition, the following matters were common general knowledge:

The specification begins by stating at [0001] that the invention provides novel rhodamine dye compounds, labelled conjugates comprising those dyes and methods for the use of these conjugates in sequencing by synthesis.

At [0002]-[0006] the specification explains the background to the invention, noting that a need has developed for fluorescent dyes and their nucleic acid conjugates which satisfy various requirements for use in sequencing by synthesis.

At [0008] the specification states that the claimed invention provides a compound of the formula shown below. As a result of an amendment to the claims, however, this no longer falls within the claims.

At [0011] the specification states that also claimed is a compound of the formula shown below. Again, this no longer falls within the claims.

At [0012] the specification states that a third aspect of the invention provides a nucleotide or nucleoside compound defined by the formula “N-L-Dye”, wherein N is a nucleotide, L is an optional linker moiety and Dye is a fluorescent compound according to the invention. Although the specification only describes L as a “moiety”, the skilled team would appreciate that L and Dye were moieties of the same molecule as well (rather than separate molecules).

At [0013] the specification states that a fourth aspect of the invention includes methods of sequencing using the dye compounds of the invention.

The specification goes on to disclose a number of dyes, including a rhodamine dye called Dye 2 at paragraph [0028]:

The specification goes on:

At [0037] the specification states:

At [0044] the specification states that nucleosides or nucleotides labelled with dyes of the invention may have the formula shown below, in which Dye is a dye compound according to the invention, B is a nucleobase, such as uracil, thymine, cytosine, adenine and guanine, and L is an optional linker group.

At [0075]-[0080] the specification discusses kits incorporating modified nucleosides and/or nucleotides labelled with dyes according to the invention. In this context it suggests a range of different dyes that may be used, according to various criteria. There is no suggestion of any interaction with the linker group.

The specification describes a series of examples at [0083]-[0203], some of which are “reference” examples i.e. ones which do not fall within the granted claims.

Example 1 first describes the synthesis of Dye 2, which is reported at [0091] to have an absorption maximum at 560 nm. It goes on to describe the attachment of a carboxyfunctional linker arm to the ortho-carboxy group of Dye 2 to form the compound shown below, which is reported at [0095] to have an absorption maximum at 570 nm:

Example 4 describes the synthesis of an azide linker called LN3. This has the following structure:

Example 5 describes the preparation of “‘Dye 2’-LN3” (building block language which is repeated in a number of other examples). This involves connecting together the derivatised dye (Dye 2 + carboxyfunctional linker arm), the azide linker (LN3) and a 3'-azidomethyl blocked nucleotide triphosphate. The nucleotide is thymidine. The resulting molecule is shown below:

The specification then describes the synthesis of three other 3'-azidomethyl blocked nucleotide triphosphate molecules, each with a different fluorescent dye (Examples 6, 8 and 9). The result is a suite of four dye labelled conjugate molecules corresponding to nucleotides A, C, G and T, each of which is labelled with a different dye so that it can be separately identified by fluorescence.

Example 9 relates to the base guanine. In this example the linker between the dye and the nucleotide includes 11 units of polyethylene glycol (PEG). This spaces the dye further away from the nucleotide for the reasons explained in [0037].

Example 11 discloses the use of the four labelled modified nucleotides in a sequencing reaction of a DNA template of known sequence using fluorescent detection by a repeated cycle of incorporation and cleavage. The templates were scanned with four colours of light. The specification states at [0203]:

As the judge found at [446]:

The only claim which it is necessary to consider is claim 1 as amended, claim 3 as granted:

As the judge explained at [448], this is a claim to a nucleotide labelled with the compound made from Dye 2 derivatised with a carboxyfunctional linker arm and linker LN3, i.e. a molecule of the formula N-L-Dye, to use the language of [0012]. One such molecule is the thymidine-based example shown in paragraph 136 above.

MGI contend that the 415 Patent is obvious over US Patent No. 4,900,686 (“Arnost”) published on 13 February 1990 and International Patent Application No. WO 2004/018493 (“Milton”) published on 4 March 2004. Arnost concerns fluorescent dye compounds and Milton concerns linkers. MGI say that the 415 Patent claims a mere collocation of a dye that is obvious over Arnost and a linker that is obvious over Milton.

Milton . The judge considered the disclosure of Milton at [471]-[479]. Milton discloses the use of labelled nucleotides with cleavable detectable fluorescent labels in a sequencing by synthesis process. The essential idea disclosed is to conjugate a suitable fluorophore, via a suitable cleavable linker, to a suitably functionalised nucleotide.

At page 18 lines 12-33 Milton explains that the method can be used with conventional detectable labels such as fluorophores. Dyes Cy3 and Cy5 are mentioned. The passage also says that other commercially available fluorescent labels include rhodamine.

At page 21 lines 11-19 Milton explains that the linker can contain a spacer unit which distances the nucleotide base from the cleavage site in the linker or from the label attached to the linker. The length of the linker is unimportant as long as the label (i.e. the fluorophore) is held a sufficient distance from the nucleotide to avoid any interference between the nucleotide and an enzyme (i.e. a polymerase).

At page 47 line 28 to page 48 Milton describes the synthesis of an azide linker which is the same as LN3 in the 415 Patent. The linker is attached to a Cy3 fluorescent dye at page 49 line 1 to page 50 line 9. The reaction is shown as follows:

At page 50 line 11 to page 52 line 3 Milton describes the conjugation of this linked dye to a derivatised nucleotide to give a labelled nucleotide. The reaction is shown as follows:

Milton explains that the linked dye and the dye-linker-nucleotide conjugate were each quantified by measuring their absorbance at 550 nm, indicating to the skilled team that these changes did not affect this aspect of the photochemical properties of Cy3.

At page 52 line 5 to page 53 line 31 Milton describes two cycles of sequencing by synthesis using a thymidine form of the same labelled nucleotide. The results are shown in the form of gels using radiolabelled ³²P. No results are presented based on using fluorescent detection. The gels show that the linker did not prevent incorporation of the nucleotide, although there is evidence in the gels that incorporation was not 100%. Incorporation at the second cycle is reasonably clear. The skilled team would see these results as supportive of the teaching of Milton that the linker should not interfere with the polymerase reaction.

The judge held at [479] that:

Arnost . The judge considered the disclosure of Arnost at [480]-[495]. Arnost discloses novel fluorescent conjugates comprising a rhodamine dye moiety and biologically active moiety for use in diagnostic assays. At column 3 line 43 a DNA probe is mentioned as one possible biologically active molecule, but there is no reference to sequencing by synthesis.

Example III of Arnost discloses the synthesis of compound XVI shown below.

As the judge explained at [489]:

The judge went on to find as follows:

Summary . The judge summarised the position in the light of this prior art as follows:

The law. The principle that one cannot validly claim a mere collocation of two features each of which is old or obvious is one that has long been recognised in English patent law, and it has also been recognised in European patent law. It is a principle which needs to be treated with some care, however.

In Williams v Nye (1890) 7 RPC 62 the patent was for a sausage machine that was a combination of a known mincing machine and a known skin-filling machine. Kekewich J held that the patent was invalid, and his decision was affirmed by the Court of Appeal on the ground that, although the claimed machine was new, it was not inventive.

In British Celanese Ltd v Courtaulds Ltd (1935) 52 RPC 171 the main patent was for a process of manufacturing artificial silk. Clauson J held that the patent was invalid, and his decision was affirmed by both the Court of Appeal and the House of Lords. In the House of Lords it was common ground that the patented process consisted of four features, each of which was old. Lord Tomlin set out at 193 the legal proposition relied upon by counsel for the plaintiffs:

In SABAF SpA v MFI Furniture Centres Ltd [2004] UKHL 45, [2005] RPC 10 the patent was directed to burners for separate gas hobs which took up as little vertical space as possible. In gas cookers and hobs the gas had to be mixed with air before it was ignited in order to burn steadily. In addition, the pressure of the gas had to be sufficient to expel it through the holes in the burner in a steady stream. In gas cookers both requirements were met by the use of a tube which passed horizontally below the hob and then turned upwards to connect with the burner. The tube had an air inlet. It also had a slight flare which, by virtue of the Venturi effect, increased the pressure of the mixed gas and air. The disadvantage of this arrangement was that it took up vertical space. The invention achieved a more compact hob by an arrangement in which both the air intake and the Venturi effect took place above, instead of below, the hob.

At trial Laddie J held that:

The relevant passages in the current (March 2021) edition of the Guidelines are little changed from those cited in SABAF. They state:

The Court of Appeal reversed Laddie J’s decision on the basis that it was impermissible to combine two prior art disclosures unless it was obvious to do so, and Laddie J had not held that it would be obvious to the skilled person to combine the teaching of either of the first pair of citations with either of the second pair of citations.

The House of Lords reversed the Court of Appeal. Lord Hoffmann said at [24]:

Lord Hoffmann went on:

In Degussa-Huls SA v Comptroller-General of Patents [2004] EWHC 3213 (Pat) [2005] RPC 29 Pumfrey J expressed the view at [33] that SABAF was probably mainly concerned with claims to mechanical inventions. In the present case, however, the judge held at [469] that the collocation principle was a general one, and so it was capable, as a matter of law, of applying to an invention consisting of chemical molecules. Illumina does not contend that he was wrong about that.

In Abbott v Evysio (cited above) Kitchin J held at [182]:

He went on to conclude at [185]:

There was some debate on the appeal in the present case as to how the court should decide whether the claim consists of one invention or a plurality of inventions. In the end I understood it to be more or less common ground that this was primarily a question of what the patent disclosed, read in the light of the common general knowledge, but that evidence was admissible either to show that an interaction between features claimed in the specification did not occur or to show that an interaction not spelt out by the specification would be apparent to the skilled person or team.

The judge’s reasoning. The judge began by noting two points which were not determinative of the issue:

He went to hold that the claimed invention was a single invention rather than a collation of two features for the following reasons:

The appeal. MGI’s case on the appeal is simple and straightforward. MGI point out that the judge made no finding that the two elements of claim 1, namely (i) the 4 carbon linker form of dye XVI and (ii) a derivatised nucleotide plus linker LN3, combined to produce a synergistic effect or otherwise interacted in any non-obvious way. No such interaction is suggested in the specification, whereas [0037] and Example 9 do suggest an interaction where a PEG spacer is used; nor did the judge find that the skilled team would think that there was any such interaction. Rather, the judge’s reasoning was that the skilled team would appreciate from their common general knowledge that the two elements had the potential to interact with each other in an unwelcome manner, but the specification showed that in fact they did not. MGI’s submission is that that is not enough to save the claimed invention from being a mere collocation of uninventive features.

Attractively though this argument was presented by counsel for MGI, I do not accept it. I agree with the judge that, even assuming that the collocation principle is applicable to an invention consisting of a class of molecules, the application of the principle must take account of that technical context. Although the molecules claimed in the 415 Patent are made up of building blocks, those building blocks are incorporated into single molecules. The judge found that the skilled team would know from their common general knowledge that, when joined together, these building blocks were capable of interacting adversely with each other in various ways and that the skilled team could not predict in advance whether this would occur or not. If it did occur, the claimed molecules would not be useful in sequencing by synthesis. The 415 Patent demonstrates that there is no such adverse interaction, and thus the claimed molecules are useful for that purpose. It follows that the 415 Patent claims a single invention that makes a technical contribution to the art which neither Milton nor Arnost makes even when taken together. If it was obvious to the skilled team to combine the teaching of Milton with the teaching of Arnost, then the claimed invention would be obvious; but the judge found that that was not obvious, and there is no appeal against that finding.

For the reasons given above I would also dismiss MGI’s appeal in respect of the 415 Patent.

I agree.

I also agree.