Pfizer Inc. v UniQure Biopharma B.V. [2024] EWHC 2672 (Pat)
UniQure has successfully defended the validity of its haemophilia gene therapy patent in a revocation action brought by Pfizer. The decision was handed down on 25 October 2024. His Honour Judge Hacon rejected Pfizer’s argument that the UniQure patent was obvious over the single cited piece of prior art, Stafford. Pfizer admitted infringement if the patent was held valid. This is one of the first patent litigation cases before UK courts directed to gene therapy.
Background
Haemophilia is a blood clotting disorder caused by a defective gene that fails to produce sufficient amounts of Factor IX (‘FIX’), one of the proteins of the coagulation cascade in humans. The dispute concerned a particular type of haemophilia, referred to as haemophilia B. By the time of the patent, some gene therapy had been attempted in clinical trials, but without any success: introducing the normal wild-type FIX gene in patients using a viral vector resulted in infections, serious immune reactions and other side effects, hampering the efficacy and longevity of any effect seen.
UniQure’s patent, EP (UK) 3 581 650, relates to a ‘gain-of-function’ mutant of the FIX gene that generates the corresponding FIX protein with an 8-9 fold increase in functional activity compared to wild-type FIX. This is disclosed in the patent to be the product of a naturally occurring mutant gene called the ‘Padua variant’. Claim 1 of the patent is drafted as an EPC 2000 medical use claim to a nucleic acid encoding a necessary minimum amino acid sequence of the mutant FIX for use in a gene therapy treatment of haemophilia B. The key modification in the mutant amino acid sequence is at position 338, where the arginine in the wild-type FIX is replaced by leucine (denoted in standard notation referring to amino acids as R338L-FIX, where R refers to ‘arginine’ and ‘L’ refers to leucine).
Pfizer’s obviousness challenge
The Judge characterised the ‘inventive concept’ of the patent to be the provision of a mutant DNA sequence that is suitable for use in a gene therapy treatment of haemophilia B. Although there was some argument from UniQure initially at trial that ‘suitability’ for gene therapy required the treatment to be effective for at least five years (presumably to overcome prior art disclosure), this time limitation was dropped in closing arguments to avoid the argument of insufficiency raised by Pfizer.
The cited prior art, Stafford, a PCT patent application, discloses non-naturally occurring FIX polypeptide mutants with various substitutions instead of the arginine at position 338, including a select group of substitutions of which leucine was one. However, no rationale for these select substitutions is provided in the document. Neither does the document propose such mutations for gene therapy. Experiments disclosed in Stafford focussed on a mutant wherein the arginine at position 338 was substituted with alanine (R338A-FIX), rather than leucine, and indeed, all the literature in the prior art referring to ‘gain-of-function’ mutants dealt with this R338A-FIX mutant rather than the patent’s R338L-FIX mutant.
Pfizer argued that making the substitution from arginine to leucine for the purposes of gene therapy would be obvious to the skilled team (consisting of a gene therapist and a structural biologist) due to the express inclusion of leucine as a potential substituent in Stafford and, inter alia, given the similarities between leucine and alanine and given the simplicity in generating and testing such a mutant. UniQure strongly resisted this argument by contending that, at the outset, the skilled team would have no motive to go down the path of the invention and, moreover, would, fail to recognise the significance of the leucine substitution disclosed in Stafford for gene therapy. In this case, since the leucine substitution was expressly disclosed in Stafford it was critical to determine whether the skilled team would contemplate the invention, having reviewed Stafford.
The Judge began his assessment by considering Lord Hodge’s non-exhaustive list of factors in Actavis Group v ICOS Group [2019] UKSC 15, particularly around the requirement of a reasonable expectation of success before an alleged invention is considered obvious. The Judge was influenced by findings of CGK that the amino acid sequence between 330-338 was highly evolutionarily conserved across species and therefore that any substitution in this region would likely cause problems with the function of the resulting protein. Accordingly, the R338A-FIX mutant in the art would be regarded by the skilled team as an “extraordinary one-off”. The skilled team would therefore have brought considerable care and caution to its review of Stafford, which proposed various substitutions at position 338 but provided no rationale for shortlisting specific substitutions. This led the Judge to finding that the skilled team would have attached “no scientific significance” to the disclosure of the leucine substitution at position 338. The Judge also accepted UniQure’s evidence that the shortlist of substitutions including leucine in Stafford was “a scientifically meaningless bit of patent drafting”.
The secondary evidence on obviousness demonstrated the failure of every team actually working in the field to try R338L-FIX over a significant period of time since the publication of Stafford and other prior art, which the Judge found to be “compelling”. In his view, the significance of the R338L-FIX variant became apparent to the gene therapy world only with the discovery of the Padua variant by the inventor’s team. The Judge found that the inventor’s work was, in fact, unexpected or surprising, and this also contributed towards the finding of inventive step (cf. Lord Hodge’s seventh factor). Ultimately, this perhaps strongly influenced the Judge in going as far as saying that in this case the skilled team would have had a “reasonable expectation of no success”, which then made it “self-evident” to the Judge that the skilled team would also have had no motive to try using the R338L-FIX mutant for gene therapy (see paragraphs 165 and 230).
Criticism of Pfizer’s experts
The evidence of Pfizer’s experts was subject to some criticism in the decision. Pfizer’s gene therapist, Dr Lili Wang, had previously acted as an expert witness for Pfizer in four proceedings before the USPTO and also in Opposition Proceedings before the EPO, and in proceedings in the Netherlands. The Judge found some of her responses during cross-examination to be unsatisfactory. Overall, the Judge felt that she was attempting “to toe the party line” and had “quite possibly been guided by lawyers as to what she should say”. Pfizer’s structural biologist was also found to have made speculative statements, especially in his written evidence.
The entire judgment can be read here.
