"The question of obviousness must be considered on the facts of each case. The court must consider the weight to be attached to any particular factor in the light of all the relevant circumstances. These may include such matters as the motive to find a solution to the problem the patent addresses, the number and extent of the possible avenues of research, the effort involved in pursuing them and the expectation of success."
“[I]f a particular route is an obvious one to take or try, it is not rendered any less obvious from a technical point of view merely because there are a number, and perhaps a large number, of other obvious routes as well.”
"There was no evidence that as at 1984 there was an identified problem to solve with the '355 (or the '920). In particular it was not shown that there was an identified problem with the '355 that it had too low a proportion of respirable particles. The only contemporary evidence is the Warentest published in Germany only which showed that the '355 device had a higher RAO than the Heyer device which was the nearest competitor. More generally, although there may have been some increase in competition in the market in the 1980s, the plaintiffs' nebulizers were better than the competition. Professor Balachandran accepted that what the skilled man would do by way of attempting to improve '355 would depend on what the commercial brief was."
“It makes no sense to say that a formulator would press on and develop a 12-hour release formulation without any apparent clinical point. Motive remains relevant on any view.”
“Standing back from the step by step analysis, it is clear that the skilled team was engaged in the familiar and routine testing of a drug to establish the appropriate dosage regime for tadalafil in order to implement the teaching of the Daugan patent. The target was never in doubt. It was obvious to embark on that exercise and carry out tests in a routine way until that appropriate dose was ascertained.”
‘9.49 From the disclosure in [the Poster] 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 [the Poster] 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. 9.50 [The Poster] 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 CH 2 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. 9.51 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.’ [Emphasis added. Underneath this paragraph, Prof Westwell showed RD162, and two RD162 analogues – one where the cyclobutyl was replaced with dimethyl and the second where it was replaced with a cyclopentyl group].
‘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.’
‘my job is interpreting assay data with the help of the biologist’
“The Skilled Chemist would find it remarkable that it is possible to preserve the desired biological activity against the target, whilst modulating the PK and other properties, by making varied changes to the RHS substitution of the compound. That gives the Skilled Chemist a portion of the compound (the RHS substitutions) that they can vary and seek to modify, while retaining a degree of confidence that the desired biological activity will be preserved.”
‘The Poster could not be clearer that it is describing a body of work that went from inception to lead compound in that research programme. To emphasise the clear direction of travel, the Poster is adorned with two large swooshing arrows – a feature which Astellas contended indicated a clear no turning back approach.’
‘A. I guess it is a little bit challenging to know how rational and driven the process was as we only have a very snapshot of molecules presented. – XX Ward T4/38610-12.’
‘There is an active selection of the cyclobutyl; that seems to me very clear’
‘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 Poster] to make a modification to RD162 so as to make a compound where the cyclobutyl substituent was replaced by a dimethyl substituent.’ iii) His reasons were set out in [9.48]-[9.56] and I have summarised or set out those paragraphs above. ‘Obvious to do a SAR’
‘I think in the common general knowledge, or our respective reports, we both noticed that there seems to be a tolerance to a variety of substituents on the right-hand ring, that that is possibly more unusual.’
‘Q. …. I was 5 putting to you that, in both your first report and your reply 6 report, when you came to look at what is obvious to do in 7 light of the slides, and you have a heading "Obvious steps to 8 take in light of the slides", you did not talk about doing a 9 SAR, you did not set out what the goal might be, you did not 10 set out what might be tested, the order of testing, why one 11 might change just the gem-dimethyl and cyclobutyl at 12 position [X]. You did not discuss what else might be done. You 13 did nothing. What you said was "Well, it is an obvious 14 change". I am putting to you that is all you thought about at 15 the time, you did not think of doing any SAR, large, small, 16 medium or otherwise? 17 A. Yes, but a medicinal chemist would do SAR. Whether it is 18 large or small, that is what they would do. They would be 19 interested in further exploration around the substituent 20 groups which would include the hydrophobic region as well as 21 the aryl. That is the nature of medicinal chemistry. 22 Q. As we discussed, one way that they would do that is either 23 because they are taking forward RD162 and they hit problems, 24 or they may have a target, given to them by the biologist, or 25 they may have another set of targets that they wish to do, a Page 159: 2 bit like you did, in their research. Of course, you have not 3 discussed any of those in your evidence, have you? 4 A. No, because I was asked to assess obviousness in terms of -- 5 you could certainly do exploratory SAR and make more wholesale 6 changes but in terms of this hydrophobic region, it is 7 reasonable, on PK grounds, any premises like LogP, that these 8 changes in the hydrophobic region having or taking away a 9 single carbon atom would not materially affect those 10 properties. So, yes, I did not discuss SAR building on 162 in 11 the expert reports because that could be done but that might 12 involve more substantial changes to the substituents. 13 Q. I think you said you did not because you were asked to assess 14 obviousness in terms of -- I am assuming what you were going 15 to say is in terms of the difference and assessing the 16 difference between a gem-dimethyl and a cyclobutyl? 17 A. Mmm-hmm. 18 Q. And with that change in mind, you were then saying well, is 19 that going to have an effect or not or make any obvious 20 changes? That is what you were doing really, is it not? 21 A. Yes, assessing the obviousness of that change in light of the 22 material presented in the public conference, yes. 23 Q. That is right. So when you say the obviousness of that 24 change, what you were thinking was "If I am asked about the 25 change between cyclobutyl and gem-dimethyl, do I think that Page 160: 2 change is an obvious one to make in light of what I have 3 here?" 4 A. Yes.’
‘they may just have had plenty of cyclobutyl in the fridge’
‘A. My concern would still be that either there has been a series of close analogues that have been made and discarded, and I would want to try and understand why those had been discarded. I would still be concerned about, notwithstanding the patent or (unclear), from a novelty perspective. I would be aware that the patents potentially have not appeared yet so we do not know what molecules, what compounds, have already been claimed. So, all of those things would encourage me to be further away structurally.’
“PS. let’s hope RD162′ is as active as RD162!”
‘Cell-based screens can be used to identify anti-androgens with greater potency than bicalumatide [sic] while avoiding the undesirable agonism side-effect SAR has defined a thiohydantoin imine derivative of the high affinity ligand RU59063 as an attractive lead Greater potency can be achieved in the absence of greater binding affinity, presumably through inducing altered AR conformation Further in vivo studies are in progress to define an optimal clinical candidate’
‘10.30 ….. The skilled team would, according to the pharmacophore, expect certain variants to have the same or similar activity and therapeutic potential. 10.31 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 molecule 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. 10.32 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. 10.33 According to the pharmacophore in Slide 8, the cyclobutyl 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 unwanted 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 simply 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 has been replaced with dimethyl will be likely to have similar therapeutic potential. This would be obvious on the data disclosed in the Slides.’
‘high potency at this stage would be indicative of an interesting compound’. 416. Prof Clarke’s evidence on what a Skilled Cancer Biologist would take from Fig. 21 was: Q. Nowhere do the inventors say that 162' may be or is superior to 162. It is not a conclusion that the inventors have drawn, is it? A. But it is evident from graphs 21A and B to me that there is a signal that it is better. Clearly that would need further testing. What a skilled biologist, particularly somebody dealing with prostate cancer all the time, would be looking for is the best agent which produces the best anti-cancer effect in this setting. 417. To the same effect, somewhat later he said: I think one has to look at the 13 data as presented in this section of the patent and try to 14 work out which one looks to be the better agent, and which 15 might be the agent which one would take forward for further 16 testing. 17 Q. So you are saying that the result at 21B trumps the result at 18 21A; is that your approach? 19 A. No, it is not my approach. I think that there is evidence of 20 greater effect at the 500 nM dose in 21A, and there is 21 evidence of greater effect at the 1,000 nM dose in 21B. So, 22 in both of the separate sets of experiments, 162' has shown 23 superiority in areas. So, if one was to ask me, if you are 24 going to pick the winner amongst this lot, what would it be, 25 I would say, well, you are going to have to go with 162', 2 accepting fully that you would have to test for its 3 other properties” (emphasis added). 418. In the light of the evidence, the criticisms levelled by the Claimants at Prof Clarke were either unfounded (re his experience and expertise) and/or they lost any real significance (re error bars). VALIDITY - SUFFICIENCY/PLAUSIBILITY The issue as identified on the pleadings 419. The Claimants alleged that the Patent does not plausibly disclose that there is any technical contribution in identifying RD162′ over the prior art. In particular it is said that the Slides and the Poster disclose a number of other compounds (referred to in the Patent as “Tier 1 compounds”), including RD162. It is alleged that there are no data in the Patent to show that RD162′ is efficacious in vivo or that its activity or suitability for treating prostate cancer is materially different (far less superior) to RD162. The Claimants’ approach 420. In their opening skeleton argument, the Claimants explained this plea as a squeeze between inventive step and technical contribution/sufficiency. Due to the way in which I have decided the obviousness allegations, no squeeze arises, but I propose to deal with the plea. The Claimants’ case was that there is no disclosure in the Patent that RD162’ has a materially different activity to RD162 or that the suitability of those two compounds for treating prostate cancer is materially different. Nor is such derivable from the application as filed ([A.1/2], which is, strictly speaking, the correct text from which to assess this issue: Sandoz v Bristol-Myers Squibb[2023] EWCA Civ 472 at [53]). 421. Further, so the Claimants’ argument went, there is no in vivo data in the Patent relating to RD162’, and specifically there is no PK data for RD162’ showing that it has a PK profile that would make it a suitable drug candidate for treating prostate cancer. 422. The Claimants contended that these points gave rise to an unavoidable squeeze with the obviousness case being run by Astellas. For it to be possible to make a reasonable prediction from the disclosure in the Patent/application that RD162’ will work to treat prostate cancer, the Claimants contended that the Skilled Team must be able to extrapolate from the limited PK data that the Patent/application provided for RD162. If that is the case, then the Claimants say it must follow that the Skilled Team would similarly be able to extrapolate from the data that the prior art provides for RD162 (and other RD compounds) to be able reasonably to predict the properties of a compound having the structure of RD162’
‘It was also contended on behalf of the appellants that, if the Patent extended to escitalopram as a product, the respondents would be accorded a monopoly which exceeded their technical contribution to the art. Although it is an extra-statutory concept, I accept that, at least as a general rule, the monopoly to be granted to the patentee is to be assessed by reference to the “technical contribution” made by the teaching of the patent. That is an approach regularly adopted by the Technical Board of Appeal of the European Patent Office (“the Board”): see, for example, T409/91 EXXON/Fuel Oils [1994] OJEPO 653, para. 3.3. However, to put it at its lowest, it can be said that the Respondent’s technical contribution in this case was to make available, for the first time, a product which had previously been unavailable, namely the isolated (+)-enantiomer of citalopram. On that basis, it would appear to follow that the respondent was entitled to claim the enantiomer.’