‘This invention concerns Factor IX in general, and particularly concerns Factor IX containing a mutation that enhances the clotting activity thereof. This invention also concerns DNA constructs encoding such Factor IX, along with vectors containing such constructs.’
‘Substitutions of the inventions are, for example, a substitution of an arginine residue for an amino acid residue selected from the group consisting of alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, glycine, serine, and threonine. In preferred embodiments of the invention, the substitution is a substitution of an arginine residue for an amino acid residue selected from the group consisting of alanine, leucine, and valine’
‘A non-naturally occurring mammalian Factor IX protein having an amino acid substitution at amino acid position 338’
‘2. A mammalian Factor IX according to claim 1, wherein said substitution of an arginine residue for an amino acid residue selected from the group consisting of alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, glycine, serine and threonine. 3. A mammalian Factor IX according to claim 1, wherein said substitution is a substitution of an arginine residue for an amino acid residue selected from the group alanine, leucine, and valine. 4. A mammalian Factor IX according to claim 1, wherein said substitution is a substitution of an arginine residue for an alanine residue. 5. A mammalian Factor IX according to claim 1, wherein said substitution is a substitution of an arginine residue for a leucine residue.’
“[The death] made the whole field of gene therapy go away, mostly, for at least a decade. Even the term gene therapy became a kind of black label. You didn’t want that in your grants.”
“While the unfortunate occurrence of the serious adverse events has slowed progress and dampened the ardor of some, it has also prompted others to undertake more detailed investigation into the behavior of viral vectors and more careful testing of all approaches, and we can be hopeful that as gene therapy technology is improved and refined the field will make greater steps forward.”
‘The study was designed to identify functionally important factor IX (FIX) residues. Using recombinant techniques and cell culture, we produced a mutant FIX with arginine at 338 changed to alanine (R338A-FIX). This molecule had approximately 3 times greater clotting activity than that of wild type FIX (wt-FIX) in the activated partial thromboplastin assay.’
‘… we propose that R338A-FIX’s increased activity is not due to an allosteric effect on the active site, but that the Arg-338 residue is part of an exosite that binds both factor X and the mucopolysaccharide, heparin.’
‘Circulating F.IX levels following intramuscular injection of AAV-F.IX -K5A/V10K, a variant with low affinity to extracellular matrix, were 2-5 fold higher compared with wild-type (WT) F.IX, while the protein specific activities remained similar. Expression of F.IX-R338A generated a protein with 2- or 6-fold higher specific activity than F.IX WT following vector delivery to skeletal muscle or liver, respectively. … These studies demonstrate that F.IX variants provided a promising strategy to improve the efficacy for a variety of gene-based therapies for hemophilia B.’
‘Knowledge of the chemical properties of the common amino acids is central to an understanding of biochemistry. The topic can be simplified by grouping the amino acids into five main classes based on the properties of the R groups (Table 3-1). In particular, their polarity or tendency to interact with water at biological pH (near pH 7.0). The polarity of the R groups varies widely, from nonpolar and hydrophobic (water-insoluble) to highly polar and hydrophilic (water-soluble).’
“… they are all small, nonpolar, hydrophobic, and have aliphatic R groups, though their ability to form α-helices do differ.”
‘This convinced us that the path forward would require a more potent vector that could drive adequate levels of FIX expression at lower vector doses. The solution to our dilemma came from a naturally occurring Factor IX variant, FIX Padua, first described in a kindred in Italy where the proband presented with a deep venous thrombosis in his early 20s.’
‘These data led to a marked change in the field – all programs made the switch to a FIX Padua transgene, and those that did not fell by the wayside. The first of these has now achieved regulatory approval in both the United States and Europe and others are expected to follow.’
‘Factor IX (FIX) Padua (R338L) has been described as a game changer for hemophilia B (HB) gene therapy. The ~8 fold increased specific activity compared to wild-type FIX (FIX WT) in aPTT-based clotting assay has recently allowed for a lowering of adeno-associated virus (AAV) vector dose compared to earlier gene therapy trials using FIX WT, while still achieving sustained near-curative FIX activity levels.’
‘The question of obviousness must be considered on the facts of each case. The court must consider the weight to be attached to any particular factor in the light of all the relevant circumstances. These may include such matters as the motive to find a solution to the problem the patent addresses, the number and extent of the possible avenues of research, the effort involved in pursuing them and the expectation of success.’
‘It cannot be said too often that the statutory question is: was the invention obvious at the priority date? It is not: was it obvious to try? In my judgment too much elaboration of the statutory question has been attached to it. The questions of the degree of expectation of success and the length of time thought to be needed to undertake a trial have taken on lives of their own. I think that this happened in our case. Insistence on the statutory question is not a novel thought. It is also an obvious one:…’ … ‘One of the important points, to my mind, is that all these considerations interact with each other. In short, it all depends. MedImmune's argument proceeded on the basis that Novartis needed to establish (a) a fair prospect of success (b) within a reasonable time, as if these were two independent conditions that had to be satisfied. They are not successive hurdles to be jumped; they are no more than aspects of the statutory question: was the invention obvious? We should stick to the statutory question, which has to be applied in all sorts of circumstances and in all sorts of different fields of endeavour.’
‘What would have been obvious will depend on all the circumstances. As I said in Norton Healthcare Ltd v Beecham Group Plc CA (unreported)19th June 1997 : “When deciding whether a claimed invention is obvious, it is often necessary to decide whether a particular avenue of research leading to the invention was obvious. In such circumstances the extent of the different avenues of research and the perceived chances of any one of them providing a successful result can be relevant to the decision whether the invention claimed was obvious. Whether the subject matter was obvious may depend upon whether it was obvious to try in the circumstances of that particular case and in those circumstances it will be necessary to take into account the expectation of achieving a good result. But that does not mean that in every case the decision whether a claimed invention was obvious can be determined by deciding whether there was a reasonable expectation that a person might get a good result from trying a particular avenue of research. Each case depends upon the invention and the surrounding facts. No formula should be substituted for the words of the statute. In every case the Court has to weigh up the evidence and decide whether the invention was obvious. This is the statutory task.”’
‘In the present case, motivation to take the step does not rely on the level of expectation of success, but on the instruction to take that step.’
‘Pfizer/BioNTech relied on the principle that there can be no invention in doing what is suggested in the prior art unless there is an established prejudice against that idea – the so-called "lion in the path" (see e.g. Pozzoli v BDMO[2007] EWCA Civ 588 at [24]-[29] ). The principle is an important one, but it applies once a specific suggestion has been identified.’
‘All of these passages are consistent with the Object/Solution approach to obviousness adopted by the Technical Board of Appeal of the EPO. Even if the step from the prior art is a small one, to prove obviousness it is necessary to demonstrate that there is some reason for taking it.’
‘[65] First, it is relevant to consider whether at the priority date something was "obvious to try", in other words whether it was obvious to undertake a specific piece of research which had a reasonable or fair prospect of success: Conor v Angiotech (above) at [42] per Lord Hoffmann; MedImmune Ltd v Novartis Pharmaceuticals UK Ltd[2012] EWCA Civ 1234 ; [2013] R.P.C. 27 , at [90] and [91] per Kitchin L.J. In many cases the consideration that there is a likelihood of success which is sufficient to warrant an actual trial is an important pointer to obviousness. But as Kitchin L.J. said in Novartis AG v Generics (UK) Ltd[2012] EWCA Civ 1623 , at [55], there is no requirement that it is manifest that a test ought to work; that would impose a straightjacket which would preclude a finding of obviousness in a case where the results of an entirely routine test are unpredictable. As Birss J. observed in this case (at [276]), some experiments which are undertaken without any particular expectation as to result are obvious. The relevance of the "obvious to try" consideration and its weight when balanced against other relevant considerations depend on the particular facts of the case. [66] Secondly, it follows that the routine nature of the research and any established practice of following such research through to a particular point may be a relevant consideration which is weighed against the consideration that the claimed process or product was not obvious to try at the outset of a research programme. Again, it is only one of several factors to be weighed in the assessment and it has no primacy and certainly no paramount status as a consideration. [67] Thirdly, the burden and cost of the research programme is relevant. But the weight to be attached to this factor will vary depending on the particular circumstances. This appeal concerns a pharmaceutical patent claiming as an invention a dosage regime. The cost and effort involved in bringing a drug to market through pre-clinical and clinical trials are notorious. Mr Waugh referred to the extrajudicial writing of Sir Hugh Laddie, "Patents - what's invention got to do with it?" (in Intellectual property in the new millennium: essays in honour of William R Cornish (2004), p. 91 et seq), in which he stated, at p. 92: "In this field it is apparent that, without patents, few new products would be marketed. The expense in producing a new pharmaceutical is in the research and development stage. Normally, once it has been discovered and given regulatory approval, the manufacture of a new pharmaceutical will be comparatively cheap and its replication by competitors easy. Without the protection of patents, there will be no ability to recoup the cost of the research and development, let alone fund such activities in the future. No private company is going to enter this business unless it can see a reasonable prospect of obtaining a return on investment." The need to facilitate expensive pharmaceutical research is an important policy consideration for legislators and others involved in intellectual property law. It was a factor behind the creation of the Swiss-form claim and the EPC 2000 claim as well as the supplementary protection certificate regime under Regulation (EC) 469/2009, which is available after market authorisation to give the patent owner the protection of the patent for up to 15 years, and the data exclusivity regime which Directive 2001/83/EC ( art. 10 ) and Regulation (EC) 726/2004 ( art. 14 ), which may confer ten years of exclusive marketing protection against competition from generic manufacturers. But the effort involved in research is only one of several factors which may be relevant to the answer to the statutory question of obviousness. [68] Fourthly, the necessity for and the nature of the value judgments which the skilled team would have in the course of a testing programme are relevant considerations as both the trial judge and the Court of Appeal held. [69] Fifthly, the existence of alternative or multiple paths of research will often be an indicator that the invention contained in the claim or claims was not obvious. If the notional skilled person is faced with only one avenue of research, a "one way street", it is more likely that the result of his or her research is obvious than if he or she were faced with a multiplicity of different avenues. But it is necessary to bear in mind the possibility that more than one avenue of research may be obvious. In Brugger v Medic-Aid Ltd (No. 2) [1996] R.P.C. 635, at p.661, Laddie J. stated: "[I]f a particular route is an obvious one to take or try, it is not rendered any less obvious from a technical point of view merely because there are a number, and perhaps a large number, of other obvious routes as well." I agree. As a result, the need to make value judgments on how to proceed in the course of a research programme is not necessarily a pointer against obviousness. [70] Sixthly, the motive of the skilled person is a relevant consideration. The notional skilled person is not assumed to undertake technical trials for the sake of doing so but rather because he or she has some end in mind. It is not sufficient that a skilled person could undertake a particular trial; one may wish to ask whether in the circumstances he or she would be motivated to do so. The absence of a motive to take the allegedly inventive step makes an argument of obviousness more difficult. In Agrevo/Triazoles (above), para 2.4.2, the Technical Board of Appeal of the EPO, having referred to the principle that the extent of the patent monopoly should correspond to and be justified by the technical contribution to the art (see [54] above) made the point in these terms: "Moreover, in the Board's judgment, it follows from this same legal principle that the answer to the question what a skilled person would have done in the light of the state of the art depends in large measure on the technical result he had set out to achieve. In other words, the notional 'person skilled in the art' is not to be assumed to seek to perform a particular act without some concrete technical reason: he must, rather, be assumed to act not out of idle curiosity but with some specific technical purpose in mind." This forms the basis of the EPO's problem-and-solution approach to obviousness which I have quoted in [61] above. [71] Seventhly, the fact that the results of research which the inventor actually carried out are unexpected or surprising is a relevant consideration as it may point to an inventive step, at least in so far as it suggests that a test was not obvious to try or otherwise the absence of a known target of the research which would make it less likely that the skilled person would conduct a test. [72] Eighthly, the courts have repeatedly emphasised that one must not use hindsight, which includes knowledge of the invention, in addressing the statutory question of obviousness. That is expressly stated in the fourth of the Windsurfing / Pozzoli questions. Where the pattern of the research programme which the notional skilled person would undertake can clearly be foreseen, it may be legitimate to take a step by step analysis. In Gedeon Richter Plc v Bayer Schering Pharma AG[2011] EWHC 583 (Pat) ; [2011] Bus LR D153, Floyd J. stated (at [114]): "I think that the guiding principle must be that one has to look at each putative step which the skilled person is required to take and decide whether it was obvious. Even then one has to step back and ask an overall question as to whether the step by step analysis, performed after the event, may not in fact prove to be unrealistic or driven by hindsight." The obvious danger of a step by step analysis is that the combination of steps by which the inventor arrived at his invention is ascertained by hindsight knowledge of a successful invention. Lord Diplock warned against this in Technograph Printed Circuits Ltd v Mills & Rockley (Electronics) Ltd [1972] R.P.C. 346, at p.362, a warning which judges have reiterated in later cases. I am not persuaded by Mr Speck's suggestion that Technograph is concerned only with a case in which a step by step approach was constructed by counsel on cross-examination in the absence of evidence of routine steps of research. The case contains a wider warning against the use of hindsight and has been interpreted as doing so. I agree with Birss J.'s analysis in Hospira UK Ltd v Genentech Inc[2014] EWHC 3857 (Pat) , at [240], where he stated: "The particular point made in Technograph was that it was wrong to find an invention was obvious if it was only arrived at after a series of steps which involve the cumulative application of hindsight. In some circumstances success at each step in a chain is a necessary predicate for the next one and it is only the hindsight knowledge of the invention as the target which could motivate a skilled person to take each step without knowledge about the next one. In a situation like that, Technograph is important." But the Technograph warning has no bearing in a case in which the steps which the notional skilled person would take can readily be ascertained without the taint of hindsight. [73] Ninthly, it is necessary to consider whether a feature of a claimed invention is an added benefit in a context in which the claimed innovation is obvious for another purpose. In Hallen & Co v Brabantia (UK) Ltd [1991] R.P.C. 195 the Court of Appeal was concerned with an alleged selection patent for a self-pulling corkscrew which had a helix coated with polytetrafluoroethylene (PTFE) which was a known friction-reducing material. At the priority date PTFE had been used for several years to coat the helix of a twin-lever type corkscrew to aid its penetration into the cork. The PTFE-coated helix had this effect also on the self-pulling corkscrew, a fact which was obvious at the priority date. The PTFE coat when applied to a self-pulling corkscrew also had a non-obvious benefit of making a striking improvement in the extraction of the cork. The trial judge, Aldous J., held that the patent was invalid on the ground of obviousness because it was obvious to select the features of the claim for the first purpose notwithstanding that it was not obvious for the other purpose: [1989] R.P.C. 307, at pp.326-327. The Court of Appeal agreed with the judge, holding (pp. 215-216) that it was self-evident that a PTFE coating would improve the penetration by any corkscrew and that the "golden bonus" or added benefit of the dramatic improvement in extraction of the cork would not found a valid patent as the claimed innovation was obvious for another purpose. Mr Waugh does not challenge this principle but submits that the 181 patent does not involve such an added benefit.’
‘Even if the step from the prior art is a small one, to prove obviousness it is necessary to demonstrate that there is some reason for taking it.’
‘… for the purpose of testing obviousness, one cannot assume that the skilled man simply makes technical trials for the sake of so doing.’
‘[76] In answering [questions arising on obviousness] it is also important to consider the secondary evidence. I shall go to the details of this in due course, but before I do so I should say something about secondary evidence generally. [77] It generally only comes into play when one is considering the question “if it was obvious, why was it not done before?” That question itself can have many answers showing it was nothing to do with the invention, for instance that the prior art said to make the invention obvious was only published shortly before the date of the patent, or that the practical implementation of the patent required other technical developments. But once all other reasons have been discounted and the problem is shown to have been long-standing and solved by the invention, secondary evidence can and often does, play an important role. If a useful development was, in hindsight, seemingly obvious for years and the apparently straightforward technical step from the prior art simply was not taken, then there is likely to have been an invention. [78] As usual Lord Reid had something perspicacious to say on the topic. In Technograph Printed Circuits Ltd v Mills & Rockley (Electronics) Ltd [1972] R.P.C. 346 he said at 353: “Being wise after the event counsel for the appellants pointed out that this was really an easy problem to solve … ” “The whole history of this matter shows the falsity of that analysis. Dozens of inventors, and no doubt others as well, had tried and failed to find a satisfactory solution.”’
‘… Stafford suggests that there may be a number of different possible substitutions for the arginine at 338, and states that the three preferred amino acids for substitution at this position are alanine, leucine and valine. The Skilled Structural Biochemist would understand that alanine had been chosen because it had been shown in the experiments discussed above to result in an increase in activity of the FIX protein. The Skilled Structural Biochemist would consider the suggestion that valine and leucine as preferred alternative substitutions made sense given that these amino acids are similar to alanine (i.e. they are all small amino acids with hydrophobic aliphatic side chains). Of the two, the skilled person would appreciate that leucine is more similar to alanine in its ability to form α-helices than valine.’
‘In my view, a strongly hydrophobic amino acid (such as valine or leucine) would not have been taken forward into in vivo studies by the Skilled Structural Biologist even if an increased clotting activity were observed in vitro. The Skilled Structural Biologist would still be concerned about having a hydrophobic amino acid at the 338 position, which as I have explained would be energetically disfavoured and lead to a risk of instability, misfolding, aggregation, and hence increased immunogenicity of FIX when it is in a natural environment (i.e. in animals and humans). These concerns would not have been put aside, even if elevated clotting activity had been demonstrated in a study from mutants expressed in (for example) HEK293 cells. As such, the Skilled Structural Biologist would be more likely to recommend taking forward into pre-clinical studies a gain-of-function mutant that is not strongly hydrophobic at this position.’
‘…there is no unifying thread in Stafford’s lists of amino acids and without any data that any of those amino acids (apart from alanine) show improved activity of FIX, the Skilled Structural Biologist would find these lists (both the list of 10 amino acids and the “sublist” of alanine, valine and leucine) to be meaningless.’
‘Stafford found unexpectedly that substituting the highly hydrophilic arginine with the hydrophobic alanine provided at position 338 increased clotting activity. It is entirely rational and logical then to suggest increasing the hydrophobicity still further (continuing down the same path) using side chains as similar to alanine as is possible. That led Stafford to leucine and valine.’
‘Yes, I mean in patents you tend to put a bag of shopping list down, and this is what I think was done by the patent attorneys.’
‘The side chains of alanine, valine, leucine and isoleucine tend to cluster together within proteins, stabilizing protein structure by means of hydrophobic interactions.’
‘It is hard to see how the notion that something is worth trying or might have some effect can be described as an invention in respect of which anyone would be entitled to a monopoly. It is therefore perhaps not surprising that the test for obviousness which Pumfrey J. devised for such an “invention” was whether it was obvious to try it without any expectation of success. This oxymoronic concept has, so far as I know, no precedent in the law of patents.’