Dr David Eyre

December 2024

Haemophilia B  

A blot clot is produced following a cascade of reactions after injury. Haemophilia is a disorder of blood clotting whereby one of the factors that contributes to this cascade of reactions is defective. Consequently, for sufferers from this condition (“haemophilics”) blood clots do not form normally or as effectively. There are various forms of haemophilia and the vast majority are due to an inherited genetic mutation. UniQure’s patent concerns the gene for Factor IX, and a defective Factor IX gene causes the condition called “Haemophilia B.” 

As the cause of Haemophilia B has long been known to be a “single-gene” disorder it has long been considered a potential target for gene therapy. However, prior to the publication of uniQure’s patent, attempts of gene therapy had been unsuccessful. Use of a viral vector to introduce and replace the defective gene with a functional “wild-type” Factor IX gene yielded infections and serious immune reactions, amongst other side effects. Necessarily, the efficacy and longevity of the therapeutic effect was adversely affected. 

UniQure’s Gene Therapy 

UniQure’s treatment is, in contrast, based on a “gain-of-function” mutant of the Factor IX gene. This gene is colloquially known as the “Padua variant” and in vivo it yields an 8–9 fold increase in functional activity of Factor IX compared with the wild-type Factor IX gene. 

This invention was disclosed in uniQure’s patent EP(UK)3581650. Claim 1 of the patent defines a modified Factor IX polypeptide for use in gene therapy of Haemophilia B. The essential feature of the polypeptide defined in claim 1 of the patent is at position 338 of Factor IX, where the arginine of the wild-type protein is replaced by leucine. 

“Stafford” 

Pfizer relied on a single document “Stafford” as prejudicing the inventive step of uniQure’s patent. is a PCT application published as WO1999/003496 that discloses Factor IX polypeptide mutants including substitutions for the wild-type arginine at position 338. Indeed, there is a select group of substitutions defined and the leucine substitution at position 338 was one of these (see Stafford, claim 5).  

However, no reasoning or rationale for choosing these particular substitutions is given in Stafford. Rather, Stafford is concerned with the arginine-to-alanine substitution (“R338A”) rather than the arginine-to-leucine (“R338L”) mutation that uniQure was focussed on. Thus whilst Stafford makes a generic reference to using the polypeptides it describes in gene therapy; its focus was on a different polypeptide than the R338L mutant that uniQure was concerned with. 

The judge in this case (Judge Hacon) characterized the inventive concept of uniQure’s patent to be the provision of a mutant DNA sequence that is suitable for use in a gene therapy treatment of Haemophilia B. 

Pfizer averred that the arginine-to-leucine substitution of the Padua variant would have been obvious to the skilled person because of the disclosures of “Stafford.” They also argued that the chemical and physical similarities between leucine and alanine would have been germane, not least of which because of the simplicity in generating and testing these two mutants. 

In contrast, uniQure argued that a person skilled in the art (or a team skilled in the art in this case) would not have been motivated by Stafford to deviate from Stafford’s central teaching to produce the R338L, arginine-to-leucine substitution and there would have been no reason that the skilled person reading Stafford would recognise the particular significance or effectiveness of the R338L mutant in gene therapy. 

Unusually for an analysis of inventive step, in this case the judge found the secondary indicia of non-obviousness to be “compelling,” and so considered these first in his judgement. Judge Hacon’s view was that the significance of the R338L mutant only became clear with the use of the Padua variant by uniQure. The judge found that the use of this variant and its effect was unexpected or surprising and thus contributed to the finding of an inventive step. Indeed, the judge said that the skilled team would have had a “reasonable expectation of no success.” This would have yielded no motivation to try the R338L mutation in gene therapy. 

In this vein, the judge noted that in the common general knowledge it was found that the amino acid sequence between residues 330 and 338 were highly evolutionarily conserved between species. Accordingly, it would have been expected that any mutation in this, apparently important, region would have been deleterious. Accordingly, a gain of function mutation in such an evolutionarily-conserved region would have been considered an “extraordinary one-off” by a team skilled in the art and one “which did not change their aversion to making changes in that region of the [Factor IX] gene.”  

Thus it appears that the skilled person would have seen that the focus of Stafford was on a particular mutation (R338A) and would therefore have been sceptical of the disclosures of Stafford that related to other mutations and were not supported by experimental evidence. Accordingly, uniQure argued successfully that the short list of substitutions in Stafford was actually “a scientifically meaningless bit of patent drafting” rather than a menu of options any one of which the skilled person might have pursued with the expectation of success. 

Conclusion 

Thus uniQure’s patent was found to be valid and infringed. The judgement is particularly notable because of the central role played by secondary indicia in reaching this decision. This case also contributes particularly to the nascent but growing body of case law relating to gene therapy and the motivation for selecting the most central feature of gene therapies – i.e. the therapeutically effective mutant gene itself.