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

Obviousness over the Poster

The Claimants’ case

The Claimants’ primary case of obviousness over the Poster before the judge, and the only case pursued on appeal, was set out in Prof Westwell’s first report at paragraphs 9.42-9.60. He started at 9.42 by stating:

“I have been asked to consider what would have been obvious to the skilled team in the light of Ouk at the Filing Date and in particular whether, without knowledge of the Patent, the inventions set out in certain claims of the Patent would have been obvious. I have in mind the importance of not contaminating my analysis with hindsight and that for the purpose of this exercise I should put out of my mind the knowledge I have from having read the Patent as part my involvement in this case, and the knowledge I acquired after the Filing Date in my own research relating to enzalutamide.”

He explained at 9.43 that he had been asked to follow the Pozzoli approach. At 9.46 he noted that the difference between claim 1 and the disclosure of the Poster “is that the compound of claim 1 (RD162’) has a dimethyl substituent at the bottom right position of the central ring whereas the RD162 compound of Ouk has a cyclobutyl substituent at that position”. He went on:

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

The skilled medicinal chemist presented with Ouk would recognise that RD162 is being presented as a compound with therapeutic potential to treat prostate cancer which shows in vitro activity, and also has acceptable pharmacokinetic properties.

From the disclosure in Ouk the skilled medicinal chemist would expect certain variants of RD162 to have the same or similar activity and therefore also have therapeutic potential. In particular, the skilled medicinal chemist knows from the teaching in Ouk that the cyclobutyl at the bottom right position can be substituted with a dimethyl or a cyclopentyl (as shown in RD7 and RD54) without having a significant impact on in vitro activity.

Ouk shows that the most significant development in achieving in vivo serum stability (at a comparable level to SOC bicalutamide) is the installation of a 3-fluoro substituent in the aryl ring joined to the central thiohydantoin, which the skilled medicinal chemist would understand to be a common method to prevent liver-based cytochrome P450 metabolism for orally administered drugs, as discussed. Therefore, although predicting the site of metabolic oxidation is often difficult based on chemical structures alone, the skilled medicinal chemist would understand that the aryl ring joined to the central thiohydantoin was the likely site of metabolic oxidation because RD162 (which includes the 3-fluoro substituent in the aryl ring) is shown to be stable. There is no reason to consider that a change from the cyclobutyl group to either a dimethyl or cyclopentyl would affect metabolic stability. This is because these are small changes which retain the same hydrocarbon functionality and are made at a site that is remote from the metabolic site. Additionally, the routine incorporation or removal of a single CH₂ group to this hydrophobic part of the molecule (going from dimethyl to cyclobutyl or vice versa) would not significantly affect properties such as logP, and consequently would not change properties such as solubility or in vivo biodistribution, in any significant way.

It would therefore be immediately obvious to the skilled team that the following two compounds would be likely to have therapeutic potential that was similar to that of RD162.

”

Prof Westwell added:

I have been asked to consider whether changes to other parts of RD162 would also result in molecules which would be expected to have similar therapeutic potential. Other changes could be investigated but the activity of such molecules prior to testing would be more uncertain and therefore their therapeutic potential as compared to RD162 would not be as immediately obvious, in particular because of the potential for disadvantageous PK-DM properties compared to RD162.

For example, based on the information in Ouk, the skilled medicinal chemist would not be confident that changes could be made to the left-hand side of RD162 (shown below) because that part of the structure has been kept fixed all the way from RU59063. It would therefore be uncertain, based on Ouk, as to whether changes to that part of the molecule are consistent with activity.

The skilled medicinal chemist would also understand that making modifications to the top right ring (shown below) could result in different properties. For example, it has been shown in Ouk that the addition of a N-methylbutamide group at the 4-position with a longer chain (as shown in RD131) does not have desirable PK properties (specifically in relation to its short half-life and resulting inability to achieve a useful steady state concentration). Furthermore, the methyl group in the same position on RD37 results in a compound with a higher LogP and potential issues with drug solubility and steady state concentration.

As I have said above the skilled medicinal chemist will understand that the inclusion of the fluorine atom was likely to improve metabolic stability. The skilled medicinal chemist would therefore retain a fluorine at this position. There is the possibility of moving from the fluorine atom from the 3-position to the 2-position (which is equivalent to the 5-position) but the effect of this would be uncertain. Whilst fluorine atoms are commonly used to resolve issues of metabolic stability, their effect is unpredictable and moving the position of the fluorine atom may have a negative impact.

”

The judge’s assessment

The judge quoted paragraphs 9.49-9.51 and 9.53 of Prof Westwell’s first report in [233] and [235] and summarised 9.54-9.56 in [236].

At [237] the judge set out three reasons advanced by Astellas as supporting a finding that RD162' was inventive. Each was based on the evidence of Prof Ward. The judge rejected each of these reasons at [238]-[276].

At [278] the judge said:

“As far as I could detect, no challenge was made to the technical reasoning which Prof Westwell put forward in support of obviousness over the Poster. Instead, Astellas accused Prof Westwell of approaching the Pozzoli analysis incorrectly. They drew attention to 9.46-9.47 (and 10.28-10.29, which I consider later) of his first report and an answer he gave in cross-examination.”

At [280]-[304] the judge considered the Claimants’ secondary case that it would be routine to conduct an SAR study starting from RD162 and that would lead the medicinal chemist to RD162'. Although this case is no longer pursued, it is necessary to note some statements made by the judge in this context.

At [285] the judge cited a passage from the cross-examination of Prof Westwell concerning the Slides. Since this is quite a long passage I will not set it all out, but I should quote the last few questions and answers:

“Q. I think you said you did not because you were asked to assess obviousness in terms of -- I am assuming what you were going to say is in terms of the difference and assessing the difference between a gem-dimethyl and a cyclobutyl?

A. Mmm-hmm.

Q. And with that change in mind, you were then saying well, is that going to have an effect or not or make any obvious changes? That is what you were doing really, is it not?

A. Yes, assessing the obviousness of that change in light of the material presented in the public conference, yes.

Q. That is right. So when you say the obviousness of that change, what you were thinking was ‘If I am asked about the change between cyclobutyl and gem-dimethyl, do I think that change is an obvious one to make in light of what I have here?’

Yes.”

The judge went on:

Later, when asked about his evidence as to what was obvious over the Poster, Prof Westwell confirmed that he had approached that issue in the same way as he had on the Slides and came to the same conclusion.

Three important points emerge from that passage:

First, that when challenged, Prof Westwell did not say that his reasoning was part of a SAR.

Second, that Prof Westwell regarded the obvious steps he had talked about in his reports as distinct from a SAR.

Third, that he was asked to assess obviousness in terms of the difference between a gem-dimethyl and a cyclobutyl. However, I keep in mind that when Prof Westwell said this, he might well have been referring to Pozzoli step 3 (identify the differences). As I have already mentioned, he set out the Pozzoli approach in [9.42] of his first report and there are clear signs in his written evidence that he was endeavouring to follow that approach.

Astellas submitted a fourth important point also emerged from the final question and answer: that in that answer Prof Westwell effectively admitted that he had the target (i.e. RD162’ i.e. with the dimethyl group) in mind when concluding the step from RD162 was obvious. However, I do not consider that was clearly established. There is a subtle difference between having the target clearly in mind and considering whether it was obvious to make a change at position X from the cyclobutyl group to a dimethyl group. The basis of Prof Westwell’s penultimate answer was ‘in light of the material presented in the public conference’ (which would not have included RD162’). That was echoed in the final question.”

The judge explained at [289]-[291] that Astellas had nevertheless submitted that it was clear from his written reports that Prof Westwell’s analysis was infected with hindsight. At the start of a drug discovery project the medicinal chemist and the cancer biologist would agree a TPP. In cross-examination, Prof Westwell agreed that what the medicinal chemist would do would be conditioned on the TPP to be discussed with the cancer biologist. The SAR would progress to identify a front runner molecule, whereupon modifications are likely to become more focussed on improving that front runner. Despite this, when it came to the question of obviousness, there had been no mention of a TPP either by Prof Hickson or Prof Westwell. Furthermore, in his written evidence Prof Westwell had not expressly mentioned conducting a SAR exercise.

The judge went on:

So, the problem with Prof Westwell’s evidence on obviousness is the absence of a proper description of the context in which his Skilled Team formed the view that it was ‘immediately obvious’ (from the Poster) that the two RD162 analogues he depicted at [9.51] would be likely to have therapeutic potential that was similar to that of RD162.

It could be said that the Professor was presented with an unusual situation, in that the Poster presented a molecule RD162 with all the attributes of a lead molecule, so there was no need for a TPP or a SAR to be conducted. Yet Prof Westwell never said as much. Equally, Prof Westwell did not say that the Skilled Team would embark on an exercise of seeking to characterise RD162 by making analogues …. He did explain why the Skilled Medicinal Chemist would have been either reluctant or uncertain about making modifications to the other parts of the molecule, apparently leaving only position X to be considered.

Furthermore, the absence of a SAR or other context could be said to be emphasised by the fact that in [9.53]-[9.56] he considered whether changes to other parts of RD162 would result in molecules expected to have similar therapeutic potential, but apparently only because he was asked to do so i.e. that consideration did not arise because of a particular scenario or context that his Skilled Team was considering.

At this point it is necessary to consider the sequence in which Prof Westwell was introduced to the various documents in the case. It is clear that the sequence was: consideration of the CGK of the Skilled Medicinal Chemist; what the Skilled Medicinal Chemist would understand from the Slides; then he was shown the Patent and asked to explain what the Skilled Medicinal Chemist would understand from its contents. He explained that many months later he was provided with a copy of the Poster and was asked to describe what the Skilled Medicinal Chemist would understand from its contents, having been told to put out of his mind what he had previously discussed with the solicitors.

…

Despite the sequence, it is curious that Prof Westwell’s report was structured so that he presented his views on obviousness over the Poster first (with the ‘immediately obvious’ wording). When it came to obviousness over the Slides, he did not use that expression and his reasoning was tied much more closely to material in the Slides, as I discuss below.”

At [305]-[319] the judge considered a third case which the Claimants had advanced in cross-examination of Prof Ward, namely that it would be obvious to carry out an SAR study starting from RD7 and that would lead the medicinal chemist to RD162'. Counsel for the Claimants showed us that this case was disavowed in closing submissions. Nevertheless, it is again necessary to note some statements made by the judge in this context.

The judge said at [306] that the problem with this line of argument was that there was no reason to want to progress RD7. As the judge explained at [308], the compound in the Poster with the best activity in the SAR studies was RD37, which was then optimised to RD162:

“… But the potential for further optimisation on the right-hand side of the molecule is clear in order further to improve PK and drug like properties.  Why go back to a discarded compound with ostensibly less activity?”

Having considered the evidence of the experts about the data in the Poster, the judge said at [311]:

“Overall, the experts agreed that whilst RD37 looks slightly ahead in the tumour volume study, it is difficult to draw conclusions, but RD37 and RD131 are both better than RD7 in the HR prostate cancer PSA level assay - something that the biologists agreed would be of real interest.”

After noting that the Poster did not permit statistical conclusions to be drawn, the judge went on:

Although no statistical analysis has been done, as Astellas submitted, the clear take home message of the Poster is that RD37 had better activity than RD7 which was why it was RD37 that went through to in vivo PK testing and it was why it is the scaffold structure of RD37 which was then shown being changed with the different right-hand side substituents.

Notwithstanding the above, the case was put to Prof Ward on an assumption that a Skilled Medicinal Chemist reading the Poster would think all of the compounds after RD6 were essentially the same or the same. The assumption was something of a moving feast: …

I agree that all of this was untethered to reality. A Skilled Team reading the Poster as a whole would understand that the message being conveyed is that the most active compounds were RD37 and RD131 and work had then been done to improve their ‘drug like’ properties leading to RD162.”

At [321]-[332] the judge considered three points of secondary evidence relied upon by one side or the other, none of which he considered persuasive.

At [333]-[345] the judge set out his conclusion. The core of his reasoning was in the following passage:

This case involves a somewhat unusual situation, in that what was published, in the Poster was a molecule RD162 which showed good efficacy and good PK-DM properties. It was clear that the Skilled Team would regard RD162 as a good candidate to take forward into further testing. The motivation to consider other molecules came from competitive and patenting considerations, in the sense that it would be prudent for the Skilled Team to view RD162 as ‘belonging’ to the authors, it being a reasonable assumption on the part of the Skilled Team that the authors/their employers would have already applied for patent protection, and therefore the Skilled Team needed to develop their own molecule, novel and different from RD162.

This case raises, in an acute form, the issue as to the extent to which competitive and patenting considerations should influence an obviousness analysis. As usual, the answer is provided by consideration of what real-life teams would do. Although some expert witnesses do have experience of patenting considerations, many do not, so the Court can be left to rely on its own experience.

I can start with the case as originally presented in Prof Westwell’s first report. There are a number of problems with this case, including the following:

Prof Westwell does not explain the scenario in which the Skilled Team decides to take the step which he says is obvious. In particular he does not explain why the Skilled Team starts by considering position X, nor why the Skilled Team starts to consider changing the cyclobutyl group at that position.

His answers in cross-examination indicate that he was not considering the situation where the Skilled Team had decided to do a SAR or characterise RD162 in order to find out information which would help to decide how to proceed. Instead, his answers indicated he was asked to consider the change from cyclobutyl to dimethyl and asked whether that change would have a material effect. Even if I assume in his favour that he was referring to Pozzoli step 3, the invitation put to him was leading.

In this regard, there is no separate body of law which is applicable if the change required to get from the prior art to the claim is said to be ‘immaterial’ or ‘trivial’. In every case, there is only one question and it is the statutory question of ‘is it obvious?’. Whether a change is properly characterised as ‘immaterial’ or ‘trivial’ is highly fact dependent and there is a real danger (as has been pointed out in some of the authorities) that the question of immateriality is substituted for that of obviousness, even though a conclusion that a change is immaterial or trivial will usually be determinative of the question of obviousness. In general terms, I agree with Astellas’ submission that these issues of ‘immateriality’ or ‘triviality’ are not well suited to the field of medicinal chemistry, but it all depends on the context.

The quest for a novel compound would have taken the Skilled Medicinal Chemist away from close analogues to RD162. The focus on close analogues was driven by the hindsight knowledge that the Patent in fact claims RD162’. Without that knowledge, on this primary case the Skilled Medicinal Chemist would not have been motivated to investigate close analogues of RD162. I have to consider this point further in the alternative ‘obvious to do a SAR’ case.

Overall, I am driven to the conclusion that Prof Westwell’s evidence that the change from cyclobutyl to dimethyl was ‘immediately obvious’ was tainted with hindsight.”