uniQure succeeds in defending UK gene therapy patent

Krishna Kakkaiyadi of Pinsent Masons was commenting after the High Court ruled that a patent owned by uniQure biopharma B.V (uniQure) and exclusively licensed to CSL Behring for a gene therapy for haemophilia B – a blood clotting disorder – was valid, and that Pfizer infringed that patent.

It is thought to be one of the first gene therapy patent validity disputes to be ruled on by the UK courts.

Haemophilia B arises in people who have a defective gene encoding the FIX protein. Scientists have been trying for years to find ways to insert a functional FIX gene without it resulting in infection, complications or major side-effects.

The inventors of uniQure’s patent discovered a variant of the FIX gene in one of their patients that was more functionally active than that found normally. Analysis revealed that this mutant FIX gene, called the ‘Padua variant’, encoded for a different amino acid, leucine, at a single position of the resulting FIX protein. A modified form of this variant is claimed in the patent as a means of treating haemophilia B using gene therapy.

Pfizer argued that the patent was invalid. It did so on the basis that it believed the use of the modified FIX gene as claimed by uniQure for haemophilia B gene therapy was obvious. In support of that argument, it cited research disclosed in an earlier patent application called ‘Stafford’. Stafford disclosed several substitutions that could be made to the FIX gene, including the leucine substitution, but said nothing about whether and why these substitutions – particularly, the leucine substitution – were suitable for gene therapy.

As is typical in patent litigation cases, the thrust of Pfizer’s argument was that if the research disclosed in Stafford was considered by a hypothetical skilled team – in this case, a gene therapist and a structural biologist – along with common general knowledge concerning the problem that the skilled team was trying to solve, it would have been obvious to use the modified FIX gene with the leucine substitution  for haemophilia B gene therapy. Evidence in this regard is referred to as ‘primary evidence’.

However, the court did not accept Pfizer’s argument that the disclosures in Stafford would have led the skilled team down such a path. It considered the fact that the invention claimed in Stafford did not refer to the suitability for use as part of a gene therapy. Nor did Stafford provide any rationale for selecting and using the modified FIX gene with the leucine substitution.

The judge considered that the skilled team would have attached “no scientific significance” to the disclosure in Stafford of the option for using the leucine substitution and accepted uniQure’s evidence that the shortlist of substitutions, including leucine, that was cited in Stafford was “a scientifically meaningless bit of patent drafting”. Therefore, he determined, the skilled team would have no expectation of success in trying this option.

Crucially in this case, the judge went on to consider ‘secondary evidence’ pertaining to what research teams in the field were actually working on. The judge found it “compelling” that every research team that had sought to find a solution for the defective FIX gene since Stafford was disclosed had failed to try the leucine substitution.

Kakkaiyadi said: “The judge was strongly influenced by what is called ‘secondary’ evidence, i.e. what actually happened in the field, which is not often relied upon in patent cases.”

“In this case, the said variant for gene therapy was the product of a naturally-occurring variant that was discovered in a patient of the inventor’s team. The discovery of the Padua variant was so unexpected and surprising that until that event, the judge found that nobody would have actually considered the leucine substitution and expected it to work for gene therapy. In other patent cases concerning ATMPs, secondary evidence as to why actual teams were or were not working on particular options could become relevant to their inventiveness, especially in the early years as these products come on the market,” he said.

Kakkaiyadi said the ruling also provided a reminder to businesses involved in patent litigation as to the critical importance of expert evidence in such cases.

“Pfizer re-used one of its experts multiple times in different proceedings, and the judge in this case found the expert to be ‘toeing the party line’ rather than acting as an independent expert,” Kakkaiyadi said. “Such findings erode the credibility of a side’s expert evidence and must be borne in mind during expert selection and instruction, although it will be difficult to identify new scientific experts in this niche and highly specialist field.”

As other patent disputes emerge over ATMPs, businesses can expect more complex questions to arise in litigation over the sufficiency of disclosure made in the patent document and whether the information provided would allow the skilled team to conclude that the claimed therapies are indeed suitable for use as cell or gene therapies. According to Kakkaiyadi, companies behind ATMPs need to balance various factors in developing strategies to enforce their patent portfolios in the months and years ahead.

“Companies operating in the ATMP space are typically developing more expensive therapies for rarer and life-long conditions, such as haemophilia B in this case,” Kakkaiyadi said. “The population groups associated with these indications and the revenue streams are markedly different to therapies for other more common conditions, so parties may choose to be more robust in the enforcement of their ATMP patent portfolios than with their other portfolios, in order to recoup investments and protect market shares.”