Case Nos: CA-2024-002655/002675/002676 - [2025] EWCA Civ 936

Obviousness over the Slides

The Claimants’ case

The essential difference between the Slides and the Poster, for present purposes, is that in the Slides there is no side-by-side testing of compounds containing geminal dimethyl groups on the one hand and a cyclobutyl group on the other hand. Instead, information is provided to the skilled team by the pharmacophore.

Again, the Claimants rely upon the evidence of Prof Westwell in his first report:

For the following reasons, I do not believe that it would require any degree of invention for the skilled medicinal chemist who had read the Slides to make a modification to RD162 so as to make a compound where the cyclobutyl substituent was replaced by a dimethyl substituent.

As I have stated, the skilled medicinal chemist would recognise RD162 to be the most promising compound disclosed in the Slides. It is the only compound identified as having antagonistic activity in vitro combined with useful pharmacokinetic properties (Slide 16). The skilled team would, according to the pharmacophore, expect certain variants to have the same or similar activity and therapeutic potential.

In terms of understanding the different parts of the molecule and their importance with respect to the performance, the skilled medicinal chemist would consult the pharmacophore from Slide 8. This explains that the left-hand side of the structure is responsible for binding affinity to AR and therefore the skilled medicinal chemist would expect that modifications here would have the potential to have a significant impact on activity.”

It also confirms that the rigid structure on the right-hand side of the molecule is required for antagonistic activity. Although certain changes to this part of the molecule are consistent with antagonistic activity in vitro (compare RD37, RD131 and RD162) it is only the inclusion of the methylamide substitution on the phenyl ring in combination with the fluorine substitution which gives rise to acceptable pharmacokinetic properties. The skilled medicinal chemist would not know whether such properties could be retained if that part of the molecule is altered.

According to the pharmacophore in Slide 8 the cyclobutyl group in RD162 is designated R1/R2. The skilled medicinal chemist is informed that this part of the molecule is involved in hydrophobic interactions. The skilled medicinal chemist would want to keep R1 and R2 the same in order to avoid introducing an unwarranted chiral centre, which I have explained in the CGK section. It would be obvious that each of R1 and R2 could be methyl as these would be expected to behave similarly to the cyclobutyl group in RD162 being only slightly smaller. They are also present in RU59063. The expectation would be that substituting two methyl groups for the cyclobutyl would not materially impact pharmacokinetic properties because they are both simple hydrocarbon groups. It follows that if RD162 is seen (as it would be) as having therapeutic potential it would be obvious to the skilled team on the basis of the data disclosed that a molecule in which the cyclobutyl group has been replaced with dimethyl will be likely to have similar therapeutic potential. This would be obvious on the data disclosed in the Slides.”

The judge’s assessment

Having noted at [370] that in 10.29 Prof Westwell had used the same wording, mutatis mutandis, as in 9.47, the judge quoted 10.30-10.33 at [371]. At [372] the judge commented that Prof Westwell’s reasoning was “closely tied to material in the Slides”. At [374] the judge noted that “the technical reasons [Prof Westwell] gave were not challenged”. At [375] the judge recorded that Astellas’ challenge was that Prof Westwell’s evidence was driven by hindsight. At [377] the judge set out four arguments advanced by Astellas as to why it would not have been obvious for the skilled team, having read the Slides, to investigate dimethyl at position X.

The judge expressed his conclusion as follows:

The obviousness arguments in this case were finely balanced, the more so in relation to the Slides. I have changed my mind on obviousness over the Slides more than once because Prof Westwell’s technical reasons were cogent and because his approach (which I infer was formulated before he saw the Poster) was less clearly redolent of hindsight.

The problem, once again, was that he did not explain the context in which his Skilled Team would make the considerations set out in his technical reasoning.

In their cross-examination of Prof Ward, the Claimants strove to provide a context - the SAR starting from RD162 - in which they suggested the Skilled Team would have made and tested RD162’, as a byproduct of their characterisation of RD162. However, my findings in relation to the ‘obvious to do a SAR’ in the context of the Poster apply equally here.

… there was a degree of exaggeration in the second, third and fourth points made by Astellas. After that exaggeration is stripped out, there remained some force in the underlying points. With those points in mind, the Skilled Team would be likely to regard a suggested change from cyclobutyl to dimethyl as something of a backward step. The advantage of the characterisation argument was that it provided a reason to ignore the fact that that step might be a backward one.

In view of my reservations about certain parts of the evidence of Prof Ward, the characterisation argument came very close to succeeding but I have to bear in mind the following points:

First, that if the steps required to get from the prior art to the claim are obvious, it ought to be possible to explain that case clearly and in evidence in chief.

Second, in the litigation process there is an intense focus and much analysis of the route(s) to obviousness and the obstacles in the way.

Third, that it is hardly surprising that, with a skilful cross-examination driven by an intense focus on the target, an argument for obviousness may appear to have force.

Naturally, I am not saying that an obviousness argument cannot be proved through cross-examination of the patentee’s expert witness. However, in the circumstances of this case, I am unable to conclude that I received sufficient primary evidence to establish the allegation of obviousness over the Slides.”