“40. … Starting from the double stranded DNA of interest, a single strand is taken and used as a template in the method. DNA polymerase is used to add complementary nucleotide bases to the single template strand, one at a time. The complementarity of DNA means that the particular nucleotide base added at a given stage by the polymerase enzyme will be determined by the template sequence. So if the relevant nucleotide in the template is G then a C will be added to the growing complementary strand …. The trick to Sanger sequencing is that the free nucleotides to be added are not in their natural form. 41. Natural nucleotides have the capacity to form chains by joining together. … The chemical group at the 3' position is a hydroxyl (OH) group and the group at the 5' position is a triphosphate ester. The two ends connect together to form a link in the chain called a phosphodiester bond, liberating a molecule called pyrophosphate. A single strand of DNA therefore consists of a chain of these nucleotides and will have a ‘3' end’ at one end of the chain and a ‘5' end’ at the other end of the chain. 42. The way natural DNA synthesis works is that when a new nucleotide is added to the complementary strand, its 5' end is linked to the 3' end of the existing nucleotide which was already present. Once incorporated the unused 3' end of that newly linked nucleotide is ready to connect to the next fresh nucleotide, and so the complementary chain will grow. 43. In Sanger sequencing the new nucleotides are not natural because their 3' ends lack the 3' hydroxyl group. In the relevant naming convention it is called a dideoxynucleotide triphosphate (ddNTP). …. 44. So in Sanger sequencing when a ddNTP is added, the chain cannot grow any further. Since there are four nucleotides (C, G, A and T) one can make four mixtures whereby each mixture has all four of C, G, A and T nucleotides in it but in each mixture, some examples of one kind of nucleotide are in the blocked ddNTP form instead of the natural dNTP form. Therefore when the DNA polymerase incorporates a ddNTP into the newly synthesised DNA strand, synthesis of the strand ceases (i.e. chain termination occurs). The Sanger sequencing process therefore results in the synthesis of a large number of copies of the template strand, which are terminated at random lengths according to the position at which a ddNTP is incorporated. A population of DNA strands of different lengths is therefore obtained, which end either with A, T, G, or C. These DNA strands of different lengths are then resolved using manual or automatic approaches and the DNA sequence can be understood. In a manual version of the process radiolabelled ddNTPs are used and the resulting radiolabelled copies of the template strand are size separated by gel electrophoresis. The DNA sequence of the template strand is determined from the order of the bands in the gel, as shown below: ”
“ … the common general knowledge would also include knowledge of the concept of reversible chain termination. A fair number of papers related to reversible chain terminators had been published before the priority date. As a matter of the common general knowledge of a sequencing by synthesis skilled team, the team would know that there was a body of papers and know how to find them. I would hold that unprompted, their common general knowledge would include knowledge of the existence of two particular groups who had published experimental results in more than one paper. They were the Gibbs/Burgess group and the [Canard/]Sarfati group. Again, unprompted, the common general knowledge would include the existence of two particular papers, which were frequently cited. They are Metzker 1994 and Canard 1994. This is not a finding that any particular content in either paper was common general knowledge. What was common general knowledge was that these papers existed, published results and represented the farthest anyone had got with reversible chain terminators as a concept.”
“120. …. By 2002 ... the view of the skilled [team] …. 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 [team]. The reason this is critical is that the evidence of [MGI’s expert witness] 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 [team] looks at Zavgorodny with the specific aim in mind of finding a blocking group [they] might be able to use in a reversible chain terminator sequencing process. Moreover the questions put to [Illumina’s expert witness] Prof Leadlay were on essentially the same premise (that the skilled [team] 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. 123. First, the skilled [team] did not lack chemical groups to try as protecting groups. The Greene & Wuts textbook [Theodora Greene and Peter Wuts, Protective Groups in Organic Synthesis, 3rd edition (John Wiley & Sons, 1999)] illustrates that. 124. Second the papers concerned with reversible chain terminators were not suggesting what was required to overcome their absence of success was to test new chemical groups as reversible chain terminators. 125. Third, as best one can tell from the patent applications filed around the priority date, of the work which independent groups did do at around that time, it did not involve trying new potential reversible chain terminators at the 3' position. One group (Amersham) was interested in making modifications at the 4' position. The other group was Genovoxx. Their approach, based on their patent application, was to avoid pursuing a 3' modification and instead put a sterically demanding group on the base to prevent incorporation. Prof Marx accepted that this approach of Genovoxx was a fair reflection of the attitude of those in the art at the time. I infer that Genovoxx were well aware of the earlier proposals to use reversible chain terminators at the 3' position, and did not lack ideas for alternative groups at that location, but took an entirely different approach. 126. Overall, in my judgment the common general knowledge of the skilled [team] in 2002 was that they knew of the concept of sequencing by synthesis with reversible chain terminators, but they also knew that it had not succeeded in practice. The skilled [team] also understood that to make it work one needed to come up with a system in which one could repeatably incorporate nucleotides linked to specific labels one at a time in a reversible way, but they did not know with any degree of specificity what particular problem or problems had to be solved so as to take this forward. It may well have been that the technique simply could not be made to work. The attitude of the skilled [team] in 2002 was not an upbeat one.”
“128. … First … the idea of a reversible protecting group in organic chemistry is very well established. They find utility throughout organic chemistry as [a] way of protecting one functional group in a molecule from reacting so that changes can be made elsewhere. The Greene & Wuts textbook which has already been mentioned is a large encyclopaedia of possible protecting groups. It includes azides. 129. Second the azide group (three nitrogens in a row) is a well known chemical group. They were known to be cleavable. …”
“Sequencing by synthesis of DNA ideally requires the controlled (i.e. one at a time) incorporation of the correct complementary nucleotide opposite the oligonucleotide being sequenced. 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. 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. The blocking group must then be removable, under reaction conditions which do not interfere with the integrity of the DNA being sequenced. The sequencing cycle can then continue with the incorporation of the next blocked, labelled nucleotide. 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.”
“To be useful in DNA sequencing, nucleotide, and more usually nucleotide triphosphates, generally require a 3'OH-blocking group so as to prevent the polymerase used to incorporate it into a polynucleotide chain from continuing to replicate once the base on the nucleotide is added. There are many limitations on the suitability of a molecule as a blocking group. It must be such that it prevents additional nucleotide molecules from being added to the polynucleotide chain whilst simultaneously being easily removable from the sugar moiety without causing damage to the polynucleotide chain. Furthermore, the modified nucleotide must be tolerated by the polymerase or other appropriate enzyme used to incorporate it into the polynucleotide chain. The ideal blocking group will therefore exhibit long term stability, be efficiently incorporated by the polymerase enzyme, cause total blocking of secondary or further incorporation and have the ability to be removed under mild conditions that do not cause damage to the polynucleotide structure, preferably under aqueous conditions. These stringent requirements are formidable obstacles to the design and synthesis of the requisite modified nucleotides.”
“Reversible blocking groups for this purpose have been described previously but none of them generally meet the above criteria for polynucleotide, e.g. DNA-compatible, chemistry.”
“… Whilst the use of an allyl group as a hydroxyl protecting group is well known - it is easy to introduce and is stable across the whole pH range and to elevated temperatures - there is to date, no concrete embodiment of the successful cleavage of a 3'-allyl group under DNA compatible conditions, i.e. conditions under which the integrity of the DNA is not wholly or partially destroyed. In other words, it has not been possible hitherto to conduct DNA sequencing using 3'OH allyl-blocked nucleotides.”
“The present invention is based on the surprising development of a number of reversible blocking groups and methods of deprotecting them under DNA compatible conditions. Some of these blocking groups are novel per se; others have been disclosed in the prior art but, as noted above, it has not proved possible to utilised these blocking groups in DNA sequencing.”
“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.”
“… the skilled person would not simply disbelieve or reject what is said in paragraph [0147]. Rather they would accept that the second cycle for C, and A (less so for G) and the fourth and later cycles for T were likely to have taken place but may not have been fully efficient, and may have involved side reactions.”
“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.”
“151. … the skilled [team] taking the patent as a whole including these figures 5 and 6 would conclude that while further optimisation of the conditions was likely to be required, they would expect it to amount to routine work. They would regard the data as showing that the incorporation and deblocking steps were sufficiently efficient to be a promising repeatable technique. The worst one was for compound 24 (G) but it was not so bad that the skilled [team] would think it would not work. Furthermore …. it would in fact be routine work for the skilled [team] to carry out. 152. Overall, the skilled [team] reading the patent as a whole and taking into account the experimental results, would accept as plausible the proposition that a nucleotide with a 3' azidomethyl blocking group satisfied the objectives set out by paragraphs [0004] and [0005].”
“A modified nucleotide triphosphate molecule comprising a purine or pyrimidine base and a deoxyribose sugar moiety having a 3'-azidomethyl group.”
“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.”
“Treatment of appropriately protected nucleosides with a mixture of acetic acid, acetic anhydride and dialkylsulfoxide was shown to give O-(1-alkylthioalkylated) nucleosides that were oxidised to the corresponding sulfoxides and sulfones, or converted via O-halogenomethyl derivatives to various O-substituted nucleosides.”
“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.”
“… A ‘synthon’ is a unit to be used in further syntheses. This sentence emphasises that what Zavgorodny is providing are chemical structures which, from Zavgorodny’s point of view, are themselves going to be used to synthesise other things. In other words, … they are synthetic intermediates. …”
“190. … It draws attention to the azidomethyl group, saying it is of special interest and can be removed under very specific and mild conditions. However it is important to appreciate that the reference to ‘special interest’ is not an assertion about sequencing by synthesis reactions. Zavgorodny is not suggesting that this group is of ‘special interest’ in that context. The skilled [team] would understand that what Zavgorodny is talking about is in the context of its use as a synthon, a chemical intermediate. Protecting groups are a routine tool in synthetic chemistry. It would be an exercise of hindsight to read that as a disclosure concerned with sequencing by synthesis or reversible chain terminators. 191. The same goes for the reference to removal under ‘very specific and mild conditions’. What Zavgorodny is referring to is specificity and mildness in the context of the work he is reporting and contemplating, i.e. organic synthesis. So, for example, ‘mild conditions’ is not a reference to their being mild relative to the stability of DNA. Whether the conditions happen to be mild vis a vis DNA is a different question. So also the specificity referred to relates to the other groups on the molecules Zavgorodny is describing. 192. Finally a point arises on what ‘triphenylphosphine in aqueous pyridine at 20 ºC’ means. It refers to using triphenylphosphine in what a skilled person would regard as an organic solvent: aqueous pyridine. It is common ground that pyridine denatures DNA.”
“In a way the difference between Zavgorodny ... and claim 1 of 578 [as amended, equivalent to claim 1 of 289] is quite small. Claim 1 claims a nucleotide (i.e. with the 5' phosphates) with an azidomethyl group at the 3' oxygen whereas Zavgorodny … discloses a nucleoside with such a group at the 3' oxygen. However in order to render claim 1 invalid the skilled [team] has to make the claimed molecule and for that to happen the skilled [team] has to have a reason to do so. As a result the inventive step(s) of all the relevant claims of the modified nucleotide patents stand or fall together. If performing sequencing by synthesis using a nucleotide with an azidomethyl blocked 3' oxygen as a reversible chain terminator is obvious over Zavgorodny …, then claim 1 also lacks inventive step because it would be obvious to make the relevant compound. If that exercise was not obvious then none of the claims, including claim 1 of 578, are obvious for the converse reason. Another way of approaching the same question would be to ask whether it was obvious to the skilled [team] given Zavgorodny …, with a reasonable prospect of success, to try out a sequencing by synthesis test using a nucleotide with an azidomethyl blocked 3' oxygen as a reversible chain terminator.”
“… A fiction in patent law is that the notional uninventive skilled man in the art is deemed to have read and assimilated any piece of prior art pleaded by the party attacking the patent claim. If the invention is obvious to that person in the light of a particular piece of prior art, the claim in invalid. It is no answer to say that in real life the prior art would never have come to the attention of a worker in the field, for example because it was tucked away on the top shelf of a public library or because it was in a language which nobody in the art knew. 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. A document directed at solving the particular problem at issue will be seized upon by the skilled addressee. Its very contents may suggest that it is a worthwhile starting point for further development. But the same may not be the case where a document comes, say, from a distant and unrelated field. …”
“As I have already mentioned, Prof Marx’s evidence that the invention was obvious was based on a premise that the skilled person would look at Zavgorodny with the specific aim in mind of finding a blocking group they might be able to use in a reversible chain terminator sequencing process, and the cross-examination of Prof Leadlay was on the same premise. However I have rejected this premise. It is tempting therefore simply to stop at this point and find the claim is not obvious.”
“198. The skilled [team] is a team working on research into sequencing by synthesis. They are aware of the idea of using reversible chain terminators but as far as they were concerned the idea had not succeeded. They knew that to make it work they would need to come up with a system in which one could repeatably incorporate a nucleotide linked to a specific label, one at a time, in a reversible way. They did not have any specific problem or problems in mind which had to be solved as a key to unlock the ability to take the method forward. It may well have been that the technique simply could not be made to work. 199. As a matter of principle, as with any item of prior art, the skilled [team] is deemed to read Zavgorodny with interest. They would see that it was a paper concerned with chemical intermediates (synthons). They would see that one such intermediate was a nucleoside in which the 3' OH had been blocked with azidomethyl. They would see the reference to removal using mild and specific conditions and that Zavgorodny regarded the azidomethyl group as of special interest. In my judgment the most likely thing such a skilled team would think having read Zavgorodny is that this paper on synthetic chemistry had nothing to do with their focus on sequencing by synthesis. To the skilled [team] the concept of protecting groups in synthetic chemistry is commonplace. At most Zavgorodny would be seen as something to add to the organic chemist team member’s general toolbox concerning chemical synthesis …. There is simply nothing, absent hindsight, to suggest that what is disclosed here has an application in relation to sequencing by synthesis using reversible chain terminators. They would read it with interest and having done so, put it down and move on.”
“201. Even if the skilled [team] saw an analogy between the blocking 3' end in Zavgorodny and the idea of blocking the 3' end of a nucleotide in sequencing by synthesis, it would not make the invention obvious. The skilled [team] did not think they needed a new group to try as a reversible chain terminator. The skilled [team] knew that there were numerous possible candidate groups and would be aware that there was a textbook in which to find such things if they had wanted help with thinking of some to try (Greene & Wuts). 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 [team] 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 [team] 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. …”
“Even if the skilled [team] got as far as considering whether to try out an azidomethyl group as a 3' blocking group on a nucleotide in a test of a single cycle, they would, as Prof Leadlay explained, have no basis for thinking that such a blocked nucleotide would be incorporated into an oligonucleotide by DNA polymerase. It might or it might not.”
“209. …. While the skilled [team] would think they could come up with conditions in which to remove an azidomethyl group without damaging DNA, that is not the only issue. To be useful in sequencing by synthesis the removal has to have a reasonable yield and reasonable speed. 210. In my judgment the position is simply that the skilled [team] has no basis from which to infer that there was a reasonable prospect of getting a reasonable yield and speed.”
“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. … 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. …”
“297. MGI is right that this conclusion highlights that all that needed to be obvious to invalidate claim 12 was to sequence a single … nucleotide using the 3' azidomethyl blocked nucleotide (with linker etc.). … 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 [team] 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 [team] 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.”
“Q. But [Zavgorodny says azidomethyl] is of special interest because it can be removed under very specific and mild conditions, and that would be particularly attractive to someone who was thinking of SBS using reversible chain terminators? A. I think that that is coloured by hindsight. I think that the skilled person would rather look closely at the fact that the conditions in Zavgorodny simply do not tell you anything about the technical details of how the experiments should be done. You are in the dark. I think if you were forced to take azidomethyl on, if you took it on, it would be entirely speculative.”
“1. 3' -OH protected with an azidomethyl group as a protected form of a hemiaminal: Nucleotides bearing this blocking group 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: ”
“Nucleotides bearing this blocking group have similar properties to the above example, though incorporate less rapidly.”
“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 provides …. 239. This assertion does not have any graphs or gels associated with it, but it is a statement that experiments have been done and that they were successful in various specific ways which are relevant to success from the point of view of the skilled person. Prof Leadlay’s evidence, which I accept, was that this document: ‘clearly discloses … 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.’”
“The requirement for claiming priority of ‘the same invention’, referred to in Article 87(1) EPC, means that priority of a previous application in respect of a claim in a European patent application in accordance with Article 88 EPC is to be acknowledged only if the skilled person can derive the subject-matter of the claim directly and unambiguously, using common general knowledge, from the previous application as a whole.’”
“The approach is not formulaic: priority is a question about technical disclosure, explicit or implicit. Is there enough in the priority document to give the skilled man essentially the same information as forms the subject-matter of the claim and enables him to work the invention in accordance with that claim?”
“So the important thing is not the consistory clause or the claims of the priority document but whether the disclosure as a whole is enabling and effectively gives the skilled person what is in the claim whose priority is in question. I would add that it must ‘give’ it directly and unambiguously. It is not sufficient that it may be an obvious development of what is disclosed.”
“The skilled person must be able to derive the subject matter of the claim directly and unambiguously from the disclosure of the priority document. Mr Tappin stressed that the question was one of what was disclosed to the skilled person, not what was made obvious to him by the priority document, for example in the light of his common general knowledge. I agree that … that is the correct approach. That does not mean, however, that the priority document should be read in a vacuum. The question of what a document discloses to a skilled person takes account of the knowledge and background of that person. A document may mean one thing to an equity lawyer and another to a computer engineer, because each has a different background. The document still only has one meaning because it is only the relevant skilled person's understanding which is relevant. What is not permissible is to go further than eliciting the explicit or implicit disclosure and take account of what a document might lead a skilled person to do or try, or what it might prompt him to think of.”
“147. Genentech submitted that the requirement for plausibility which is part of the law of sufficiency was not relevant in the context of priority and referred to a EPO decision T903/05 Gemvax in which the Technical Board of Appeal rejected the suggestion that to be entitled to priority it was necessary for the priority document to contain data which made it plausible that the claimed invention worked (paragraph 11). Hospira did not agree and submitted that in a case like this one, plausibility was as much part of the test for priority as it was part of the test for sufficiency. The investigation of whether an invention is plausible is part of the requirement for enablement. Hospira argued that enablement was not challenged in Gemvax. 148. Although Hospira are right that enablement was not challenged in Gemvax, the Board regarded plausibility as a separate requirement distinct from enablement. Genentech is right that the Board of Appeal held that plausibility was not a requirement for priority in any event. 149. Although I am reluctant to do so I disagree with the statement in Gemvax. The requirement for priority is that the earlier application must be in respect of the same invention as the patent. The establishment of priority includes a requirement for an enabling disclosure (Biogen v Medeva [1997] RPC at 48–49). In order to make an enabling disclosure of an invention it must be possible to make a reasonable prediction that the invention will work (Regeneron [v Genentech[2013] EWCA Civ 93 ,[2013] RPC 28 ] paragraph 100). In the context of an invention which includes the achievement of a therapeutic effect as one of its features, absolute proof is not required but the patentee must show that the therapeutic effect is plausible (Regeneron paragraph 103). It seems to me that this logic applies just as much to priority as it does to sufficiency of disclosure (see also Biogen on the relationship between priority and sufficiency). The alternative would be a recipe for abuse. A patentee could file a speculative priority application and obtain an earlier priority date, thereby stealing a march on the competition. I find that in law the test for priority includes the requirement for plausibility in a case like this one.”
“the specification must disclose some reason for supposing that the implied assertion of efficacy in the claim is true”
“Although the onus is on [the patentee], it would be strange if this had the result in most cases of requiring the patentee to carry out experiments simply to prove entitlement failing which the defendant could simply assert that early priority had not been proved. Although the onus is on the patentee, in a normal case the court will proceed on the basis that the technical results set out in the priority document can be achieved as asserted. It is enough if the patentee asserts that the instructions in the priority document work to produce the results claimed for them. A claim to priority is, implicit[l]y, such an assertion of enablement. If that is not effectively challenged then the patentee has done enough. It follows that a defendant should do more than merely issue a challenge to priority. He must explain the manner in which he says there is failure to enable. This should be set out in his pleadings. He will have to support his assertions by evidence. The court should be able to proceed on the basis that the experimental data in the priority document is not only right but reasonably repeatable. Although the onus remains on the patentee, the evidential burden shifts to the defendant. In some cases he may not be able to discharge it without supporting experiments.”
“240. Based on this, it seems to me that the conclusion that the claims are entitled to priority must follow. The same invention is disclosed in both the priority document and the patent. The disclosure in the priority document supports the claims and is an enabling disclosure. It also provides plausible information which supports the idea that a sequencing by synthesis scheme based on the claimed 3' O-azidomethyl blocking group will work. 241. One might have a degree of scepticism, from the way example 1 is written, the assertion of 100% yield, and the absence of gels, whether such a test really had been carried out or whether this was a so called ‘prophetic’ example. However on the facts of this case I find that that does not matter. It does not render what is described any less plausible. 242. There is no squeeze relating to Zavgorodny and no inconsistency between this conclusion and the finding of non-obviousness.”
“…. the question of plausibility must be tested by reference to the contents of the Application. If the claimed inventions are only plausible when considered by reference to the contents of the Patent, and not when considered by reference to the contents of the Application, then it must follow that the Patent is invalid for added matter.”
“430. …. the idea of functionalising a dye molecule in order to conjugate it to a biological molecule. Common functional groups are carboxyl groups and amino groups. They join together to form an amide bond. When the target biomolecule had one of them it was well known to put the other on the dye to create the amide. The ortho-carboxy group in rhodamines was used for this purpose. … Commercial dyes would often be available in a variety of different activated or functionalised forms to allow for conjugation to different biomolecules. 431. Linkers were a well known tool to use to connect a fluorophore to a biomolecule and help to prevent interaction between the two. A linker needs a functional group at each end to allow the two molecules to be joined. It should be stable under the relevant conditions and should not fluoresce. … 433. In terms of selecting fluorophores for labelling biological molecules, the skilled [team] would select a fluorophore with spectral properties suitable for their equipment and suitable to allow unambiguous detection. So if four fluorophores were to be used to sequence DNA, they would need to be distinguishable. The fluorophores should be bright and photostable and not interfere with the reactions taking place in sequencing by synthesis. … 434. An important issue is the effect which the exercise of connecting a fluorophore to a biomolecule could have on the photochemical properties of fluorophores. Those properties include the absorbance and emission wavelengths, quantum yield and extinction coefficient, and more generally the brightness, photostability and tendency to quench. In the end the evidence was clear. The skilled [team] knew that the spectral properties of xanthene based dyes [such as rhodamines] can be altered by changes or substitutions on the xanthene core. That is because they affect the delocalised [electron] system in that core. So a linker which affected the delocalised system in the xanthene core may affect the photochemical properties of the dye. The skilled [team] also knew that changes made further away from that xanthene core were less likely to make any change to the spectral properties of the system while changes closer to the core were more likely to have an effect. 435. However in the end this is an empirical field. The characteristics of individual moieties within a chemical structure are influenced by their environment. Molecules can be drawn out flat on a page but as the skilled [team] knows they are in fact three dimensional structures which can move. Parts which look remote on the page can interact with more distant parts because the whole molecule can adopt a shape in which that is true. Given a known fluorescent molecule and a new molecule derived from that known fluorescent molecule e.g. by adding a linker of some kind to it, and given the photochemical properties of both forms, the skilled [team] can rationalise whatever differences do or do not exist in the photochemical properties by reference to those structural changes. However that is not the same as being able to predict in advance with any degree of precision what the effect of a given change would be.”
“[0034] According to a second aspect of the invention there are provided dye compounds suitable for attachment to substrate moieties, particularly comprising linker groups to enable attachment to substrate moieties. Substrate moieties … may include nucleosides, nucleotides … More particularly the covalent attachment is by means of a linker group. [0035] The dyes according to the invention may include a reactive linker group at one of the substituent positions for covalent attachment of the dye to another molecule. Reactive linking groups are moieties capable of forming a covalent bond. In a particular embodiment the linker may be a cleavable linker. … The cleavage site can be located at a position on the linker that ensures that part of the linker remains attached to the dye and/or substrate moiety after cleavage. … The use of a cleavable linker to attach the dye compound to a substrate moiety ensures that the label can, if required, be removed after detection, avoiding any interfering signal in downstream steps.”
“… the inventors have determined … that by altering, and in particular increasing, the length of the linker between a fluorescent dye (fluorophore) and the guanine base, by introducing a polyethylene glycol spacer group, it is possible to increase the fluorescence intensity compared to the same fluorophore attached to the guanine base through other linkages known in the art. The design of the linkers, and especially their increased length, also allows improvements in the brightness of fluorophores attached to the guanine bases of guanosine nucleotides when incorporated into polynucleotides such as DNA. Thus, when the dye is for use in any method of analysis which requires detection of a fluorescent dye label attached to a guanine-containing nucleotide, it is advantageous if the linker comprises a spacer group of formula -((CH 2)2O)n- wherein n is an integer between 2 and 50 …”
“The images were analysed to pick the brightest colour for each cluster, and this image intensity analysis was used to call the base for each cluster at each cycle. Images from each cycle were colocalised to obtain the sequence corresponding to each cluster. As the sequence of each cluster is known; and is the same for every cluster in the above experiment, the error rates (i.e. clusters not called as the correct sequence) can be analysed for each cycle of nucleotide incorporation. The error rates were less than 1% for the first 20 cycles of the experiment, meaning the known sequence of the mono-template was correctly identified.”
“This indicates that the [sequencing by synthesis] performed well and that the fluorescently labelled modified nucleotides produced a clear signal to permit reliable detection.”
“A nucleotide labelled with a compound according to the formula: ”
“… 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. … ”
“… molecule XVI of Arnost is Dye 2 of the 415 patent. Therefore Arnost discloses a molecule identical with the left hand side of the formula of claim 1 and teaches its use in making conjugates with biologically active molecules. Note however that molecule XVI stops at the ortho-carboxyl group on the benzyl group below the xanthene core. Arnost does not disclose the linker arm of claim 1 which goes from that carboxyl group to the middle amide of claim 1.”
“490. … 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. …. 492. It would be obvious to use a linker of some sort rather than attempting to conjugate the dye directly to the biological molecule. … An obvious group to use at the end of the linker which was to connect to the dye would be an amine. … A linker 3-6 carbons long would be a sensible choice here …. It would be an obvious option to have a suitable functional group at the other end of this linker in order to link to the next thing. So a carboxyl group would be used to link to an amine group. 493. Accordingly I find that given Arnost, an obvious molecule for the skilled person to make in the context of labelling biologically active molecules in a bioassay, is the left hand end of the formula of claim 1 of the 415 patent up to the middle amide. It is the 4 carbon option. I will call this molecule the 4 carbon linker form of dye XVI. … 495. However, there is no case that it would be obvious for that skilled person in those circumstances to alight on the disclosure of Milton in these circumstances or onto a nucleotide conjugated to what is linker LN3 as shown (but not named that way) in Milton.”
“501. On the conclusions I have reached, it follows that claim 1 will be invalid if it is a 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. 503. The place where they join is the middle amide bond. The findings so far mean that each of the two elements of claim 1, taken on its own, is obvious, but it would not be obvious to combine these two elements.”
“It is accepted as sound law that a mere placing side by side of old integers so that each performs its own proper function independently of any of the others is not a patentable combination, but that where the old integers when together have some working inter-relation producing a new or improved result then there is patentable subject-matter in the idea of the working inter-relation brought about by the collocation of the integers.”
“In truth and in fact there is no inter-related working between the integers in the sense that any one of the integers is doing something which it could not do without the presence of one or more of the others. Each integer is fact performing its own part and is not functionally dependent upon the presence of any other integer at all. I think therefore that the invention lacks subject-matter.”
“… the two important features of the SABAF burners which are said to constitute an invention are (i) drawing primary air in from above the hob unit and (ii) the use of a flow path under the flame spreader in which the Venturi effect will be present [a ‘radial’ Venturi]. … there is nothing in the specification to suggest, nor has it been seriously argued, that these two features interact with each other.”
“Part GChapter VII – Inventive step … 5. 2 Formulation of the objective technical problem … Sometimes, the objective technical problem must be regarded as an aggregation of ‘partial problems’. This is the case where there is no technical effect achieved by all the distinguishing features taken in combination, but rather a plurality of partial problems is independently solved by different sets of distinguishing features (see G-VII, 6 …). … 6. Combining pieces of art … A different situation occurs where the invention is a solution to a plurality of independent ‘partial problems’ (see G-VII, 7 and 5.2). Indeed, in such a case it is necessary to separately assess, for each partial problem, whether the combination of features solving the partial problem is obviously derivable from the prior art. … … 7. Combination vs. juxtaposition or aggregation The invention claimed must normally be considered as a whole. When a claim consists of a ‘combination of features’, it is not correct to argue that the separate features of the combination taken by themselves are known or obvious and that ‘therefore’ the whole subject-matter claimed is obvious. However, where the claim is merely an ‘aggregation or juxtaposition of features’ and not a true combination, it is enough to show that the individual features are obvious to prove that the aggregation of features does not involve an inventive step (see G-VII, 5.2, last paragraph). A set of technical features is regarded as a combination of features if the functional interaction between the features achieves a combined technical effect which is different from, e.g. greater than, the sum of the technical effects of the individual features. In other words, the interactions of the individual features must produce a synergistic effect. If no such synergistic effect exists, there is no more than a mere aggregation of features … Annex … 2. 1 Obvious and consequently non-inventive combination of features: The invention consists merely in the juxtaposition or association of known devices or processes functioning in their normal way and not producing any non-obvious working inter-relationship. Example: Machine for producing sausages consists of a known mincing machine and a known filling machine disposed side by side.”
“In my opinion the approach of the Court of Appeal is contrary to well established principles both in England and in the European Patent Office, as stated in the quotation from Lord Tomlin and the EPO Guidelines to which I have referred. 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.”
“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.That, in my opinion, is what Laddie J. meant by the law of collocation. 27. If one approaches the matter on this basis, it is clear that Laddie J. correctly applied the relevant principles at each stage. He found that taking the air above the hob and having a radial Venturi had no effect upon each other and that he was therefore dealing with two alleged inventions, each of which had to pass the test laid down in s.3 . He identified the inventive step in each. He asked himself what in each case were the differences between the relevant prior art and the invention. He found that there were virtually none. He concluded that it would have required no invention on the part of the skilled man armed with common general knowledge in the art to design a product in accordance with the alleged invention. In other words, he applied s.3 according to the Windsurfing structure to each of the features alleged to constitute the invention.”
“… The first step is to determine whether the claim is concerned with a single invention or not. If two integers interact upon each other, if there is synergy between them, they constitute a single invention having a combined effect. If each integer performs its own proper function independently of the others then each is a separate invention and can be considered as such for obviousness purposes.”
“In the light of the evidence I am satisfied that these patents cannot be considered as simply a collocation of elements which perform their own functions independently of each other. There is an interaction between them which the designer of the stent must take into consideration. Each element cannot be regarded as an individual invention for obviousness purposes.”
“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. 505. As mentioned already, the claimed molecule as a whole has useful properties (fluorescent detection, 20 cycles, 1% error rate etc.). However just because the combined molecule has useful properties does not answer the question. The hob in Sabaf was useful - it took up as little vertical space as possible. However this useful property was the result of two obvious independent features operating independently, and so it was invalid.”
“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. … 511. As I have indicated already, unlike Sabaf this case is about unwelcome interactions. The dye fluoresces satisfactorily in the 415 patent because in fact the linker and nucleotide do not interact with it in an unfavourable way. They could have but they do not. The dye/linker combination, which is different from the one tested in Milton, does not in fact prevent incorporation of the nucleotide with the DNA polymerase. It might have but it did not. In this sense the circumstances are quite different from Sabaf. There was no suggestion there that combining the primary air flow from above with a flame spreader using the Venturi effect was even capable of having an unfavourable interaction. The designer in that case would have regarded the two parts as entirely functionally distinct before putting them in one oven. 512. If a single molecule were made consisting of the 4 carbon linker form of dye XVI and a derivatised nucleotide plus linker LN3, the skilled [team] would believe that these two parts are capable of interacting with one another. There is nothing inherent in either element to mean that it is incapable of interacting with the other element. The dye part is not a priori immune from the effects of the linker or the nucleotide. The skilled [team] would hope the molecule worked satisfactorily because the two elements did not interact but they would need that to be demonstrated by an experiment testing the combination as a whole. That means that the collocation principle does not apply. … 514. Putting it another way, the molecule of claim 1 is a single invention. Its beneficial properties derive from the functional relationship, which includes non-interference, between the constituent parts. I find that claim 1 of the 415 patent is valid.”